stilbenes and combretastatin

Although significant progress over several decades has been evidenced in cancer therapy, there remains a need for the development of novel and effective therapeutic strategies to treat several relapsed and intractable cancers. In this regard, tubulin protein has become one of the efficient and major targets for anticancer drug discovery. Considering the antimitotic ability, several tubulin inhibitors have been developed to act against various cancers. Among various tubulin inhibitors available, combretastatin-A4 (CA-4), a naturally occurring lead molecule, offers exceptional cytotoxicity (including the drugresistant cell lines) and antivascular effects. Although CA-4 offers exceptional therapeutic efficacy, several new advancements have been proposed, in terms of structural modification via A and B rings, as well as cis-olefinic bridging, which provide highly efficient analogs with improved tubulin-binding efficiency to meet the anticancer drug development requirements. This review systematically emphasizes the recent trends and latest developments in the anticancer drug design and discovery using CA-4 analogs as the tubulin inhibiting agents by highlighting their structure-activity relationships (SAR) and resultant pharmacological efficacies.

Topics: Antineoplastic Agents; Bibenzyls; Cell Line, Tumor; Cell Proliferation; Drug Design; Humans; Neoplasms; Stilbenes; Structure-Activity Relationship; Tubulin; Tubulin Modulators

The concept of a scaffold concerns many aspects at different steps on the drug development path. In medicinal chemistry, the choice of relevant "drug-likeness" scaffold is a starting point for the design of the structure dedicated to specific molecular targets. For many years, the chemical uniqueness of the stilbene structure has inspired scientists from different fields such as chemistry, biology, pharmacy, and medicine. In this review, we present the outstanding potential of the stilbene-based derivatives. Naturally occurring stilbenes, together with powerful synthetic chemistry possibilities, may offer an excellent approach for discovering new structures and identifying their therapeutic targets. With the development of scientific tools, sophisticated equipment, and a better understanding of the disease pathogenesis at the molecular level, the stilbene scaffold has moved innovation in science. This paper mainly focuses on the stilbene-based compounds beyond resveratrol, which are particularly attractive due to their biological activity. Given the "fresh outlook" about different stilbene-based compounds starting from stilbenoids with particular regard to isorhapontigenin and methoxy- and hydroxyl- analogues, the update about the combretastatins, and the very often overlooked and underestimated benzanilide analogues, we present a new story about this remarkable structure.

Topics: Animals; Bibenzyls; Drug Discovery; Humans; Resveratrol; Stilbenes

The stilbene scaffold is a basic element for a number of biologically active natural and synthetic compounds, and it is considered as a privileged structure. Stilbenes exemplified by resveratrol, combretastatin A-4 and pterostilbene are of significant interest for drug research and development because of their potential in therapeutic and preventive application. Resveratrol, present in grapes and other food products, plays a role in the prevention of several human pathological processes and has been suggested as an anticancer agent. Moreover, recent evidence has revealed its potential effect on the aging process, diabetes and neurological dysfunction. Combretastatin A-4, from the bark of South African bush willow Combretum caffrum, also shows significant antitumor activity. Pterostilbene is closely related to resveratrol, sharing the same unique therapeutic potential as anti-inflammatory, antineoplastic and antioxidant agent. Therefore, research and development of stilbene-based medicinal chemistry have become rapidly evolving and increasingly active topics covering almost the whole range of therapeutic fields. In the present review, we provide an overview of the role of stilbenes in medicinal chemistry. In this context, we highlight the chemical methodologies adopted for the synthesis of stilbene derivatives, and outline the successful design of novel stilbene based hybrids in the field of cancer, Alzheimer's and other relevant diseases. This information may be useful in further design of stilbene-based molecules as new leads for the development of novel agents with clinical potential or as effective chemical probes to dissect biological processes.

Topics: Alzheimer Disease; Antineoplastic Agents, Phytogenic; Bibenzyls; Chemistry, Pharmaceutical; Drug Design; Humans; Neoplasms; Resveratrol; Stilbenes; Structure-Activity Relationship

Antivascular approaches aim to cause rapid and catastrophic shutdown in the vascular function of the tumour, leading to extensive tumour cell death. Tumour vascular disrupting agents (VDAs) are a new class of cancer therapies that target the existing vasculature of tumours, taking advantage of the relative instability of tumour vasculature and its supporting structures. Treatment with VDAs induces a rapid collapse and regression of tumour vessels, with a consequent deprivation of blood and oxygen which leads to ischemic or hemorrhagic necrosis of the tumour. In this review, an overview of the most recently developed vascular disrupting agents is reported, focusing on the biological effects exerted by these compounds on endothelial cells and tumour vasculature, potentially effective in the treatment of several malignancies including upper gastrointestinal tumours. In particular, we have focused on the antimitotic agent combretastatin and its numerous synthetic analogues such as combretastatin A-4-phosphate, OXI4503, and AVE8062, and on the colchicine analogue ZD6126.

Topics: Angiogenesis Inhibitors; Animals; Bibenzyls; Diphosphates; Gastrointestinal Neoplasms; Humans; Neovascularization, Pathologic; Organophosphorus Compounds; Serine; Stilbenes; Upper Gastrointestinal Tract

Vascular disrupting agents (VDAs) have presented a new kind of anti-cancer drug in recent years. VDAs take advantage of the weakness of established tumor endothelial cells and their supporting structures. In contrast to anti-angiogenic therapy, which inhibits the outgrowth of new blood vessels, vascular targeting treatments selectively attack the existing tumor vasculature. Here we summarized the anti-tumor activities, mechanisms and clinical applications of small molecule VDAs.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Bibenzyls; Diphosphates; Endothelial Cells; Humans; Molecular Structure; Neoplasms; Neovascularization, Pathologic; Oligopeptides; Organophosphorus Compounds; Serine; Stilbenes; Tubulin Modulators; Xanthones

The design of novel anticancer agents based on the combretastatins, a group of antimitotic agents isolated from the bark of the South African willow tree Combretum caffrum Kuntz, is of considerable contemporary interest. Combretastatin A-4, the most active compound in the group, due to its unique dual features of antitubulin and antivascular properties, has drawn significant attention of medicinal chemists for the design of analogues as novel antitumor agents. To date, 252 references have been published since 1982 and 187 references have been published since 1998 related to combretastatins research. The 102 references related to chemistry efforts can be classified into three different categories including one-atom, two-atom, and three-atom bridgeheads as linker between two aryl rings of combretastatins. This review will particularly elucidate the rationale and strategic tactics towards the development of novel classes of antimitotic agents, based upon combretastatin A-4 as a promising lead.

Topics: Animals; Antineoplastic Agents; Bibenzyls; Clinical Trials as Topic; Drug Design; Humans; Stilbenes

Low-molecular-weight vascular-disrupting agents (VDAs) cause a pronounced shutdown in blood flow to solid tumours, resulting in extensive tumour-cell necrosis, while they leave the blood flow in normal tissues relatively intact. The largest group of VDAs is the tubulin-binding combretastatins, several of which are now being tested in clinical trials. DMXAA (5,6-dimethylxanthenone-4-acetic acid) - one of a structurally distinct group of drugs - is also being tested in clinical trials. A full understanding of the action of these and other VDAs will provide insights into mechanisms that control tumour blood flow and will be the basis for the development of new therapeutic drugs for targeting the established tumour vasculature for therapy.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Bibenzyls; Capillary Permeability; Clinical Trials as Topic; Endothelial Cells; Humans; Neoplasms; Neovascularization, Pathologic; Stilbenes; Xanthones

Synthesis and evaluation of new combretastatin analogues with varied modifications on the bridge and the aromatic rings, have shown that the 2-naphthyl moiety is a good surrogate for the 3-hydroxy-4-methoxyphenyl (B-ring) of combretastatin A-4. Other bicyclic systems, such as 6(7)-quinolyl and 5-indolyl, can replace the B-ring, but they produce less potent analogues in the cytotoxicity and tubulin polymerization inhibition assays. Other modifications are detrimental for the potency of the studied analogues. The 2-naphthyl combretastatin 53 and the related 6-quinolyl combretastatin 106 analogues are the most potent among the derivatives of this type, whereas 92 and 95 are the most potent among the naphthalene derivatives with a heterocycle in the bridge. Previous and new results in this family of combretastatin analogues are discussed.

Topics: Animals; Bibenzyls; Cell Line, Tumor; Cell Survival; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Naphthalenes; Stilbenes; Structure-Activity Relationship; Tubulin; Tubulin Modulators

The combretastatins are a group of anti-mitotic agents isolated from the bark of the South African tree Combretum caffrum. The most potent member is combretastatin A-4, and this compound together with a phosphate pro-drug form have already progressed through into clinical trails for the treatment of solid tumours. What makes this class of compounds rather more interesting than other anti-mitotic agents is that they are also angiogenesis inhibitors, and are being evaluated for their efficacy in the treatment of diabetic retinopathy which is the biggest single cause of blindness They are thus of considerable contemporary interest.

Topics: Antineoplastic Agents, Phytogenic; Bibenzyls; Biological Products; Combretum; Molecular Structure; Plant Bark; South Africa; Stilbenes; Structure-Activity Relationship

In recent years, enormous progress has been made in the field of tubulin targeting agents. Several companies and academic laboratories have entered this field and competition has become very strong. Nevertheless, clinically promising compounds often face substantial limitations, such as high systemic toxicity, poor water solubility and bioavailability, as well as complex synthesis and isolation procedures. As a drawback of established drugs, like paclitaxel or the vinca alkaloids, the outcome of cancer chemotherapy is often affected by the emergence of the multidrug resistance phenotype. Among the recently disclosed tubulin polymerization inhibitors, there are several interesting low molecular weight compounds with improved oral bioavailability and demonstrated activity against multi-drug resistance positive phenotypes. As documented by the imidazole-based combretastatin analogs, to name just one example, chemical optimization of a lead structure resulted in compounds with potent in vitro and in vivo activity along with appropriate pharmacodynamic and pharmacokinetic requirements for a potential therapeutic candidate. Currently, several compounds are undergoing Phase I or Phase II clinical trials, among them orally bioavailable sulfonamides or dolastatin 10. Several other compounds are close to entering Phase I trials. The purpose of this review is to focus on the most recent advances in tubulin polymerization inhibitors from a survey of the published patent literature and related publications between late 1999 and April 2002. However, biological data, especially for the inhibition of tubulin polymerization, obtained from different laboratories cannot easily be compared.

Topics: Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Bibenzyls; Biological Factors; Drug Design; Humans; Neoplasms; Protein Binding; Stilbenes; Tubulin; Tubulin Modulators

The tumour vasculature is an attractive target for therapy. Combretastatin A-4 (CA-4) and A-1 (CA-1) are tubulin binding agents, structurally related to colchicine, which induce vascular-mediated tumour necrosis in animal models. CA-1 and CA-4 were isolated from the African bush willow, Combretum caffrum, and several synthetic analogues are also now available, such as the Aventis Pharma compound, AVE8062. More soluble, phosphated, forms of CA-4 (CA-4-P) and CA-1 (CA-1-P) are commonly used for in vitro and in vivo studies. These are cleaved to the natural forms by endogenous phosphatases and are taken up into cells. The lead compound, CA-4-P, is currently in clinical trial as a tumour vascular targeting agent. In animal models, CA-4-P causes a prolonged and extensive shut-down of blood flow in established tumour blood vessels, with much less effect in normal tissues. This paper reviews the current understanding of the mechanism of action of the combretastatins and their therapeutic potential.

