noscapine and Neoplasms

noscapine has been researched along with Neoplasms* in 22 studies

Reviews

8 review(s) available for noscapine and Neoplasms

ArticleYear
Insight into the Tubulin-Targeted Anticancer Potential of Noscapine and its Structural Analogs.
    Anti-cancer agents in medicinal chemistry, 2023, Volume: 23, Issue:6

    Cancer is known as a notorious disease responsible for threatening millions of lives every year. Natural products which act by disrupting the microtubule assembly and dynamics have proven to be highly successful as anticancer agents but their high toxicity owing to lower selectivity has limited their usage. Recently, Noscapine (NOS), a known anti-tussive, has come out to be an effective anti-tubulin candidate with far lesser toxicity. Since its first report as an anti-mitotic agent in 1998, NOS has been extensively studied and modified by various groups of researchers to optimize its anti-tubulin activity. In this review, the recent advancements about the potential of these therapeutic candidates against various cancers have been compiled and analyzed for their inhibitory mechanism in distinct health conditions. It has been observed that the non-polar substitutions (e.g., halides, aryl groups) at specific sites (9-position and N-sites of isoquinoline ring; and modification of a methoxy group) have an enhanced effect on efficacy. The mechanistic studies of NOS and its modified analogs have shown their inhibitory action primarily through interaction with microtubules dynamics thus disrupting the cell-cycle and leading to apoptosis. This review highlights the latest research in the field by providing a rich resource for the researchers to have a hands-on analysis of NOS analogs and the inhibitory action in comparison to other microtubule disrupting anti-cancer agents. The article also documents the newer investigations in studying the potential of noscapine analogs as possible anti-microbial and antiviral agents.

    Topics: Antineoplastic Agents; Humans; Microtubules; Neoplasms; Noscapine; Tubulin; Tubulin Modulators

2023
Taking aim at a dynamic target: Noscapinoids as microtubule-targeted cancer therapeutics.
    Pharmacological reports : PR, 2015, Volume: 67, Issue:1

    Noscapine and its synthetic derivatives called noscapinoids have been shown to possess potential anticancer properties. These alkaloids target microtubules and inhibit cell proliferation. Noscapinoids are microtubule poisons that induce minor alterations in the innate dynamic instability of microtubules leading to mitotic arrest and cell death. Over the past decade, a number of noscapine derivatives have been synthesized that, compared to the parent compound, show superior anticancer potential, enhanced tumor specificity and tumor regression, and little or no toxicity to normal tissues. Based on their successive synthetic modifications at different points in the scaffold structure of noscapine, aided by computational design and structure-activity relationship studies, the derivatives of noscapine have been classified into different "generations" based on modifications. Several studies have reported the potential to develop noscapinoids as anticancer drugs. Increasing their tumor specificity - either through antibody conjugation or nanoparticle-based carriers - may facilitate the progression of maytansinoid-based cancer drugs to the clinic.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Humans; Microtubules; Neoplasms; Noscapine; Tubulin

2015
The Noscapine Chronicle: A Pharmaco-Historic Biography of the Opiate Alkaloid Family and its Clinical Applications.
    Medicinal research reviews, 2015, Volume: 35, Issue:5

    Given its manifold potential therapeutic applications and amenability to modification, noscapine is a veritable "Renaissance drug" worthy of commemoration. Perhaps the only facet of noscapine's profile more astounding than its versatility is its virtual lack of side effects and addictive properties, which distinguishes it from other denizens of Papaver somniferum. This review intimately chronicles the rich intellectual and pharmacological history behind the noscapine family of compounds, the length of whose arms was revealed over decades of patient scholarship and experimentation. We discuss the intriguing story of this family of nontoxic alkaloids, from noscapine's purification from opium at the turn of the 19th century in Paris to the recent torrent of rationally designed analogs with tremendous anticancer potential. In between, noscapine's unique pharmacology; impact on cellular signaling pathways, the mitotic spindle, and centrosome clustering; use as an antimalarial drug and cough suppressant; and exceptional potential as a treatment for polycystic ovarian syndrome, strokes, and diverse malignancies are catalogued. Seminal experiments involving some of its more promising analogs, such as amino-noscapine, 9-nitronoscapine, 9-bromonoscapine, and reduced bromonoscapine, are also detailed. Finally, the bright future of these oftentimes even more exceptional derivatives is described, rounding out a portrait of a truly remarkable family of compounds.