Topics: Animals; Antineoplastic Agents, Phytogenic; Bibenzyls; Endothelium, Vascular; Humans; Neoplasms; Neovascularization, Pathologic; Stilbenes

Topics: Animals; Antineoplastic Agents, Phytogenic; Bibenzyls; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Mice; Neoplasms; Neovascularization, Pathologic; Quantitative Structure-Activity Relationship; Rats; Stilbenes; Transplantation, Heterologous

Microtubules (MT) are cylindrical polymers of the protein tubulin (TN) alpha, beta-heterodimer, and are known to be the main component of spindles in mitotic apparatus of eucaryotic cells. MT are also involved in many other basic and essential cell functions. There are a number of natural and synthetic compounds that interfere with MT function to cause the mitotic arrest of eucaryotic cells. Such antimitotic agents show a broad biological activity, and can be used for medicinal and agrochemical purposes. On the other hand, they are important also as the biochemical tools for understanding the dynamics of MT network. Most of such antimitotic agents, with a few exceptions, bind to beta-TN. Among them, colchicine (CLC), vinblastine and taxol have played major roles in practical uses as well as in biochemical studies of MT functions. They all bind to beta-TN but their binding sites are different. We have worked on a variety of antimitotic agents that bind to either of colchicine-site, vinblastine-site and taxol-site, in discovery, structures, biological actions and/or interactions with TN. In this paper, the results of our studies on CLC-site ligands were summarized; (1) synthetic analogs of combretastatin A-4 (CBS A-4), isolated as a cytotoxic compound produced by a species of South African tree Combretum caffrum, (2) curacin A (CU-A), a cytotoxic metabolite of a marine cyanobacteria Lyngbya majuscula, and its related compounds. Interactions of these compounds with TN were studied and structure-activity relationships of these two classes of compounds were discussed.

Topics: Bibenzyls; Binding Sites; Cell Cycle; Colchicine; Cyclopropanes; Ligands; Microtubules; Protein Binding; Stilbenes; Structure-Activity Relationship; Thiazoles; Tubulin

Topics: Animals; Bibenzyls; Colchicine; Cytoskeletal Proteins; Fertilization; Microtubules; Mitosis; Paclitaxel; Sea Urchins; Stilbenes; Zearalenone

A large number of antimicrotubule agents are known that bind to tubulin in vitro and disrupt microtubule assembly in vitro and in vivo. Many of these agents bind to the same site on the tubulin molecule, as does colchicine. Of these, the natural products podophyllotoxin, steganacin and combretastatin are the subjects of this review. For each of these, the chemistry and biochemistry are described. Particular attention is given to stereochemical considerations. Biosynthetic pathways for podophyllotoxin and congeners are surveyed. The binding to tubulin and the effects on microtubule assembly and disassembly are described and compared. In addition, structural features important to binding are examined using available analogs. Several features significant for tubulin interaction are common to these compounds and to colchicine. These are described and the implications for tubulin structure are discussed. The manifold results of applying these agents to biological systems are reviewed. These actions include effects that are clearly microtubule mediated and others in which the microtubule role is less obvious. Activity of some of these compounds due to inhibition of DNA topoisomerase is discussed. The range of species in which these compounds occur is examined and in the case of podophyllotoxin is found to be quite broad. In addition, the range of species that are sensitive to the effects of these compounds is discussed.

Topics: 4-Butyrolactone; Animals; Antineoplastic Agents, Phytogenic; Bibenzyls; Binding Sites; Cell Division; Lignans; Podophyllotoxin; Polymers; Stilbenes; Structure-Activity Relationship; Tubulin

A phase I trial was performed with combretastatin A4 phosphate (CA4P), a novel tubulin-binding agent that has been shown to rapidly reduce blood flow in animal tumors.. The drug was delivered by a 10-minute weekly infusion for 3 weeks followed by a week gap, with intrapatient dose escalation. Dose escalation was accomplished by doubling until grade 2 toxicity was seen. The starting dose was 5 mg/m2.. Thirty-four patients received 167 infusions. CA4P was rapidly converted to the active combretastatin A4 (CA4), which was further metabolized to the glucuronide. CA4 area under the curve (AUC) increased from 0.169 at 5 mg/m2 to 3.29 micromol * h/L at 114 mg/m2. The mean CA4 AUC in eight patients at 68 mg/m2 was 2.33 micromol * h/L compared with 5.8 micromol * h/L at 25 mg/kg (the lowest effective dose) in the mouse. The only toxicity that possibly was related to the drug dose up to 40 mg/m2 was tumor pain. Dose-limiting toxicity was reversible ataxia at 114 mg/m2, vasovagal syncope and motor neuropathy at 88 mg/m2, and fatal ischemia in previously irradiated bowel at 52 mg/m2. Other drug-related grade 2 or higher toxicities seen in more than one patient were pain, lymphopenia, fatigue, anemia, diarrhea, hypertension, hypotension, vomiting, visual disturbance, and dyspnea. One patient at 68 mg/m2 had improvement in liver metastases of adrenocortical carcinoma.. CA4P was well tolerated in 14 of 16 patients at 52 or 68 mg/m2; these are doses at which tumor blood flow reduction has been recorded.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Area Under Curve; Bibenzyls; Chromatography, High Pressure Liquid; Drug Administration Schedule; Female; Humans; Infusion Pumps; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasms; Statistics, Nonparametric; Stilbenes; Tomography, Emission-Computed; Treatment Outcome

A new series of vinyl amide-, imidazolone-, and triazinone-linked combretastatin A-4 analogues have been designed and synthesised. These compounds have been evaluated for their cytotoxic activity against MDA-MB-231 breast cancer cells. The triazinone-linked combretastatin analogues (6 and 12) exhibited the most potent cytotoxic activity, in sub-micromolar concentration compared with combretastatin A-4 as a reference standard. The results of β-tubulin polymerisation inhibition assay appear to correlate well with the ability to inhibit β-tubulin polymerisation. Additionally, these compounds were subjected to biological assays relating to cell cycle aspects and apoptosis induction. In addition, the most potent compound

Topics: Amides; Antineoplastic Agents; Bibenzyls; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Molecular Structure; Nanoparticles; Solubility; Stilbenes; Structure-Activity Relationship; Tubulin; Tubulin Modulators

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Bibenzyls; CTLA-4 Antigen; Diphosphates; Disease Progression; Drug Resistance, Neoplasm; Female; Immune Checkpoint Inhibitors; Male; Mammary Neoplasms, Animal; Mice; Mice, Inbred C3H; Neovascularization, Pathologic; Stilbenes; Treatment Outcome

The photoisomerisation of non-toxic trans-combretastatin CA4 to its cytotoxic cis isomer demonstrates the high potential of this and similar compounds for localised cancer therapy. The introduction of intramolecular charge-transfer character by altering the substituents of combretastatin systems opens up possibilities to tailor these stilbene derivatives to the special demands of anticancer drugs. In this TDDFT study we explore how absorption wavelengths for both the trans and cis isomers can be red shifted to enable deeper light penetration into tissue and how the trans → cis and cis → trans isomerisations are affected by charge transfer effects to different degrees.

Topics: Antineoplastic Agents; Bibenzyls; Humans; Isomerism; Light; Models, Molecular; Molecular Structure; Neoplasms; Photochemical Processes; Stilbenes; Structure-Activity Relationship; Thermodynamics

Combretastatin A-4 phosphate (CA4P) selectively blocks tumor blood flow. However, the detailed mechanisms through which CA4P specifically affects tumor blood vessels are not well understood. Recent reports revealed that tumor tissue-derived endothelial cells (TECs) have various specific features in comparison with normal tissue-derived endothelial cells (NECs). Thus, abnormalities in TECs may be involved in the selective vascular blockade mechanism of CA4P. In this study, we evaluated the effects of CA4P on canine NECs and TECs using confocal microscopy. NECs exhibited different susceptibilities at subconfluence and at 100% confluence. In addition, inhibition of vascular endothelial cadherin (VE-cadherin) in NECs increased the sensitivity of the cells to CA4P. TECs seemed to be more susceptible to CA4P than NECs. The expression pattern of VE-cadherin in TECs was abnormal compared with that of NECs, suggesting that VE-cadherin may have functional abnormalities in these cells. Taken together, these results indicate that the tumor-vascular selectivity of CA4P may be related to VE-cadherin dysfunction in TECs.

Topics: Animals; Bibenzyls; Cells, Cultured; Dogs; Endothelial Cells; Endothelium, Vascular; Humans; Neoplasms; Neovascularization, Pathologic; Phosphates; Stilbenes

The present study aimed to prospectively monitor the vascular disrupting effect of M410 by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in rabbits with VX2 liver tumors. Twenty-eight rabbits bearing VX2 tumors in the left lobe of the liver were established and randomly divided into treatment and control groups, intravenously injected with 25 mg/kg M410 or sterile saline, respectively. Conventional and DCE-MRI data were acquired on a 3.0-T MR unit at pretreatment, 4 h, 1, 4, 7 and 14 days post-treatment. Histopathological examinations [hematoxylin and eosin (H&E) and CD34 immunohistochemisty staining] were performed at each time point. The dynamic changes in tumor volume, kinetic DCE-MRI parameter [volume transfer constant (Ktrans)] and histological data were evaluated. Tumors grew slower in the M410 group 4-14 days following treatment, compared with rapidly growing tumors in the control group (P<0.05). At 4 h, 1 and 4 days, Ktrans significantly decreased in the M410 group compared with that in the control group (P<0.05). However, Ktrans values were similar in the two groups for the other time points studied. The changes in DCE-MRI parameters were consistent with the results obtained from H&E and CD34 staining of the tumor tissues. DCE-MRI parameter Ktrans may be used as a non-invasive imaging biomarker to monitor the dynamic histological changes in tumors following treatment with the vascular targeting agent M410.

Topics: Angiogenesis Inhibitors; Animals; Bibenzyls; Biomarkers, Tumor; Cell Line, Tumor; Liver Neoplasms, Experimental; Magnetic Resonance Imaging; Male; Organophosphates; Rabbits; Stilbenes

A series of new analogs of combretastatin A-4 (CA-4, 1) with the A or B-ring replaced by a 3-oxo-2,3-dihydrofurocoumarin or a furocoumarin residue have been designed and synthesized by employing a cross-coupling approach. All the compounds were evaluated for their cytotoxic activity with respect to model cancer cell lines (CEM-13, MT-4, U-937) using conventional MTT assays. Structure-activity relationship analysis reveals that compounds 2, 3, 6-8 in which the (Z)-styryl substituent was connected to the 2-position of the 3-oxo-2,3-dihydrofurocoumarin core, demonstrated increased potency compared to 3-(Z)-styrylfurocoumarins 4, 5, 9-11. The methoxy-, hydroxyl- and formyl- substitution on the aromatic ring of the (Z)-styryl moiety seems to play an important role in this class of compounds. Compounds 2 and 3 showed the best potency against the CEM-13 cell lines, with CTD50 values ranging from 4.9 to 5.1 μM. In comparison with CA-4, all synthesized compounds presented moderate cytotoxic activity to the T-cellular human leucosis cells MT-4 and lymphoblastoid leukemia cells CEM-13, but most of them were active in the human monocyte cell lines U-937.

Topics: Antineoplastic Agents, Phytogenic; Bibenzyls; Cell Line, Tumor; Coumarins; Drug Screening Assays, Antitumor; Ficusin; Furocoumarins; Humans; Molecular Structure; Neoplasms; Stilbenes; Structure-Activity Relationship; Tubulin Modulators

The structures of a new family of macrocyclic analogues of combretastatins B combining oxygenated substituents on the phenyl rings and indole rings are described. The effects of the stereochemistry, of the length of the spacer linking both aryl groups, and of the decoration of the macrocycles on the kinematics of the system have been studied by means of NMR studies at several temperatures and in different solvents combined with theoretical studies including Monte Carlo conformational searches and molecular dynamics simulations at different temperatures. The new indole macrocycles provide a more rigid view of this kind of macrocycles than that previously held. The tubulin polymerization activity of this new class of macrocycles has been assayed and analyzed.

Topics: Antimitotic Agents; Bibenzyls; Colchicine; Macrocyclic Compounds; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Polymerization; Stilbenes; Tubulin Modulators

We synthesised seven 2-aminestilbenes with methoxy substitents in reactions of dinitrostilbenes with sodium azide. In order to study the positioning of the nitro groups, the optimum structure of obtained stilbenes using the DFT B3LYP/6-311++G(2d,p) method was calculated. Very interesting aspect of this regioselectivity reaction is the fact that in all substrates and synthetized compounds the nitro groups in position 2 were not coplanar whereas the para-nitro groups were coplanar with respect to the benzene ring. Due to unique features of stilbene derivatives, such as antitumor agents, we undertook the studies on the biological properties of new stilbene derivatives. Using five cancer cell lines, we investigated the effects of 2-aminestilbenes with methoxy substitents on cell growth.

Topics: Bibenzyls; Cell Death; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Resveratrol; Stilbenes

A set of novel selenium-containing heterocyclic analogues of combretastatin A-4 (CA-4) have been designed and synthesised using a rigid 1,2,5-selenadiazole as a linker to fix the cis-orientation of ring-A and ring-B. All of the target compounds were evaluated for their in vitro anti-proliferative activities. Among these compounds, compounds 3a, 3i, 3n and 3q exhibited superior potency against different tumour cell lines with IC50 values at the nanomolar level. Moreover, compound 3n significantly induced cell cycle arrest in the G2/M phase, inhibited tubulin polymerisation into microtubules and caused microtubule destabilisation. A molecular modelling study of compound 3n was performed to elucidate its binding mode at the colchicine site in the tubulin dimer and to provide a basis for the further structure-guided design of novel CA-4 analogues.

Topics: Antineoplastic Agents, Phytogenic; Bibenzyls; Cell Cycle; Cell Proliferation; Drug Screening Assays, Antitumor; Flow Cytometry; Fluorescent Antibody Technique; Heterocyclic Compounds; Humans; Models, Molecular; Molecular Structure; Neoplasms; Selenium; Stilbenes; Structure-Activity Relationship; Tumor Cells, Cultured

The natural products colchicine and combretastatin A-4 are potent inhibitors of tubulin assembly, and they have inspired the design and synthesis of a large number of small-molecule, potential anticancer agents. The indole-based molecular scaffold is prominent among these SAR modifications, leading to a rapidly increasing number of agents. The water-soluble phosphate prodrug 33 (OXi8007) of 2-aryl-3-aroylindole-based phenol 8 (OXi8006) was prepared by chemical synthesis and found to be strongly cytotoxic against selected human cancer cell lines (GI₅₀ = 36 nM against DU-145 cells, for example). The free phenol, 8 (OXi8006), was a strong inhibitor (IC₅₀ = 1.1 μM) of tubulin assembly. The corresponding phosphate prodrug 33 (OXi8007) also demonstrated pronounced interference with tumor vasculature in a preliminary in vivo study utilizing a SCID mouse model bearing an orthotopic PC-3 (prostate) tumor as imaged by color Doppler ultrasound. The combination of these results provides evidence that the indole-based phosphate prodrug 33 (OXi8007) functions as a vascular disrupting agent that may prove useful for the treatment of cancer.

Topics: Animals; Antineoplastic Agents; Bibenzyls; Colchicine; Drug Screening Assays, Antitumor; Humans; Indoles; Inhibitory Concentration 50; Male; Mice; Molecular Structure; Organophosphates; Prodrugs; Prostatic Neoplasms; Stilbenes; Structure-Activity Relationship; Tubulin

To investigate within live mammalian cells the uptake and disposition of combretastatins, fluorescence lifetime imaging was used with two-photon excitation (2PE). Combretastatin A4 (CA4) and analogues are potential anticancer drugs due to their ability to inhibit angiogenesis. E(trans)-combretastatins are considerably less active than the Z(cis)-combretastatins proposed for clinical use. However the E-combretastatins exhibit stronger intrinsic fluorescence with quantum yields and lifetimes that depend markedly on solvent polarity and viscosity. It is proposed that 2PE in the red and near-infrared tissue window may allow in situ isomerization of E-combretastatins to the more active Z-isomer, offering spatial and temporal control of drug activation and constitute a novel form of photodynamic therapy. In the present work we have characterised 2PE of E-CA4 and have used fluorescence lifetime imaging with 2PE to study uptake and intracellular disposition of E-CA4 and an analogue. The results show that these molecules accumulate rapidly in cells and are located mainly in lipidic environments such as lipid droplets. Within the droplets the local concentrations may be up to two orders of magnitude higher than that of the drug in the surrounding medium.

Topics: Animals; Bibenzyls; CHO Cells; Cricetinae; HeLa Cells; Humans; Microscopy, Fluorescence, Multiphoton; Stilbenes

Thirteen methylpyrazoline analogs (1a-m) of combretastatin A-4 (CA-4, 2) were synthesized. The trans-geometry of the two substituted phenyl moieties was ascertained by a single crystal X-ray diffraction study of compound 1d. The cytotoxicities of the analogs against the growth of murine B16 melanoma and L1210 lymphoma cells in culture were measured using the MTT assay. One of the derivatives, 1j, which has the same substituents as CA-4 was the most active in the series with IC(50) values of 3.3 μM and 6.8 μM against the growth of L1210 and B16 cells, respectively. The activity of this analog against human cancer cell lines was confirmed in the NCI 60 panel. The other active analogs against L1210 were 1b and 1f, which gave IC(50) values in the 6-8 μM range. Compound 1j caused microtubule depolymerization with an EC(50) value of 4.1 μM. This compound has good water solubility of 372 μM. Molecular modeling studies using DFT showed that compound 1j adopts a "twisted" conformation mimicking CA-4 that is optimal for binding to the colchicine site of tubulin.

Topics: Animals; Antineoplastic Agents, Phytogenic; Bibenzyls; Cell Line, Tumor; Cell Survival; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; Leukemia L1210; Melanoma, Experimental; Mice; Microtubules; Molecular Docking Simulation; Pyrazoles; Stilbenes; Structure-Activity Relationship; Tubulin Modulators

Forty-four novel chalcone-inspired analogs having a 3-aryl-2-propenoyl moiety derived from alicyclic ketones were designed, synthesized, and investigated for cytotoxicity against murine B16 and L1210 cancer cell lines. The analogs belong to four structurally divergent series, three of which (series g, h, and i) contain differently substituted cyclopentanone units and the fourth (series j) contains a 3,3-dimethyl-4-piperidinone moiety. Of these, the analogs in series j showed potential cytotoxic activity against murine B16 (melanoma) and L1210 (lymphoma) cells. The most active compounds 5j, 11j, 15j, and 12h produced IC(50) values from 4.4 to 15 μm against both cell lines. A single-crystal X-ray structure analysis and molecular modeling studies confirmed that these chalcones have an E-geometry about the alkene bond and possess a slightly 'twisted' conformation similar to that of combretastatin A-4. At a concentration of 30 μm, compounds 5j, 11j, and 15j did not cause microtubule depolymerization in cells, suggesting that they have a different mechanism of action.

Topics: Animals; Antineoplastic Agents; Bibenzyls; Cell Line, Tumor; Cell Survival; Chalcones; Drug Design; Humans; Ketones; Mice; Models, Molecular; Neoplasms; Stilbenes; Structure-Activity Relationship; Tubulin Modulators

Human cancer and other clinical trials under development employing combretastatin A-4 phosphate (1b, CA4P) should benefit from the availability of a [(11)C]-labeled derivative for positron emission tomography (PET). In order to obtain a suitable precursor for addition of a [(11)C]methyl group at the penultimate step, several new synthetic pathways to CA4P were evaluated. Geometrical isomerization (Z to E) proved to be a challenge, but it was overcome by development of a new CA4P synthesis suitable for 4-methoxy isotope labeling.

Topics: Bibenzyls; Isotope Labeling; Molecular Structure; Positron-Emission Tomography; Stereoisomerism; Stilbenes

DMF (N,N-dimethylformamide)/KOH was found to be an efficient hydrogen source in the Pd(OAc)(2)-catalyzed transfer semihydrogenation of various functionalized internal alkynes to afford cis-alkenes in good to high yields with excellent chemo- and stereoselectivity. This catalytic process was also applied to the synthesis of analogues of combretastatin A-4.

Topics: Alkenes; Alkynes; Bibenzyls; Catalysis; Dimethylformamide; Hydrogen; Hydrogenation; Hydroxides; Molecular Structure; Palladium; Potassium Compounds; Stereoisomerism; Stilbenes

The effects of the tubulin-binding vascular-disrupting agents (VDAs), combretastatin A4 phosphate (CA4P), OXi4503/CA1P and OXi8007, in subcutaneous mouse models of the Ewing's sarcoma family of tumours (ESFTs) have been investigated alone and in combination with doxorubicin. Delay in subcutaneous tumour growth was observed following treatment of mice with multiple doses of OXi4503/CA1P but not with CA4P or OXi8007. A single dose of OXi4503/CA1P caused complete shutdown of vasculature by 24h and extensive haemorrhagic necrosis by 48h. However, a viable rim of proliferating cells remained, which repopulated the tumour within 10 days following the withdrawal of treatment. Combined treatment with doxorubicin 1h prior to administration of OXi4503/CA1P enhanced the effects of OXi4503/CA1P causing a synergistic delay in tumour growth (p<0.001). This study demonstrates that OXi4503/CA1P is a potent VDA in ESFT and in combination with conventional cytotoxic agents represents a promising treatment strategy for this tumour group.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bibenzyls; Bone Neoplasms; Cell Proliferation; Diphosphates; Disease Models, Animal; Doxorubicin; Drug Evaluation, Preclinical; Mice; Mice, Nude; Necrosis; Neoplasm Transplantation; Neovascularization, Pathologic; Sarcoma, Ewing; Stilbenes

As part of a broad-based SAR investigation of E-resveratrol (strong sirtuin activator and antineoplastic) and the anticancer vascular-targeting combretastatin-type stilbenes, a series of twenty-three beta-E-nitrostyrenes was synthesized in order to evaluate potential antineoplastic, antitubulin, and antimicrobial activities. The beta-E-nitrostyrenes evaluated ranged from monosubstituted phenols to trimethoxy and 3-methoxy-4,5-methylenedioxy derivatives. Two of the beta-nitrostyrenes were synthesized as water-soluble sodium phosphate derivatives (4t, 4v). All except four (4r, 4s, 4t, 4u) of the series significantly inhibited a minipanel of human cancer cell lines. All but eight led to an IC(50) of <10 microM for inhibition of tubulin polymerization, and all except three (4l, 4t, 4v) displayed antimicrobial activity.

Topics: Anti-Infective Agents; Antineoplastic Agents; Bacteria; Bibenzyls; Cell Line, Tumor; Cell Proliferation; Fungi; Humans; Molecular Structure; Resveratrol; Stilbenes; Structure-Activity Relationship; Styrenes; Tubulin; Tubulin Modulators

As an extension of our earlier structure/activity investigation of resveratrol (1a) cancer cell growth inhibitory activity compared to the structurally related stilbene combretastatin series (e.g., 2a), an efficient synthesis of E-stilstatin 3 (3a) and its phosphate prodrug 3b was completed. The trans-stilbene 3a was obtained using a convergent synthesis employing a Wittig reaction with phosphonium bromide 9 as the key reaction step. Deprotection of the Z-silyl ether 13 gave E-stilstatin 3 (3a) as the exclusive product. The structure and stereochemistry of 3a was confirmed by X-ray crystal structure determination.

Topics: Antineoplastic Agents; Bibenzyls; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Humans; Molecular Conformation; Molecular Structure; Prodrugs; Resveratrol; Stereoisomerism; Stilbenes; Structure-Activity Relationship

A method is described to enhance the sensitivity of fluorescence detection of cis-combretastatins using a short post-column photolysis coil with a mercury lamp, by inducing the rapid conversion to the trans isomer. Although all the compounds studied showed enhanced fluorescence after photolysis, there were large differences in the absolute level, with the inherent response of the catechol CA1 being much lower than the corresponding phenolic CA4. Brief exposure to the deuterium lamp in a photodiode array detector also resulted in significant enhancement.

Topics: Bibenzyls; Chromatography, High Pressure Liquid; Photolysis; Spectrometry, Fluorescence; Stilbenes

Several stilbenoid compounds having structural similarity to the combretastatin group of natural products and characterized by the incorporation of two nitrogen-bearing groups (amine, nitro, serinamide) have been prepared by chemical synthesis and evaluated in terms of biochemical and biological activity. The 2',3'-diamino B-ring analogue 17 demonstrated remarkable cytotoxicity against selected human cancer cell lines in vitro (average GI 50 = 13.9 nM) and also showed good activity in regard to inhibition of tubulin assembly (IC 50 = 2.8 microM). In addition, a single dose (10 mg/kg) of compound 17 caused a 40% tumor-selective blood flow shutdown in tumor-bearing SCID mice at 24 h, thus suggesting the potential value of this compound and its corresponding salt formulations as new vascular-disrupting agents.