    Topics: Alkaloids; Animals; Antineoplastic Agents; Centrosome; Chemistry, Pharmaceutical; Drug Evaluation, Preclinical; Female; Humans; Male; Microtubules; Neoplasms; Noscapine; Papaver; Plant Extracts; Stroke; Warfarin

2015
A review on noscapine, and its impact on heme metabolism.
    Current drug metabolism, 2013, Volume: 14, Issue:3

    This review introduces the Noscapine, which is being used as an antitussive drug for a long time has been recently discovered as a novel tubulin-binding, anti-angiogenic anticancer drug that causes cell cycle arrest and induces apoptosis in cancer cells both in vitro as well as in vivo. Noscapine is a multifunctional molecule i.e. it possesses various functional moieties. We maneuvered various amenable sites and have synthesized analogs, which might prove to be more efficacious and less cytotoxic. Moreover, development of oral controlled release anticancer formulation of noscapine is severely hampered due to short biological half-life (<2-h), poor absorption, low aqueous solubility, and extensive first pass metabolism, thereby requiring large doses for effective treatment.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Antitussive Agents; Cell Cycle; Heme; Humans; Microtubules; Neoplasms; Noscapine

2013
Implications of nanoscale based drug delivery systems in delivery and targeting tubulin binding agent, noscapine in cancer cells.
    Current drug metabolism, 2012, Volume: 13, Issue:10

    Noscapine, a tubulin binding anticancer agent undergoing Phase I/II clinical trials, inhibits tumor growth in nude mice bearing human xenografts of breast, lung, ovarian, brain, and prostrate origin. The analogues of noscapine like 9-bromonoscapine (EM011) are 5 to 10-fold more active than parent compound, noscapine. Noscapinoids inhibit the proliferation of cancer cells that are resistant to paclitaxel and epothilone. Noscapine also potentiated the anticancer activity of doxorubicin in a synergistic manner against triple negative breast cancer (TNBC). However, physicochemical and pharmacokinetic (ED50˜300-600 mg/kg bodyweight) limitations of noscapine present hurdle in development of commercial anticancer formulations. Therefore, objectives of the present review are to summarize the chemotherapeutic potential of noscapine and implications of nanoscale based drug delivery systems in enhancing the therapeutic efficacy of noscapine in cancer cells. We have constructed noscapine-enveloped gelatin nanoparticles, NPs and poly (ethylene glycol) grafted gelatin NPs as well as inclusion complex of noscapine in β-cyclodextrin (β-CD) and evaluated their physicochemical characteristics. The Fe3O4 NPs were also used to incorporate noscapine in its polymeric nanomatrix system where molecular weight of the polymer governed the encapsulation efficiency of drug. The enhanced noscapine delivery using μPAR-targeted optical-MR imaging trackable NPs offer a great potential for image directed targeted delivery of noscapine. Human Serum Albumin NPs (150-300 nm) as efficient noscapine drug delivery systems have also been developed for potential use in breast cancer.

    Topics: Animals; Antineoplastic Agents; Cyclodextrins; Drug Delivery Systems; Humans; Nanoparticles; Neoplasms; Noscapine; Serum Albumin; Tubulin

2012
The anti-cancer activity of noscapine: a review.
    Recent patents on anti-cancer drug discovery, 2009, Volume: 4, Issue:1

    Noscapine is an isoqiunoline alkaloid found in opium latex. Unlike most other alkaloids obtained from opium latex, noscapine is not sedative and has been used as antitussive drug in various countries. Recently, it has been introduced as an anti-mitotic agent. This drug can be used orally. When the resistance to other anti-cancer drugs such as paclitaxel manifests, noscapine might be effective. Therefore, noscapine and its analogs have great potential as novel anti-cancer agents.