Topics: Animals; Antineoplastic Agents; Bibenzyls; Disease Models, Animal; Drug Design; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; Leukemia P388; Mice; Molecular Structure; Neoplasms; Regional Blood Flow; Stilbenes; Tubulin

With the aim of understanding the influence of fluorine on the double bond of the cis-stilbene moiety of combretastatin derivatives and encouraged by a preliminary molecular modeling study showing a different biological environment on the interaction site with tubulin, we prepared, through various synthetic approaches, a small library of compounds in which one or both of the olefinic hydrogens were replaced with fluorine. X-ray analysis on the difluoro-CA-4 analogue demonstrated that the spatial arrangement of the molecule was not modified, compared to its nonfluorinated counterpart. SAR analysis confirmed the importance of the cis-stereochemistry of the stilbene scaffold. Nevertheless, some unpredicted results were observed on a few trans-fluorinated derivatives. The position of a fluorine atom on the double bond may affect the inhibition of tubulin polymerization and cytotoxic activity of these compounds.

Topics: Animals; Antineoplastic Agents; Bibenzyls; Biopolymers; Cattle; Cell Line, Tumor; Cells, Cultured; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Endothelial Cells; Fluorine; Humans; Microcirculation; Microtubules; Stereoisomerism; Stilbenes; Structure-Activity Relationship; Tubulin

Topics: 3-Iodobenzylguanidine; Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Bibenzyls; Combined Modality Therapy; Enzyme Inhibitors; Humans; Medical Oncology; Neoplasms; Norepinephrine Plasma Membrane Transport Proteins; Poly(ADP-ribose) Polymerase Inhibitors; Proteomics; Stilbenes; Thioredoxins; Topotecan

Novel phenstatin analogues with a 2-naphthyl moiety combined with either a 2,3,4- or a 3,4,5-trimethoxyphenyl ring have been synthesized, and their tubulin polymerization inhibiting and cytotoxic activities have been evaluated. The 2-naphthyl ring is a better replacement for the 3-hydroxy-4-methoxyphenyl ring in the phenstatin series than in the combretastatin series. For the naphthylphenstatins, the carbonyl is required, and the preferred orientation of the trimethoxyphenyl ring is the one found in combretastatins.

Topics: Antineoplastic Agents; Bibenzyls; HeLa Cells; Humans; Inhibitory Concentration 50; Models, Chemical; Naphthalenes; Stereoisomerism; Stilbenes; Structure-Activity Relationship; Tubulin; Tubulin Modulators; Tumor Cells, Cultured

The aim of this study was to quantify tumor cell proliferation and growth, analyze tumor blood vessel development, and determine the efficacy of antiangiogenic and angiostatic therapy in targeting mature vessels in retinal tumors of the LH(BETA)T(AG) mouse model for retinoblastoma.. LH(BETA)T(AG) mouse retinas were analyzed at 4, 8, 12, and 16 weeks of age. Tumor burden was analyzed by histology; cell proliferation, vessel density, angiogenesis, and vessel maturation were detected by immunofluorescence. To assess the efficacy of mature vessel targeting, 16-week-old mice were treated with single subconjunctival injections of the selective vascular-targeting drug combretastatin A4 prodrug (CA4P) or anecortave acetate, and eyes were analyzed 1 day and 1 week after injection to determine microvessel density and the number of angiogenic and mature vessels.. Increased cell proliferation and angiogenesis were detected in the retinal inner nuclear layer (INL) before morphologic neoplastic changes were evident. As tumor size increased, angiogenesis diminished concomitantly with the appearance of mature vessels. Treatment with CA4P and anecortave acetate resulted in significant reductions in total vessel density. However, neither drug reduced the amount of alpha-smooth muscle actin (SMA)-positive, mature vessels.. Results of this study provide new insight into the relationship between tumor growth and blood vessel development in the LH(BETA)T(AG) mouse and establish the framework for defining the selective action of two vessel-targeting drugs against new blood vessels compared with mature blood vessels. These findings suggest a high potential value in targeting the process of angiogenesis in the treatment of children with retinoblastoma.

Topics: Actins; Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Bibenzyls; Biomarkers, Tumor; Cell Proliferation; Disease Models, Animal; Endoglin; Endothelium, Vascular; Intracellular Signaling Peptides and Proteins; Ki-67 Antigen; Mice; Mice, Transgenic; Microscopy, Fluorescence; Neovascularization, Pathologic; Pericytes; Pregnadienediols; Retinal Neoplasms; Retinoblastoma; Stilbenes

A new family of diphenylethanes has been synthesized as conformationally restricted analogues of antimitotic combretastatins. The two phenyl rings are linked between the para-phenolic positions through a 3-oxapentamethylene or hexamethylene chain. The key macrocyclization step was achieved in moderate yields by using an intramolecular McMurry pinacol coupling of linked aromatic dialdehydes, except for the nitro-substituted compounds. The relative stereochemistry of the isomeric pinacols was determined by a combination of spectroscopic, chemical derivatization, and molecular-modeling approaches. The NMR spectra of these compounds (with a polyoxygenated crownophane skeleton) indicate severe conformational restrictions relative to their parent combretastatins; the rotation of the phenyl rings is hampered by interactions of their substituents and the linker and the conformational restrictions imposed by the substituted bridge.

Topics: Antineoplastic Agents; Bibenzyls; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Molecular Structure; Stereoisomerism; Stilbenes; Structure-Activity Relationship

A series of all-trans-1-aryl-4-aryl-5-aryl-2,4-pentanediene-1-one (3), a hybridized form of chalcone and combretastatin, was synthesized and evaluated against a panel of cancer cell lines, including B16, murine melanoma; HCT116, colon cancer; A431, human epidermoid carcinoma; and human umbilical venous endothelial cells (HUVEC). Structure-activity relationships analysis of this series revealed that a 2,5-dihydroxyphenyl at position 1 of the 2,4-pentanediene-1-one was essential for cytotoxicity. all-trans-1-(2,5-Dihydroxyphenyl)-5-(4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-2,4-pentanediene-1-one (3a) was the most potent compound from this series.

Topics: Bibenzyls; Cell Line; Cell Survival; Chalcone; Humans; Molecular Structure; Neoplasms; Stilbenes; Structure-Activity Relationship

New analogues of combretastatins have been evaluated as inhibitors of tubulin polymerization. These compounds present a macrocyclic structure, in which the para positions of the aromatic moieties have been linked by a 5- or 6-atoms chain, in order to produce a conformational restriction. This could contribute to determine the active conformation for these ligands. Such a conformational restriction and/or the steric hindrance makes them less potent inhibitors than the model compound CA-4.

Topics: Bibenzyls; Macrocyclic Compounds; Models, Molecular; Molecular Conformation; Stilbenes; Structure-Activity Relationship; Tubulin; Tubulin Modulators

A concise and convergent route to combretastatin D2 is described together with some preliminary biological data.

Topics: Antineoplastic Agents; Bibenzyls; Boronic Acids; Breast Neoplasms; Cell Line; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Crystallography, X-Ray; Endothelial Cells; Female; Humans; Lactones; Magnetic Resonance Spectroscopy; Male; Molecular Structure; Phenol; Phenyl Ethers; Plants, Medicinal; Stilbenes

A series of analogs with nitro or serinamide substituents at the C-2'-, C-5'-, or C-6'-position of the combretastatin A-4 (CA4) B-ring was synthesized and evaluated for cytotoxic effects against heart endothelioma cells, blood flow reduction to tumors in SCID mice, and as inhibitors of tubulin polymerization. The synthesis of these analogs typically featured a Wittig reaction between a suitably functionalized arylaldehyde and an arylphosphonium salt followed by separation of the resultant E- and Z-isomers. Several of these nitrogen-modified CA4 derivatives (both amino and nitro) demonstrate significant inhibition of tubulin assembly as well as cytotoxicity and in vivo blood flow reduction. 2'-Aminostilbenoid 7 and 2'-amino-3'-hydroxystilbenoid 29 proved to be the most active in this series. Both compounds, 7 and 29, have the potential for further pro-drug modification and development as vascular disrupting agents for treatment of solid tumor cancers and certain ophthalmological diseases.

Topics: Animals; Benzaldehydes; Bibenzyls; Cattle; Cell Proliferation; Drug Design; Isomerism; Mice; Molecular Structure; Neoplasms; Regional Blood Flow; Stilbenes; Structure-Activity Relationship; Tubulin; Xenograft Model Antitumor Assays

We studied the anticancer activity of a series of new combretastatin derivatives with B-ring modifications. The structure-activity relationship (SAR) information confirmed the importance of cis-stereochemistry and of a phenolic moiety in B-ring. We selected the benzo[b]thiophene and benzofuran combretastatin analogues 11 (ST2151) and 13 (ST2179) and their phosphate prodrugs (29 and 30) for their high antitumor activity in in vitro and in vivo models. Cell exposure to IC50 of 11, 13, and CA-4 led to the arrest of various cell types in the G2/M phase of the cell cycle and induction of apoptosis. Mainly, 11 and 13 induced the formation of multinucleated cells with abnormal chromatin distribution, with only a minimal effect on the microtubule organization, with respect to CA-4. Interestingly, both the pharmacokinetic profile of 29 and its in vivo antitumor effect and those of 30, active even after oral administration, suggest additional pharmacological differences between these compounds and CA-4P.

Topics: Animals; Antineoplastic Agents; Benzofurans; Bibenzyls; Binding, Competitive; Biopolymers; Cell Line, Tumor; Cell Nucleus; Colchicine; Endothelial Cells; Endothelium, Vascular; Female; Humans; Mice; Mice, Nude; Microtubules; Organophosphates; Prodrugs; Stereoisomerism; Stilbenes; Structure-Activity Relationship; Thiophenes; Tubulin; Xenograft Model Antitumor Assays

We have synthesized rigid analogues of combretastatin bearing a furan ring in place of the olefinic bridge. These compounds are cytotoxic at nanomolar concentrations in neuroblastoma cells, display a similar structure-activity relationship compared to combretastatin A4, and inhibit tubulin polymerization. We also show that the furan ring can be further functionalized. Thus, it is possible that combretafurans could act as scaffolds for the development of dual-action antitumoral agents.

Topics: Anisoles; Antineoplastic Agents; Bibenzyls; Cell Death; Cell Line, Tumor; Drug Screening Assays, Antitumor; Furans; Humans; Molecular Structure; Neuroblastoma; Stilbenes; Structure-Activity Relationship; Tubulin

A molecular modeling study was carried out to develop a predictive model for combretastatin-like analogues populating the colchicine-binding site of beta-tubulin. A series of compounds built around a framework including two aromatic groups linked by various moieties such as alkenes (stilbenes), enones (chalcones), or ethers was selected for the study. The 5D-QSAR model was developed stepwise. First a model was generated for the chalcone series (19 compounds, 71 conformations), then for the stilbene series (18 compounds, 59 conformations), and finally for the combined dataset (47 ligands, 160 conformers). Although the models for the chalcone and stilbene series appeared slightly different when represented by QSAR colored surfaces, the combined model seems to reconcile the differences without compromise and represents a highly predictive model for compounds that bind to the colchicine-binding site of tubulin.

Topics: Antineoplastic Agents; Bibenzyls; Binding Sites; Colchicine; Ligands; Models, Molecular; Molecular Conformation; Monte Carlo Method; Quantitative Structure-Activity Relationship; Stilbenes; Tubulin; Tubulin Modulators

Compounds with three aromatic systems, carrying a 2-naphthalene and a 3,4,5-trimethoxyphenyl moieties bonded to five-membered, six-membered or fused heterocycles display potent cytotoxic effect and inhibition of tubulin polymerization, in agreement with their structural similarity to combretastatins and their heterocyclic analogues.

Topics: Animals; Bibenzyls; Cattle; Ethylenes; Inhibitory Concentration 50; Molecular Structure; Naphthalenes; Stilbenes; Structure-Activity Relationship; Tubulin

Chemical investigation of biologically active compounds of Getonia floribunda led to the isolation of two new macrocyclic lactones, combretastatins D-3 (1) and D-4 (2). The structures of these compounds were confirmed by spectroscopic analyses. Combretastatin D-3 (1) exhibited cytotoxicity towards the small-cell lung cancer cell line (NCI-H187, IC50=13.0 +/- 0.2 microg/mL) but was inactive against KB, BC-1, and Vero cell lines. Combretastatin D-3 (1) showed weak antitubercular activity with a minimum inhibitory concentration (MIC) of 100.0 microg/mL, and was inactive towards the malarial parasite. Combretastatin D-4 (2) was inactive in all antitubercular, antiplasmodial, and cytotoxic assays.

Topics: Antineoplastic Agents, Phytogenic; Antitubercular Agents; Bibenzyls; Cell Line, Tumor; Combretaceae; Humans; Inhibitory Concentration 50; Lactams, Macrocyclic; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Phytotherapy; Plant Extracts; Stilbenes

To evaluate diffusion-weighted magnetic resonance (MR) imaging for monitoring tumor response in rats after administration of combretastatin A4 phosphate.. Study protocol was approved by local ethical committee for animal care and use. Rhabdomyosarcomas implanted subcutaneously in both flanks of 17 rats were evaluated with 1.5-T MR unit by using four-channel wrist coil. Transverse T2-weighted fast spin-echo sequences, T1-weighted spin-echo sequences before and after gadodiamide administration, and transverse echo-planar diffusion-weighted MR examinations were performed before, 1 and 6 hours, and 2 and 9 days after intraperitoneal injection of vascular targeting agent (combretastatin A4 phosphate, 25 mg/kg). Apparent diffusion coefficient (ADC) was automatically calculated from diffusion-weighted MR imaging findings. These findings were compared with histopathologic results at each time point. For statistical analysis, paired Student t tests with Bonferroni correction for multiple testing were used.. T1-weighted images before combretastatin administration showed enhancement of solid tumor tissue but not of central necrosis. At 1 and 6 hours after combretastatin injection, enhancement of solid tissue disappeared almost completely, with exception of small peripheral rim. At 2 and 9 days after combretastatin injection, enhancement progressively reappeared in tumor periphery. ADC, however, showed decrease early after combretastatin injection ([1.26 +/- 0.16]x 10(-3) mm2/sec before, [1.18 +/- 0.17]x 10(-3) mm2/sec 1 hour after [P=.0005] and [1.08 +/- 0.14]x 10(-3) mm(2)/sec 6 hours after [P=.0007] combretastatin A4 phosphate injection), histologically corresponding to vessel congestion and vascular shutdown in periphery but no necrosis. An increase of ADC ([1.79 +/- 0.13]x 10(-3) mm2/sec) (P <.0001) 2 days after combretastatin A4 phosphate injection was paralleled by progressive histologic necrosis. A significant (P <.0001) decrease in ADC 9 days after treatment ([1.41 +/- 0.15]x 10(-3) mm2/sec) corresponded to tumor regrowth.. In addition to basic relaxation-weighted MR imaging and postgadolinium T1-weighted MR imaging to enable prompt detection of vascular shutdown, diffusion-weighted MR imaging was used to discriminate between nonperfused but viable and necrotic tumor tissues for early monitoring of therapeutic effects of vascular targeting agent.

Topics: Animals; Antineoplastic Agents, Phytogenic; Bibenzyls; Contrast Media; Diffusion Magnetic Resonance Imaging; Gadolinium DTPA; Image Processing, Computer-Assisted; Injections, Intraperitoneal; Male; Rats; Rhabdomyosarcoma; Stilbenes

To examine the feasibility of using the MRI blood pool agent NC100150 for evaluation of tumor blood volume (TBV) estimates by both dynamic contrast-enhanced MRI (DCE-MRI) and susceptibility contrast MRI assays in an experimental tumor. Contrast agent clearance (K(trans); depends on perfusion and permeability) from the DCE-MRI time curves was estimated, and changes in TBV and K(trans) were measured after administration of two drugs that reduce perfusion by different mechanisms.. The DCE-MRI experiments were simulated with expected physiologic values for the C3H mouse mammary carcinoma. The C3H tumor was examined by DCE-MRI and susceptibility contrast MRI with NC100150 (NC100150 Injection, Clariscan; Amersham Health, Oslo, Norway) after treatment with either hydralazine or combretastatin (Oxigene, Boston, MA).. Simulations showed that reliable estimates of changes in TBV and K(trans) could be performed with DCE-MRI. Hydralazine was shown to reduce TBV as measured by both assays and to reduce K(trans). Dynamic contrast-enhanced MRI also suggested that TBV and K(trans) were reduced in combretastatin-treated tumors, and the TBV reduction was confirmed by susceptibility contrast MRI. Data suggested the drug to affect mainly the total TBV, whereas microvessels as such seemed less altered.. The study supports the use of the combined DCE-MRI and susceptibility contrast MRI assay with a blood pool agent in characterizing tumors and their response to treatment.

Topics: Animals; Antineoplastic Agents, Phytogenic; Bibenzyls; Contrast Media; Dextrans; Female; Ferrosoferric Oxide; Hydralazine; Iron; Magnetic Resonance Imaging; Magnetite Nanoparticles; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C3H; Oxides; Stilbenes; Vasodilator Agents

A series of combretastatins substituted with epoxides, amides and small alkyl groups has been synthesised and evaluated for cytotoxicity and their ability to inhibit the assembly of tubulin. The methyl and ethyl substituted phenols 36, 44 have shown potent antimitotic effects whilst exhibiting reduced cytotoxicity.

Topics: Amides; Antineoplastic Agents; Bibenzyls; Cell Cycle; Cell Survival; Epoxy Compounds; Formazans; Humans; Inhibitory Concentration 50; K562 Cells; Magnetic Resonance Spectroscopy; Molecular Structure; Spectrophotometry, Ultraviolet; Stilbenes; Tetrazolium Salts; Tubulin; Tubulin Modulators

A series of chimeric compounds bearing the combretastatin and the nitrogen mustard cores were synthesized. All the compounds were cytotoxic and inhibited tubulin polymerization. When combretastatin was joined to chlorambucil via an ester linkage, the resultant compound proved to be significantly more potent than the two compounds put together. When combretastatin was joined to nitrogen mustard via an ether linkage or when a true hybrid was synthesized, loss of potency was observed. Nonetheless, these latter compounds appeared to be more efficacious and surprisingly were able to inhibit tubulin depolymerization at high concentrations.

Topics: Antineoplastic Agents; Bibenzyls; Humans; Inhibitory Concentration 50; Mustard Plant; Neuroblastoma; Nitrogen; Polymers; Stilbenes; Structure-Activity Relationship; Tubulin; Tubulin Modulators; Tumor Cells, Cultured

The aim of the study is to evaluate the effects of targeting the antivascular drug combretastatin to irradiated mouse melanomas.. Combretastatin was incorporated into liposomes with surfaces modified by the addition of cyclo(Arg-Gly-Asp-D-Phe-Cys) (RGD) to create an immunoliposome (IL). This addition of RGD allows the liposome to be preferentially targeted to alphavbeta3, an integrin up-regulated in the vasculature of irradiated tumors. C57BL mice bearing a transplanted B16-F10 melanoma were randomly assigned to one of the following treatment groups: untreated, a single dose of 5-Gy radiation (IR), IL (14.5 mg/kg of combretastatin), 5-Gy radiation plus IL, and a systemic administration of free drug (81.0 mg/kg of combretastatin).. In this transplanted tumor model, there was no significant increase in the volume of the IL + IR (5 Gy) treated tumors during the initial 6 days posttreatment; all other treatment groups exhibited exponential growth curves after day 3. The IL + IR (5 Gy) treatment resulted in a 5.1-day tumor growth delay compared to untreated controls.. These findings indicate that preferential targeting of antivascular drugs to irradiated tumors results in significant tumor growth delay.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Bibenzyls; Combined Modality Therapy; Drug Delivery Systems; Liposomes; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Stilbenes; Tumor Burden

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Bibenzyls; Doxorubicin; Drug Delivery Systems; Drug Therapy, Combination; Humans; Mice; Nanotechnology; Neoplasms; Neovascularization, Pathologic; Stilbenes; Time Factors

In the continuing search for effective treatments for cancer, the emerging model is the combination of traditional chemotherapy with anti-angiogenesis agents that inhibit blood vessel growth. However, the implementation of this strategy has faced two major obstacles. First, the long-term shutdown of tumour blood vessels by the anti-angiogenesis agent can prevent the tumour from receiving a therapeutic concentration of the chemotherapy agent. Second, inhibiting blood supply drives the intra-tumoural accumulation of hypoxia-inducible factor-1alpha (HIF1-alpha); overexpression of HIF1-alpha is correlated with increased tumour invasiveness and resistance to chemotherapy. Here we report the disease-driven engineering of a drug delivery system, a 'nanocell', which overcomes these barriers unique to solid tumours. The nanocell comprises a nuclear nanoparticle within an extranuclear pegylated-lipid envelope, and is preferentially taken up by the tumour. The nanocell enables a temporal release of two drugs: the outer envelope first releases an anti-angiogenesis agent, causing a vascular shutdown; the inner nanoparticle, which is trapped inside the tumour, then releases a chemotherapy agent. This focal release within a tumour results in improved therapeutic index with reduced toxicity. The technology can be extended to additional agents, so as to target multiple signalling pathways or distinct tumour compartments, enabling the model of an 'integrative' approach in cancer therapy.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Bibenzyls; Carcinoma, Lewis Lung; Coculture Techniques; Doxorubicin; Drug Delivery Systems; Drug Therapy, Combination; Endothelial Cells; Humans; Melanoma, Experimental; Mice; Nanotechnology; Neoplasms; Neovascularization, Pathologic; Stilbenes; Time Factors; Tissue Distribution

Twenty-six epoxide and corresponding pyrazole derivatives, of the structurally related chalcones and combretastatin A-4 (CA-4), were synthesized and tested for in vitro cytotoxicity. These molecules were synthesized by epoxidation of the relevant chalcones, followed by reaction with hydrazine. The structures of epoxides 3 and 7, and pyrazole 17, were confirmed by X-ray diffraction studies. The relatively coplanar conformation of a 3',3'',4',4'',5',5''-hexamethoxypyrazole 17 was in good agreement with the shape for 3',3'',4',4'',5'-pentamethoxypyrazole 16, which was determined from molecular mechanics optimization. In vitro cytotoxicity of each class of compounds was obtained using a 72 h continuous exposure MTT assay against two murine cancer cell lines; B16 melanoma and L1210 leukemia. The effect of substitution in the A-ring is addressed: three methoxy groups versus two, generally increased cytotoxicity across both cell lines. In the majority of cases, the pyrazoles are generally more active than the epoxides, with the most active, 5-(3''-amino-4''-methoxyphenyl)-3-(3',4',5'-trimethoxyphenyl)pyrazole 21, possessing an IC(50) value of 5 and 2.4 microM (B16 and L1210, respectively). Due to their planar conformations, the pyrazoles are typically less active than the corresponding chalcones, which adopt angular conformations similar to CA-4. B-ring modifications confirmed that in general the amino compounds are more active than the corresponding nitro compounds. Varying the number and orientation of methoxy groups on the A-ring did not produce any significant differences in toxicity in the cell lines studied.