    Topics: Animals; Antineoplastic Agents; Apoptosis; Humans; Neoplasms; Noscapine

2009
Recent patents reveal microtubules as persistent promising target for novel drug development for cancers.
    Recent patents on anti-infective drug discovery, 2009, Volume: 4, Issue:3

    Conventionally, the successful targets for the drug development in cancer range from the DNA damage, replication, signal transduction pathways, hormones, cytokines, anti-angiogenic agents, and radio/photo-sensitizers. They dominate the therapeutic arena after the initial debulking surgery. More recently, tubulin, the primary constituent of microtubules (MTs), has made a fairly successful debut in the therapeutic armamentarium. Tubulin binding drugs come in two classes: that depolymerize microtubules and that over-polymerize and bundle them. Microtubule (MT) binding drugs are in some ways superior in nature primarily because of their less debilitating side effects when compared to the generalized DNA metabolism targeting agents, and many new promising patents are being funneled into the drug development pipeline. Nevertheless, many of these relatively new agents still face challenges relating to their delivery methods, bioavailability, toxicities, and the inevitable resistance shared by all chemotherapeutics. Finally, we disclose a new genre of anti-MT drugs, noscapinoids that have just begun climbing the clinical trials ladder. The lead compound, noscapine, is a plant derived, orally available, minimally-toxic (if at all) agent that has shown phenomenal promise in the preclinical experimentation and Phase-I clinical trial. A rational approach based upon the precise molecular model of the tubulin-noscapine complex is bound to inspire novel and better therapeutic analogs in future.

    Topics: Animals; Antineoplastic Agents; Drug Discovery; Humans; Microtubules; Neoplasms; Noscapine; Patents as Topic; Tubulin

2009
Targeting microtubules for cancer chemotherapy.
    Current medicinal chemistry. Anti-cancer agents, 2005, Volume: 5, Issue:1

    Chemical compounds that interfere with microtubules such as the vinca alkaloids and taxanes are important chemotherapeutic agents for the treatment of cancer. As our knowledge of microtubule-targeting drugs increases, we realize that the mechanism underlying the anti-cancer activity of these agents may mainly lie in their inhibitory effects on spindle microtubule dynamics, rather than in their effects on microtubule polymer mass. There is increasing evidence showing that even minor alteration of microtubule dynamics can engage the spindle checkpoint, arresting cell cycle progression at mitosis and eventually leading to apoptotic cell death. The effectiveness of microtubule-targeting drugs for cancer therapy has been impaired by various side effects, notably neurological and hematological toxicities. Drug resistance is another notorious factor that thwarts the effectiveness of these agents, as with many other cancer chemotherapeutics. Several new microtubule-targeting agents have shown potent activity against the proliferation of various cancer cells, including cells that display resistance to the existing microtubule-targeting drugs. Continued investigation of the mechanisms of action of microtubule-targeting drugs, development and discovery of new drugs, and exploring new treatment strategies that reduce side effects and circumvent drug resistance may provide more effective therapeutic options for cancer patients.

    Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Binding Sites; Cell Cycle; Colchicine; Drug Resistance, Neoplasm; Humans; Microtubules; Neoplasms; Noscapine; Taxoids; Tubulin; Vinca Alkaloids

2005

Other Studies

14 other study(ies) available for noscapine and Neoplasms

ArticleYear
Substrate-directed Synthesis of Isocoumarin and 3-Ylidenephthalide Conjugated Noscapinoids and their Antiproliferative Activities.
    Chemistry, an Asian journal, 2023, Jan-17, Volume: 18, Issue:2

    A series of new noscapinoids designed; synthesized and assessed whether its 3-ylidenephthalide and isocoumarin conjugates improved cytotoxicity. Cu-catalysed Sonogashira coupling of N-propargyl noscapine with 2-bromobenzoic acids followed by in-situ substrate-directed 5-exo-dig or 6-endo-dig cyclization produced 3-ylidenephthalide 6 a-6 f and isocoumarin 7 a-7 h analogues in very good yields. In comparison to the lead drug, noscapine, all the newly synthesised derivatives exhibited strong cytotoxic potential in vitro with IC

    Topics: Antineoplastic Agents; Cyclization; Humans; Isocoumarins; Neoplasms; Noscapine

2023
Overcoming P-Glycoprotein-Mediated Drug Resistance with Noscapine Derivatives.
    Drug metabolism and disposition: the biological fate of chemicals, 2019, Volume: 47, Issue:2