Topics: Animals; Bibenzyls; Cell Line; Crystallography, X-Ray; Epoxy Compounds; Mice; Molecular Structure; Pyrazoles; Stilbenes; Structure-Activity Relationship

Topics: Animals; Antineoplastic Agents, Phytogenic; Bibenzyls; Contrast Media; Diffusion Magnetic Resonance Imaging; Gadolinium DTPA; Image Processing, Computer-Assisted; Injections, Intraperitoneal; Male; Rats; Rhabdomyosarcoma; Statistics as Topic; Stilbenes

Combretastatin A4 phosphate (CA4P) and its structural analog, combretastatin A1 phosphate (CA1P), are soluble prodrugs capable of interacting with tubulin and causing rapid vascular shutdown within tumors. CA4P has completed Phase I clinical trials, but recent preclinical studies have shown that CA1P displays a greater antitumor effect than the combretastatin A4 (CA4) analog at equal doses. The aim of this study, therefore, is to compare pharmacokinetics and metabolism of the two compounds to determine whether pharmacokinetics plays a role in their differential activity.. NMRI mice bearing MAC29 tumors received injection with either CA4P or CA1P at a therapeutic dose of 150 mg x kg(-1), and profiles of both compounds and their metabolites analyzed by a sensitive and specific liquid chromatography/mass spectroscopy method.. The metabolic profile of both compounds is complex, with up to 14 metabolites being detected for combretastatin A1 (CA1) in the plasma. Many of these metabolites have been identified by liquid chromatography/mass spectroscopy. Initial studies, however, focused on the active components CA4 and CA1, where plasma and tumor areas under the curve were 18.4 and 60.1 microg x h x ml(-1) for CA4, and 10.4 and 13.1 microg x h x ml(-1) for CA1, respectively. In vitro metabolic comparisons of the two compounds strongly suggest that CA1 is metabolized to a more reactive species than the CA4.. Although in vitro studies suggest that variable rates of tumor-specific prodrug dephosphorylation may explain these differences in pharmacokinetics profiles, the improved antitumor activity and altered pharmacokinetic profile of CA1 may be due to the formation of a more reactive metabolite.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Area Under Curve; Bibenzyls; Calibration; Cell Line, Tumor; Chromatography; Chromatography, High Pressure Liquid; Coloring Agents; Female; Humans; Inhibitory Concentration 50; Mass Spectrometry; Mice; Models, Chemical; Phosphorylation; Prodrugs; Stilbenes; Tetrazolium Salts; Thiazoles; Time Factors

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzoquinones; Bibenzyls; Diagnostic Imaging; Down-Regulation; ErbB Receptors; Gefitinib; Heterocyclic Compounds, 1-Ring; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Magnetic Resonance Imaging; Molecular Probe Techniques; Mutation; Neoplasms; Phthalazines; Physiological Phenomena; Positron-Emission Tomography; Protein Binding; Protein Kinase Inhibitors; Pyridines; Quinazolines; Receptor Protein-Tyrosine Kinases; Receptor, ErbB-2; Receptors, Vascular Endothelial Growth Factor; Rifabutin; Stilbenes; Tissue Distribution; Trastuzumab

We have developed a simple yet sensitive dual color fluorescence-based technique for dissecting the tumor-neovascularization relationship and evaluated the susceptibility of each component to therapeutic interventions. Green fluorescent protein (GFP)-expressing melanoma cells were cocultured with endothelial cells on different three-dimensional (3-D) matrices and exposed to multiple growth factors and molecules with established anti-angiogenic or anticancer activities. Cells were fixed and stained with propidium iodide, imaged using a confocal microscope, and stereologically analyzed. Three-dimensionality of the system was tested by depth-coding and pseudocolor 3-D reconstruction in the z-axis. Selective ablation of the tumor cells was affected by the anthracycline antibiotic doxorubicin. Treatment with vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) promoted the neovascular responses on matrigel and collagen-1 matrices. VEGF-induced angiogenesis was inhibited after treatment with combretastatin and thalidomide. In contrast, HGF exerted a protective effect against these anti-angiogenics in a matrigel matrix. However, this effect was lost when the matrix was substituted with collagen, suggesting that the extracellular matrix impinges on cellular function, possibly through an Akt-mediated mechanism. The VEGF-receptor antagonist PTK787 also selectively ablated the VEGF-induced angiogenic effect without inhibiting the HGF-induced response, demonstrating the sensitivity of the system to detect modulation of distinct signal cascades. The current model encompasses the possibility of studying tumor-angiogenesis-matrix interaction on the same platform, expanding the rapid screening of novel molecules in a simulated clinicopathological setting.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Bibenzyls; Cell Line, Tumor; Coculture Techniques; Doxorubicin; Extracellular Matrix; Fluorescence; Hepatocyte Growth Factor; Humans; Melanoma; Neoplasms; Neovascularization, Pathologic; Phthalazines; Pyridines; Stilbenes; Thalidomide; Vascular Endothelial Growth Factor A

Compounds 1-5, structurally related to combretastatin A-4 showed excellent cytotoxic activities against a panel of human cancer cell lines including multi-drug resistant cell lines. The X-ray three-dimensional structural analysis shows that proton donor in B ring may be required for cytotoxic activity, with intermolecular hydrogen bonding playing an important role.

Topics: Antineoplastic Agents; Benzophenones; Bibenzyls; Cell Cycle; Crystallography, X-Ray; Drug Resistance, Multiple; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; Models, Molecular; Molecular Structure; Stilbenes; Structure-Activity Relationship; Tumor Cells, Cultured

To determine whether there is a therapeutic interaction between the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and nine chemotherapy drugs against an early-passage mouse mammary tumour (MDAH-MCa-4), and to investigate the mechanism of any such interaction.. Female C3H/HeN mice bearing intramuscular MDAH-MCa-4 tumours were injected intraperitoneally with DMXAA (80 micro mol/kg) or chemotherapy drug (at a range up to the maximum tolerated dose) alone, or coadministered. A small reduction in the dose of the chemotherapy drug was required in most cases, but the increase in antitumour effect was much greater than the increase in host toxicity (body weight loss). The therapeutic gain increased in the order 5-fluorouracil (no gain)<(etoposide, carboplatin, cyclophosphamide, doxorubicin, cisplatin)<(docetaxel, vincristine)

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bibenzyls; Carboplatin; Dose-Response Relationship, Drug; Drug Synergism; Female; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C3H; Paclitaxel; Stilbenes; Time Factors; Xanthenes; Xanthones

Peptide hormones are often rapidly internalized after binding to and activation of their receptors which are sometimes over-expressed on tumor cells. Thus, peptide ligands are increasingly being utilized for specific tumor cell targeting and internalization of radioactive isotopes for tumor imaging and for specifically delivering and internalizing cytotoxic moieties. Here, we describe a new carbamate linker system containing a series of built-in nucleophile assisted releasing (BINAR) groups which enable the 'fine-tuning' of intracellular cleavage rates of free cytotoxic agents containing reactive OH groups. Release rates were found to fit well with the chemical model and several conjugates of camptothecin and one of combretastatin were shown to have potent cytotoxic effects on cultures of human neuroblastoma IMR-32 cells which over-express somatostatin receptors.

Topics: Amino Acid Sequence; Animals; Antineoplastic Agents; Bibenzyls; Camptothecin; Carbamates; Cross-Linking Reagents; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; Neuroblastoma; Peptides; Rats; Somatostatin; Stilbenes; Structure-Activity Relationship; Tumor Cells, Cultured

Topics: Animals; Antineoplastic Agents, Phytogenic; Bibenzyls; Clinical Trials, Phase I as Topic; Decision Making; Humans; Magnetic Resonance Imaging; Neoplasms; Rats; Stilbenes; Tomography, Emission-Computed

A novel combretastatin A-4 derivative, AC7700, which is now in Phase I clinical trials under a new code, AVE8062, has shown strong antitumour effects against solid tumours in rodents because of its powerful and continued stanching of the tumour blood flow (TBF). Despite the strong tumour-suppressing qualities of AC7700, it does not produce an immediate reduction in tumour size. To elucidate the reason for this effect, we investigated the relationship between the change in tumour size in Sato lung carcinoma (SLC) and circulatory functions after therapy with AC7700, doxorubicin (Adriamycin [ADR]), or mitomycin C (MMC). To measure time-lapse changes in TBF with the hydrogen clearance method at the same site after drug administration, we developed a new apparatus for keeping electrodes within a tumour. AC7700 led to the destruction of both cancer cells and tumour vessels by interrupting the supply of nutrients. Intravenous (i.v.) administration of fluorescent dyes after AC7700 treatment revealed no fluorescence within the tumour vessels, which confirmed that the tumour microcirculation had been completely blocked. In contrast, ADR led to the destruction of SLC tumour cells, but did not have the same effect on tumour vessels. Intravenously administered fluorescent dyes immediately reached the tumour, which indicated that the tumour vasculature remained intact, and the TBF remained at the preadministration level, even 6 days after ADR treatment. In addition, although the size of the tumour increased slightly for 2 days with ADR treatment, possibly because of swelling of the cancer cells, thereafter it continued to decrease. MMC had virtually no effect on SLC tumour cells, tumour size or tumour vessels. We conclude that changes in tumour size brought about by cancer chemotherapy depend not only on the sensitivity of the cancer cells to the drug in question, but also on the nature of changes in the microcirculatory functions of the tumour brought about by the therapy. When both tumour cells and the tumour vasculature are destroyed, the effectiveness of therapy can not be determined from changes in tumour size alone.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Bibenzyls; Blood Flow Velocity; Cell Division; Doxorubicin; Lung Neoplasms; Male; Microcirculation; Mitomycin; Neoplasm Transplantation; Rats; Stilbenes; Treatment Outcome

A series of combretastatins possessing both a trimethoxy unit and other substituents on ring A has been synthesised and tested for cytotoxicity and their ability to interact with the protein tubulin. All previous studies have indicated that the trimethoxy unit is essential for interaction with tubulin. The studies herein show that molecules possessing functionalities other than trimethoxy can also interact with tubulin. Importantly a trimethyl substituted agent 52a has shown reduced cytotoxicity, but increased potency in its ability to inhibit the assembly of tubulin.

Topics: Animals; Antineoplastic Agents; Bibenzyls; Cell Line; Chlorocebus aethiops; Drug Screening Assays, Antitumor; Humans; Immunohistochemistry; Inhibitory Concentration 50; K562 Cells; Molecular Structure; Stilbenes; Structure-Activity Relationship; Tubulin; Vero Cells

Topics: Angiogenesis Inhibitors; Angiogenic Proteins; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Phytogenic; Bevacizumab; Bibenzyls; Biological Availability; Biomarkers; Carcinoma, Renal Cell; Clinical Trials as Topic; Combined Modality Therapy; Drug Resistance, Neoplasm; Endostatins; Endothelial Growth Factors; Endothelium, Vascular; Growth Inhibitors; Humans; Kidney Neoplasms; Microtubules; Neoplasms; Neovascularization, Pathologic; Ontario; Receptors, Vascular Endothelial Growth Factor; Stilbenes

A series of 2-(3,4,5-trimethoxyphenyl)-3-arylcyclopent-2-ene-1-ones (8a-8e) and their related analogues, including pentenone 9a, pentenol 10a, pentene 12a, and furane 15, were synthesized and evaluated for cytotoxicity against murine and human tumor cell lines. Compounds 8a-c, 8e and 9a showed strong cytotoxicity with IC(50) values in the range of 8-34ng/mL. Compound 8e exhibited significant anti-tumor activity in BDF1 mice bearing Lewis lung carcinoma cells with an inhibition ratio of 59%.