    The antitussive agent noscapine has been shown to inhibit the proliferation of cancer cells by disruption of tubulin dynamic. However, the efficacy of several anticancer drugs that inhibit tublin dynamics (vinca alkaloids and taxanes) is reduced by the multidrug resistance phenotype. These compounds are substrates for P-glycoprotein (P-gp)-mediated extrusion from cells. Consequently, the antiproliferative activity of noscapine and a series of derivatives was measured in drug-sensitive and drug-resistant cells that overexpress P-gp. None of the noscapine derivatives displayed lower potency in cells overexpressing P-gp, thereby suggesting a lack of interaction with this pump. However, the cellular efflux of a fluorescent substrate by P-gp was potently inhibited by noscapine and most derivatives. Further investigation with purified, reconstituted P-gp demonstrated that inhibition of P-gp function was due to direct interaction of noscapine derivatives with the transporter. Moreover, coadministration of vinblastine with two of the noscapine derivatives displayed synergistic inhibition of proliferation, even in P-gp-expressing resistant cell lines. Therefore, noscapine derivatives offer a dual benefit of overcoming the significant impact of P-gp in conferring multidrug resistance and synergy with tubulin-disrupting anticancer drugs.

    Topics: Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; MCF-7 Cells; Neoplasms; Noscapine; Papaver; Recombinant Proteins; Tubulin Modulators; Vinblastine

2019
Progress Toward the Development of Noscapine and Derivatives as Anticancer Agents.
    Journal of medicinal chemistry, 2015, Aug-13, Volume: 58, Issue:15

    Many nitrogen-moiety containing alkaloids derived from plant origins are bioactive and play a significant role in human health and emerging medicine. Noscapine, a phthalideisoquinoline alkaloid derived from Papaver somniferum, has been used as a cough suppressant since the mid 1950s, illustrating a good safety profile. Noscapine has since been discovered to arrest cells at mitosis, albeit with moderately weak activity. Immunofluorescence staining of microtubules after 24 h of noscapine exposure at 20 μM elucidated chromosomal abnormalities and the inability of chromosomes to complete congression to the equatorial plane for proper mitotic separation ( Proc. Natl. Acad. Sci. U. S. A. 1998 , 95 , 1601 - 1606 ). A number of noscapine analogues possessing various modifications have been described within the literature and have shown significantly improved antiprolific profiles for a large variety of cancer cell lines. Several semisynthetic antimitotic alkaloids are emerging as possible candidates as novel anticancer therapies. This perspective discusses the advancing understanding of noscapine and related analogues in the fight against malignant disease.

    Topics: Antineoplastic Agents; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Neoplasms; Noscapine

2015
Combination of electrochemistry with chemometrics to introduce an efficient analytical method for simultaneous quantification of five opium alkaloids in complex matrices.
    Talanta, 2015, Volume: 131

    For the first time, an analytical methodology based on differential pulse voltammetry (DPV) at a glassy carbon electrode (GCE) and integration of three efficient strategies including variable selection based on ant colony optimization (ACO), mathematical pre-processing selection by genetic algorithm (GA), and sample selection (SS) through a distance-based procedure to improve partial least squares-1 (PLS-1, ACO-GA-SS-PLS-1) multivariate calibration (MVC) for the simultaneous determination of five opium alkaloids including morphine (MOP), noscapine (NOP), thebaine (TEB), codeine (COD), and papaverine (PAP) was used and validated. The baselines of the DPV signals were modeled as a smooth curve, using P-splines, a combination of B-splines and a discrete roughness penalty. After subtraction of the baseline we got a signal with a two-component probability density. One component was for the peaks and it was approximated by a uniform distribution on the potential axis. The other component was for the observed noise around the baseline. Some sources of bi-linearity deviation for electrochemical data were discussed and analyzed. The lack of bi-linearity was tackled by potential shift correction using correlation optimized warping (COW) algorithm. The MVC model was developed as a quinternary calibration model in a blank human serum sample (drug-free) provided by a healthy volunteer to regard the presence of a strong matrix effect which may be caused by the possible interferents present in the serum, and it was validated and tested with two independent sets of analytes mixtures in the blank and actual human serum samples, respectively. Fortunately, the proposed methodology was successful in simultaneous determination of MOP, NOP, TEB, COD, and PAP in both blank and actual human serum samples and its results were satisfactory comparable to those obtained by applying the reference method based on high performance liquid chromatography-ultraviolet detection (HPLC-UV).

    Topics: Algorithms; Alkaloids; Calibration; Carbon; Chromatography, High Pressure Liquid; Codeine; Electrochemical Techniques; Electrodes; Humans; Least-Squares Analysis; Morphine; Neoplasms; Noscapine; Opium; Papaverine; Thebaine

2015
Non-addictive opium alkaloids selectively induce apoptosis in cancer cells compared to normal cells.
    Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences, 2015, Feb-20, Volume: 23

    Cytotoxic effects of some of the members of papaveraceae family have been reported in Iranian folk medicine. Recent reports has indicated that alkaloids fraction of opium may be responsible for its cytotoxic effect; however, the mechanism of this effect is not fully understood. This study has been designed to investigate the selective cytotoxic, genotoxic and also apoptosis induction effects of noscapine, papaverine and narceine, three non-addictable opium alkaloids, on HT29, T47D and HT1080 cancer cell lines. Mouse NIH3T3 cell line was chosen to present non-cancerous cells and Doxorubicin was selected as the positive control.. Cells were treated by different concentrations of Noscapine, Papaverine, Narceine and doxorubicin; viability was assessed by MTT assay. The genotoxicity and apoptosis induction were tested with comet assay and Annexin-V affinity when the concentration of each these drugs is less than its IC50. In addition, the DNA damage and caspase activity of the T47D cells were examined and the results were compared.. This study noted the cytotoxicity and genotoxicity of noscapine and papaverine, specifically on cancerous cell lines. Furthermore, papaverine induces apoptosis in all studied cancer cell lines and noscapine showed this effect in T47D and HT29 cells but not in NIH-3 T3 cells as noncancerous cell line. narceine also showed genototoxicity in the studied cell lines at its IC50 concentration.. This experiment suggests that noscapine and papaverine may be of use in cancer treatment due to their specific cytotoxicity and genotoxicity. However, further in vivo studies are needed to confirm its usefulness in cancer treatment.

    Topics: Animals; Antineoplastic Agents; Apoptosis; Benzodioxoles; Cell Line, Tumor; Cell Proliferation; DNA, Neoplasm; Doxorubicin; HT29 Cells; Humans; Indole Alkaloids; Mice; Neoplasms; NIH 3T3 Cells; Noscapine; Opiate Alkaloids; Papaverine

2015
The synthesis and biological evaluation of multifunctionalised derivatives of noscapine as cytotoxic agents.
    ChemMedChem, 2014, Volume: 9, Issue:2

    Noscapine, a phthalideisoquinoline alkaloid derived from Papaver somniferum, is a well-known antitussive drug that has a relatively safe in vitro toxicity profile. Noscapine is also known to possess weak anticancer efficacy, and since its discovery, efforts have been made to design derivatives with improved potency. Herein, the synthesis of a series of noscapine analogues, which have been modified in the 6', 9', 1 and 7-positions, is described. In a previous study, replacement of the naturally occurring N-methyl group in the 6'-position with an N-ethylaminocarbonyl was shown to promote cell-cycle arrest and cytotoxicity against three cancer cell lines. Here, this modification has been combined with other structural changes that have previously been shown to improve anticancer activity, namely halo substitution in the 9'-position, regioselective O-demethylation to reveal a free phenol in the 7-position, and reduction of the lactone to the corresponding cyclic ether in the 1-position. The incorporation of new aryl substituents in the 9'-position was also investigated. The study identified interesting new compounds able to induce G2/M cell-cycle arrest and that possess cytotoxic activity against the human prostate carcinoma cell line PC3, the human breast adenocarcinoma cell line MCF-7, and the human pancreatic epithelioid carcinoma cell line PANC-1. In particular, the ethyl urea cyclic ether noscapinoids and a compound containing a 6'-ethylaminocarbonyl along with 9'-chloro, 7-hydroxy and lactone moieties exhibited the most promising biological activities, with EC50 values in the low micromolar range against all three cancer cell lines, and these derivatives warrant further investigation.