Topics: Animals; Antineoplastic Agents; Bibenzyls; Carcinoma, Lewis Lung; Cyclopentanes; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; Mice; Stereoisomerism; Stilbenes; Structure-Activity Relationship; Tumor Cells, Cultured

The anti-vascular effects of the tubulin binding agent, disodium combretastatin A-4 3-O-phosphate (CA-4-P), have been investigated in the rat P22 carcinosarcoma by measurements of radiolabelled iodoantipyrine uptake and dynamic contrast-enhanced MRI. The iodoantipyrine estimates of absolute tumour blood flow showed a reduction from 0.35 to 0.04 ml g(-1) min(-1) 6 h after 10 mg kg(-1) CA-4-P and to <0.01 ml g(-1) min(-1) after 100 mg kg(-1). Tumour blood flow recovered to control values 24 h after 10 mg kg(-1) CA-4-P, but there was no recovery by 24 h after the higher dose. Dynamic contrast-enhanced MR images were obtained at 4.7 T, following injection of 0.1 mmol kg(-1) Gd-DTPA and analysed assuming a model arterial input function. A parameter, K(trans), which is related to blood flow rate and permeability of the tumour vasculature to Gd-DTPA, was calculated from the uptake data. K(trans) showed a reduction from 0.34 to 0.11 min(-1) 6 h after 10 mg kg(-1) CA-4-P and to 0.07 min(-1) after 100 mg kg(-1). Although the magnitude of changes in K(trans) was smaller than that in tumour blood flow, the time course and dose-dependency patterns were very similar. The apparent extravascular extracellular volume fraction, nu(e), showed a four-fold reduction 6 h after 100 mg kg(-1) CA-4-P, possibly associated with vascular shutdown within large regions of the tumour. These results suggest that K(trans) values for Gd-DTPA uptake into tumours could be a useful non-invasive indicator of blood flow changes induced by anti-vascular agents such as combretastatin.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Antipyrine; Bibenzyls; Carcinosarcoma; Contrast Media; Gadolinium DTPA; Iodine Radioisotopes; Magnetic Resonance Imaging; Male; Radionuclide Imaging; Rats; Stilbenes

The purpose of this study was to determine the reproducibility of dynamic contrast-enhanced (DCE)-MRI and compare quantitative kinetic parameters with semi-quantitative methods, and whole region-of-interest (ROI) with pixel analysis. Twenty-one patients with a range of tumour types underwent paired MRI examinations within a week, of which 16 pairs were evaluable. A proton density-weighted image was obtained prior to a dynamic series of 30 T(1)-weighted spoiled gradient echo images every 11.9 s with an intravenous bolus of gadopentetate dimeglumine given after the third baseline data point. Identical ROIs around the whole tumour and in skeletal muscle were drawn by the same observer on each pair of examinations and used for the reproducibility analysis. Semi-quantitative parameters, gradient, enhancement and AUC (area under the curve) were derived from tissue enhancement curves. Quantitative parameters (K(trans), k(ep), v(e)) were obtained by the application of the Tofts' model. Analysis was performed on data averaged across the whole ROI and on the median value from individual pixels within the ROI. No parameter showed a significant change between examinations. For all parameters except K(trans), the variability was not dependent on the parameter value, so the absolute values for the size of changes needed for significance should be used for future reference rather than percentages. The size of change needed for significance in a group of 16 in tumours for K(trans), k(ep) and v(e) was -14 to +16%, -0.20 ml/ml/min (15%) and -1.9[?]ml/ml (6%), respectively (pixel analysis), and -16 to +19%, -0.23 ml/ml/min (16%) and +/- 1.9[?]ml/ml (6%) (whole ROI analysis). For a single tumour, changes greater than -45 to +83%, +/- 0.78 ml/ml/min (60%) and +/- 7.6 ml/ml (24%), respectively, would be significant (pixel analysis). For gradient, enhancement and AUC the size of change needed for significance in tumours was -0.24 (17%), -0.05 (6%) and -0.06 (8%), respectively for a group of 16 (pixel analysis), and +/- 0.96 (68%), +/- 0.20 (25%) and +/- 0.22 (32%) for individuals. In muscle, the size of change needed for significance in a group of 16 for K(trans), k(ep) and v(e) was -30 to +44%, +/- 0.81 ml/ml/min (61%) and +/- 1.7 ml/ml (13%). For gradient, enhancement and AUC it was +/- 0.09 (20%), +/- 0.02 (8%) and +/- 0.03 (12%). v(e), enhancement and AUC are highly reproducible DCE-MRI parameters. K(trans), k(ep) and gradient have greater variability, with larger changes i

Topics: Antineoplastic Agents; Bibenzyls; Contrast Media; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Muscle, Skeletal; Neoplasms; Reproducibility of Results; Stilbenes; Xanthenes; Xanthones

Combretatropone is a hybrid of combretastatin and colchicine in which the o-methoxyphenol of dihydrocombretastatin A-4 is replaced by an alpha-methoxytropone. Derivatives of combretatropone have been synthesized and evaluated for antimicrotubule activity. All combretatropones were less active than the corresponding colchicine derivatives, supporting the idea that loss of ligand conformational entropy upon tubulin binding results in decreased potency for colchicinoid ligands. The structure-activity relationship of the combretatropone series was different than that of the colchicine series. These data indicate that conformationally mobile and conformationally rigid colchicinoids do not interact with the receptor site in the same manner.

Topics: Antineoplastic Agents; Bibenzyls; Colchicine; Magnetic Resonance Spectroscopy; Microtubules; Molecular Structure; Stilbenes; Structure-Activity Relationship; Tubulin; Tubulin Modulators

Topics: Angiostatins; Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Bibenzyls; Humans; Matrix Metalloproteinase Inhibitors; Neoplasms; Neovascularization, Pathologic; Peptide Fragments; Plasminogen; Stilbenes

A methanol extract of Combretum erythrophyllum showed inhibitory bioactivities in a yeast-based microtiter assay for DNA-damaging agents. Bioassay-guided fractionation of this extract yielded two known bioactive compounds, combretastatin A-1 and (-)-combretastatin, and two new bioactive glucosides, combretastatin A-1 2'-beta-D-glucoside (1) and combretastatin B-1 2'-beta-D-glucoside (2). The structures of the new compounds were assigned by (1)H and (13)C NMR, DEPT, HMQC, and HMBC spectra.

Topics: Antineoplastic Agents, Phytogenic; Bibenzyls; Carbohydrate Sequence; DNA Damage; DNA Repair; Drug Screening Assays, Antitumor; Glycosides; Humans; Magnetic Resonance Spectroscopy; Mass Spectrometry; Molecular Sequence Data; Plant Extracts; Plants, Medicinal; South Africa; Spectrophotometry, Ultraviolet; Stilbenes; Tumor Cells, Cultured; Wood

A molecular modeling study using Comparative Molecular Field Analysis (CoMFA) was undertaken to develop a predictive model for combretastatin binding to the colchicine binding site of tubulin. Furthermore, we examined the potential contribution of lipophilicity (log P) and molecular dipole moment and were unable to correlate these properties to the observed biological data. In this study we first confirmed that tubulin polymerization inhibition (IC50) correlated (R2 = 0.92) with [3H]colchicine displacement. Although these data correlated quite well, we developed two independent models for each set of data to quantify structural features that may contribute to each biological property independently. To develop our predictive model we first examined a series of molecular alignments for the training set and ultimately found that overlaying the respective trimethoxyphenyl rings (A ring) of the analogues generated the best correlated model. The CoMFA yielded a cross-validated R2 = 0.41 (optimum number of components equal to 5) for the tubulin polymerization model and an R2 = 0.38 (optimum number of components equal to 5) for [3H]colchicine inhibition. Final non-cross-validation generated models for tubulin polymerization (R2 of 0.93) and colchicine inhibition (R2 of 0.91). These models were validated by predicting both biological properties for compounds not used in the training set. These models accurately predicted the IC50 for tubulin polymerization with an R2 of 0.88 (n = 6) and those of [3H]colchicine displacement with an R2 of 0.80 (n = 7). This study represents the first predictive model for the colchicine binding site over a wide range of combretastatin analogues.

Topics: Bibenzyls; Binding Sites; Biopolymers; Colchicine; Molecular Conformation; Stilbenes; Tubulin

We have developed a rapid [3H]colchicine competition-binding scintillation proximity assay (SPA) to evaluate antimitotic compounds that bind to the colchicine-binding site on tubulin. The premise of our assay is that compounds will compete with radiolabeled colchicine for the tubulin-binding domain. Biotin-labeled tubulin is incubated first with unlabeled compound and radiolabeled ligand. Streptavidin-labeled SPA beads are added, and the radiolabel associated with tubulin is directly counted with no separation steps. Under our experimental conditions, the dissociation constant of binding (Kd) for colchicine to tubulin was determined to be 1.4 microM, which was consistent with previously reported values. Assay validation was performed by competitively inhibiting [3H]colchicine binding to tubulin with known microtubule inhibitors and comparing their inhibition constants (Ki). Our SPA bead method is a powerful tool since it overcomes the disadvantage of traditional filtration techniques, as there are no separation steps. It is extremely easy to set up, multiple samples can be assayed and supply and labor costs are reduced because of the minimal volume and test reagents used.

Topics: Aminophenols; Bibenzyls; Binding Sites; Binding, Competitive; Biotinylation; Colchicine; Demecolcine; Mebendazole; Microspheres; Podophyllotoxin; Scintillation Counting; Solvents; Stilbenes; Streptavidin; Sulfonamides; Tritium; Tubulin; Yttrium

Tubulin, the major structural component of the microtubules, participates actively in mitotic spindle formation and chromosomal organization during cell division. Tubulin is the major target for a variety of anti-mitotic drugs. Some of the drugs, such as Vinca alkaloids and taxol, are routinely used for cancer chemotherapy. It is unfortunate that our knowledge of the binding sites on tubulin of these drugs is limited because of lack of a useful and appropriate tool. The photoaffinity labeling approach is the major technique available at present to detect the binding sites of drugs on tubulin. This method, however, has several limitations. First, only part of the binding site can be identified, namely, the residues which react with the photoaffinity label. Second, there are regions of tubulin which are not at the binding site but are affected by the binding of the drug; these regions can not be detected by the photoaffinity labeling approach. The third, and perhaps most serious, limitation is that the traditional approach can detect areas which have nothing to do with the binding of the ligand but which are within a certain distance of the binding site, that distance being less than the length of the photoreactive moiety attached to the ligand. There has been a great deal of controversy on the localization of the binding site of colchicine on tubulin, with some reports suggesting that the binding site is on alpha and some supporting a binding site on beta. Colchicine also has significant effects on tubulin conformation, but the regions which are affected have not been identified. We have attempted here to address these questions by a novel "footprinting" method by which the drug-binding sites and as well as the domain of tubulin affected by drug-induced conformational changes could be determined. Here, we report for the first time that the interaction of the B-ring of colchicine with the alpha-subunit affects a domain of tubulin which appears to be far from its binding site. This domain includes the cysteine residues at positions 295, 305, 315 and 316 on alpha-tubulin; these residues are located well away from the alpha/beta interface where colchicine appears to bind. This is correlated with the stabilizing effect of colchicine on the tubulin molecule. Furthermore, we also found that the B-ring of colchicine plays a major role in the stability of tubulin while the A and the C-rings have little effect on it. Our results therefore, support a model whereby co

Topics: Amino Acid Sequence; Animals; Bibenzyls; Binding Sites; Cattle; Chromatography, High Pressure Liquid; Colchicine; Fluorescence; Models, Molecular; Molecular Sequence Data; Peptide Fragments; Podophyllotoxin; Protein Conformation; Protein Footprinting; Stilbenes; Tropolone; Tryptophan; Tubulin; Urea

Taking into account the structure of Combretastatins, we have synthesized and assayed for cytotoxic activity of new indole derivatives. Two aryl groups are maintained in the cis orientation required for activity by means of an indole moiety built up on less active ketoderivatives used as starting materials.

Topics: Antineoplastic Agents, Phytogenic; Bibenzyls; Drug Screening Assays, Antitumor; Humans; Stilbenes; Tumor Cells, Cultured

We have investigated the in vitro leishmanicidal activity of representative members from series II-V of combretastatin analogues and heteroanalogues. Most of them exhibited different degrees of activity against various strains of Leishmania spp. The diaryl(heteroaryl)ethane system or the more complex fused heterocyclic stilbenoids, constitute useful skeletal bases to support some kind of antiparasitic activity. Particularly, the incorporation of 2-furyl substituents led to potent antileishmanial compounds, which have been selected for in vivo testing on murine models.

Topics: Animals; Antiprotozoal Agents; Bibenzyls; Leishmania; Mice; Species Specificity; Stilbenes

The effect of five derivatives of Combretastatin D on tubulin polymerization was investigated. All of them were found to stabilize microtubules to various degrees. The derivatives bearing polar substituents were found to be the most active.

Topics: Bibenzyls; Microtubules; Molecular Structure; Stilbenes

Combretastatins have tubulin-binding activity and are being investigated for their toxicity against tumour vasculature. We report the use of 31P and 'H magnetic resonance (MR) spectroscopy and 1H MR imaging for monitoring the effects of combretastatin A-4 prodrug (100mg/kg, i.p.) on energy metabolism and necrosis, respectively, in the C3H murine mammary tumour.. The tumours (volume ca. 200mm3) were grown in the hind foot of mice. MR examinations were performed without anaesthesia within a 7.1 Tesla magnet. 31P MRS (TR = 6 s) was performed before treatment and at 1-, 2-, 3-, and 24-h after injection of drug or saline via an i.p. line. 1H MRS (PRESS; 24microl voxel; TR = 2 s; TE = 135 ms) and both T1-weighted (TR = 0.2 s; TE = 0.02 s) and T2-weighted (TR = 2 s; TE = 0.20 s) 1H MRI were performed before treatment and 2.5 and 24 h afterwards.. The ratio beta-nucleotide triphosphate/inorganic phosphate fell by 33% within 1 h of treatment and remained constant for a further 2 h. A small but significant fall in pH (by 0.11 units) was observed at 1 h. Although an increase in the 1H MR spectroscopy signal at about 1.32 ppm (predominantly from lactate) was observed in some tumours following combretastatin treatment, this effect was not seen consistently. No changes in the intensity of T2-weighted 1H MR images or in tumour necrosis (measured histologically) were detected within 3 h of treatment.. The reduction in tumour energetics and pH was consistent with a reduction in tumour blood flow but this occurred before any significant incidence of haemorrhagic necrosis was detected. The combretastatin dose used to achieve these effects was less than one tenth of the maximum tolerated dose in mice.

Topics: Animals; Antineoplastic Agents, Phytogenic; Bibenzyls; Drug Screening Assays, Antitumor; Energy Metabolism; Hydrogen; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Mammary Neoplasms, Animal; Mice; Necrosis; Phosphorus; Stilbenes

A series of B-ring modified combretastatin analogues were synthesized and their inhibitory activity against microtubule assembly, cytotoxic activity against Colon 26 adenocarcinoma cancer cell line were evaluated. Among these, pyridone derivative (19) showed strong antimitotic activity and cytotoxicity, along with excellent water-solubility.

Topics: Antineoplastic Agents, Phytogenic; Bibenzyls; Drug Stability; Humans; Stilbenes; Structure-Activity Relationship

Series of diaryl ethers, amines and amides have been synthesized and tested for antitumor activity. These diaryl compounds possess some of the structural features of combretastatin A-4 (a potent antimitotic agent). They were designed to discover whether transferring these structural motifs from stilbenes to heterosubstituted diaryl compounds would enhance their biochemical activities. Molecular modeling studies suggested that these diaryl compounds could adopt conformations similar to combretastatin A-4. However, although some agents (5-7) were cytotoxic and others (10 and 12) could interact with tubulin, none were as potent as combretastatin A-4.

Topics: Animals; Antineoplastic Agents, Phytogenic; Bibenzyls; Drug Screening Assays, Antitumor; Leukemia P388; Mice; Stilbenes; Structure-Activity Relationship; Tumor Cells, Cultured

(E)-3-(beta-D-Glucopyranosyloxy)-4',5-dihydroxystilbene (resveratrol 3-beta-D-glucoside, piceid), (Z)-2',3'-dihydroxy-3,4,4',5-tetramethoxystilbene (combretastatin A-1), (Z)-3'-hydroxy-3,4,4',5-tetramethoxystilbene (combretastatin A-4), (Z)-2'-hydroxy-3-4-4'-5-tetramethoxystilbene (combretastatin iso-A-4), alpha, beta-dihydro-2',3'-dihydro-2',3'-dihydroxy-3,4,4',5-tetramethoxystilb ene (combretastatin B-1), the corresponding glucosides, and related compounds have been synthesized via Wittig reactions followed by glucosylation under phase-transfer catalysis. Most of the compounds synthesized have been tested with respect to biological activity (cytostatic, cytotoxic, antimitotic, neurotoxic, antiplatelet, aggregation activity).

Topics: Antineoplastic Agents; Bibenzyls; Cell Division; Ganglia, Spinal; Glucosides; Glycosylation; Magnetic Resonance Spectroscopy; Mass Spectrometry; Mitosis; Molecular Structure; Platelet Aggregation Inhibitors; Resveratrol; Stilbenes; Tumor Cells, Cultured

We have assessed the vascular effects of vinblastine and four other tubulin binding agents (dolastatin 10, dolastatin 15, combretastatin A1 and combretastatin A4), which are awaiting clinical evaluation. All five agents induce a reduction in tumour blood flow as measured by uptake of RbCI 24 h post drug administration. The degree of reduction ranged from 50% with combretastatin A1 to 90% with dolastatin 10. These reductions were similar to that seen with flavone acetic acid (FAA) and indicate that antivascular effects are a common feature of tubulin binding agents. We subsequently evaluated whether the blood flow reductions, induced by FAA and vinblastine, could be used to enhance the activity of the bioreductive drug tirapazamine. Since the kinetics and extent of blood flow reductions induced by the agents is comparable, similar therapeutic response was expected. Potentiation was only evident with FAA, indicating that this effect is not directly related to killing of hypoxic tumour cells induced as a consequence of blood flow reduction.

Topics: Animals; Antineoplastic Agents; Bibenzyls; Depsipeptides; Flavonoids; Mice; Mice, Inbred CBA; Neoplasms, Experimental; Oligopeptides; Regional Blood Flow; Stilbenes; Tirapazamine; Triazines; Tubulin; Tumor Necrosis Factor-alpha; Vinblastine

The computer-automated structure evaluation programs MultiCASE and CASE were used to perform a quantitative structure-activity relationship study on tubulin polymerization inhibitors. A learning set of 536 chemicals (202 active. 27 marginal, and 307 inactive), built using IC50 values for inhibition of tubulin polymerization or mitosis from this and previous studies, was used for artificial intelligence self-teaching. The algorithms successfully predicted the activity of agents in the learning set with > 90% accuracy. Seventeen MultiCASE and twelve CASE (mostly included in the MultiCASE set) biophores (substructures significantly correlated with activity) were identified with a probability > 0.95. Here we present the biophores of podophyllotoxins, colchicinoids, and certain combretastatins, each examined for structure-activity relationships. For the podophyllotoxins and colchicinoids in the learning set, the correlations between observed and predicted potencies were > 0.85. The algorithms recognized the importance of several known site, electronic, and steric effects in the two classes. A predictive QSAR (R2 = 0.98) was developed for combretastain A-2 and dihydrocombretastatin analogues. The MultiCASE/CASE analyzes were used in combination with molecular models to study relative orientations of colchicine, podophyllotoxin, combretastatin A-4, and steganacin at the colchicine site. This resulted in a new hypothesis, consistent with extensive published experimental data, in which the C-ring and part of the B-ring of colchicine overlap with the A- and B-rings of podophyllotoxin. Consequently, the trimethoxyphenyl rings of colchicine and podophyllotoxin occupied different regions of space, each pointing out from a hydrophobic 'core' occupied by the overlapping biophores. The molecular model of the highly potent combretastatin A-4 could fit into the model binding site in at least three different ways. The developed QSARs were used to identify the potent microtubule stabilizer discodermolide. Its identification, in concert with recently reported findings, suggest potential overlap in the colchicine and paclitaxel binding sites on tubulin.

Topics: Antineoplastic Agents, Phytogenic; Bibenzyls; Binding Sites; Colchicine; Models, Molecular; Paclitaxel; Podophyllotoxin; Protein Conformation; Software; Stilbenes; Tubulin; Tubulin Modulators

Combretastatin B1, a polyhydroxybibenzyl compound extracted from the fruit of Combretum kraussii, known to contain 'hiccup nut' toxin, reversibly increased the duration, but not the peak or the rate of rise, of the action potential in rat sensory neurones by approximately 300%. This effect was only seen when it was applied to the extracellular side of the membrane. No effects on the resting potential were observed. K+ delayed rectifier currents were inhibited in neurones and in human myotubes with an IC50 of about 300 microM; the HERG-type inward rectifier channels in tumour cells were inhibited to a greater degree. Due to its selective action and the similarity of its blockade to that produced by class III antiarrhythmic drugs, the toxin could be the origin of compounds of potentially significant pharmacological interest.

Topics: Animals; Antineoplastic Agents, Phytogenic; Bibenzyls; Dose-Response Relationship, Drug; Ganglia, Spinal; Humans; Potassium Channels; Rats; Stilbenes

A new and versatile synthesis of combretastatins has been developed. Starting from commercially available materials, 2-phenyl-2-benzyl-1,3-dithianes were easily prepared and used as intermediates in the synthesis of several families of combretastatins. This approach facilitates the preparation of representative intermediates in a few steps, with or without an oxygenated function in the ethylenic residue. Many different analogues suitable for pharmacological evaluation can also be obtained from some of these intermediates.

Topics: Antineoplastic Agents, Phytogenic; Bibenzyls; Magnetic Resonance Spectroscopy; Spectrophotometry, Ultraviolet; Stilbenes

A number of cytostatic compounds (2-4, 7, and 8), which can be described as "diaryl", inhibit tubulin polymerization, cause cells to accumulate in mitotic arrest, and competitively inhibit the binding of colchicine to tubulin. They differ, however, in the separation of the two aryl moieties. To attempt to understand this variability we prepared a series of analogues modeled on 3 and 4 ("benzodioxole series") and on 7 and 8 ("combretastatin series") which differed only in the number of methylene units (ranging from none to four) separating the aryl moieties. These compounds were evaluated for their effects on tubulin polymerization, colchicine binding, and the growth of L1210 murine leukemia cells. In terms of inhibitory effects on tubulin polymerization, for the combretastatin series there was an optimal separation of the two phenyl rings by a two-carbon bridge (compound 24), with progressively decreasing inhibitory activity when the separation was by one carbon (20), three carbons (25), or four carbons (28) (the biphenyl analogue 16 was inactive). The benzodioxole series, however, did not permit us to generalize this finding, because the least active agents prepared (39 and 40) had a two-carbon bridge, while those with one- (5 and 6) and three-carbon (46 and 47) bridges were nearly equivalent in potency. Submicromolar IC50 values for inhibition of L1210 cell growth were only obtained for compounds 20 (IC50, 0.2 microM), 24 (0.07 microM), and 25 (0.4 microM). While evaluating the effects of these agents on tubulin polymerization, we noted with the combretastatin series and with several standard agents that apparent potency (in terms of IC50 values) was always lower if the reaction was performed at 30 degrees C, with 0.25 mM MgCl2, than at 37 degrees C, with 1.0 mM MgCl2. This enhancement of IC50 values in the former system as compared with the latter was particularly dramatic for the less active agents (e.g., 28) as compared with the more active (e.g. 24).

Topics: Animals; Antineoplastic Agents; Bibenzyls; Binding Sites; Bridged-Ring Compounds; Colchicine; Leukemia L1210; Mice; Stilbenes; Structure-Activity Relationship; Tubulin

Combretastatin, an antineoplastic and antimitotic agent, was isolated from the bark of Combretum caffrum [Can. J. Chem. 60: 1374-1376 (1982); Biochem. Pharmacol. 32:3864-3867 (1983)]. Structurally, combretastatin consists of two substituted benzene rings linked by a saturated, hydroxy-substituted two-carbon bridge. A large number of combretastatin analogs have now been synthesized or obtained from C. caffrum. These vary in substituents on the phenyl rings or bridge carbons, bridge length, unsaturation of the bridge (i.e., stilbene derivatives, with the two phenyl rings oriented either cis or trans), and in precise ring structure (two major variants, with the bridge incorporated into a third six-member ring to form a phenanthrene structure or a methyl group eliminated from vicinal methoxy substituents to form a benzodioxole ring). Available analogs (17 natural products and 22 synthetic agents) were examined for antimitotic and cytotoxic activity and for effects on tubulin polymerization and colchicine binding. Nineteen compounds inhibited cell growth by 50% or more at concentrations of 1 microM or less, and 14 inhibited tubulin polymerization by at least 50% at stoichiometric drug concentrations. The most potent cytotoxic agents generally strongly inhibited both tubulin polymerization and the binding of colchicine to tubulin. The most promising compound is the (cis)-stilbene derivative (cis)-1-(3,4,5-trimethoxyphenyl)-2-(3'-hydroxy-4'-methoxyphenyl)ethene, which has been named combretastatin A-4. This compound inhibited cell growth by 50% at 7 nM, inhibited tubulin polymerization by 50% at 2.5 microM (1/4 molar equivalent), and competitively inhibited colchicine binding with an apparent Ki of 0.14 microM.

Topics: Animals; Anisoles; Antineoplastic Agents; Bibenzyls; Binding Sites; Binding, Competitive; Colchicine; Leukemia L1210; Mice; Mitosis; Podophyllotoxin; Protein Binding; Stilbenes; Structure-Activity Relationship; Tubulin

Topics: Animals; Anisoles; Bibenzyls; Binding Sites; Brain Chemistry; Cattle; Cells, Cultured; Colchicine; Leukemia L1210; Mice; Mitosis; Protein Binding; Stilbenes; Tubulin