    Topics: Antineoplastic Agents, Phytogenic; Cell Cycle; Cell Line, Tumor; Female; Humans; Male; Neoplasms; Noscapine; Papaver; Structure-Activity Relationship

2014
Antifibrotic effects of noscapine through activation of prostaglandin E2 receptors and protein kinase A.
    The Journal of biological chemistry, 2014, Mar-14, Volume: 289, Issue:11

    Myofibroblast differentiation is a key process in the pathogenesis of fibrotic disease. We have shown previously that differentiation of myofibroblasts is regulated by microtubule polymerization state. In this work, we examined the potential antifibrotic effects of the antitussive drug, noscapine, recently found to bind microtubules and affect microtubule dynamics. Noscapine inhibited TGF-β-induced differentiation of cultured human lung fibroblasts (HLFs). Therapeutic noscapine treatment resulted in a significant attenuation of pulmonary fibrosis in the bleomycin model of the disease. Noscapine did not affect gross microtubule content in HLFs, but inhibited TGF-β-induced stress fiber formation and activation of serum response factor without affecting Smad signaling. Furthermore, noscapine stimulated a rapid and profound activation of protein kinase A (PKA), which mediated the antifibrotic effect of noscapine in HLFs, as assessed with the PKA inhibitor, PKI. In contrast, noscapine did not activate PKA in human bronchial or alveolar epithelial cells. Finally, activation of PKA and the antifibrotic effect of noscapine in HLFs were blocked by the EP2 prostaglandin E2 receptor antagonist, PF-04418948, but not by the antagonists of EP4, prostaglandin D2, or prostacyclin receptors. Together, we demonstrate for the first time the antifibrotic effect of noscapine in vitro and in vivo, and we describe a novel mechanism of noscapine action through EP2 prostaglandin E2 receptor-mediated activation of PKA in pulmonary fibroblasts.

    Topics: Animals; Antineoplastic Agents; Antitussive Agents; Bleomycin; Cell Line, Tumor; Cyclic AMP-Dependent Protein Kinases; DNA; Fibroblasts; Fibrosis; Gene Expression Regulation; Humans; Hydroxyproline; Luciferases; Lung; Mice; Mice, Inbred C57BL; Microtubules; Myofibroblasts; Neoplasms; Noscapine; Pulmonary Fibrosis; Receptors, Prostaglandin E

2014
Molecular insight of isotypes specific β-tubulin interaction of tubulin heterodimer with noscapinoids.
    Journal of computer-aided molecular design, 2014, Volume: 28, Issue:7

    Noscapine and its derivatives bind stoichiometrically to tubulin, alter its dynamic instability and thus effectively inhibit the cellular proliferation of a wide variety of cancer cells including many drug-resistant variants. The tubulin molecule is composed of α- and β-tubulin, which exist as various isotypes whose distribution and drug-binding properties are significantly different. Although the noscapinoids bind to a site overlapping with colchicine, their interaction is more biased towards β-tubulin. In fact, their precise interaction and binding affinity with specific isotypes of β-tubulin in the αβ-heterodimer has never been addressed. In this study, the binding affinity of a panel of noscapinoids with each type of tubulin was investigated computationally. We found that the binding score of a specific noscapinoid with each type of tubulin isotype is different. Specifically, amino-noscapine has the highest binding score of -6.4, -7.2, -7.4 and -7.3 kcal/mol with αβI, αβII, αβIII and αβIV isotypes, respectively. Similarly 10 showed higher binding affinity of -6.8 kcal/mol with αβV, whereas 8 had the highest binding affinity of -7.2, -7.1 and -7.2 kcal/mol, respectively with αβVI, αβVII and αβVIII isotypes. More importantly, both amino-noscapine and its clinical derivative, bromo-noscapine have the highest binding affinity of -46.2 and -38.1 kcal/mol against αβIII (overexpression of αβIII has been associated with resistance to a wide range of chemotherapeutic drugs for several human malignancies) as measured using MM-PBSA. Knowledge of the isotype specificity of the noscapinoids may allow for development of novel therapeutic agents based on this class of drugs.

    Topics: Binding Sites; Cell Proliferation; Colchicine; Humans; Neoplasms; Noscapine; Protein Binding; Protein Isoforms; Protein Multimerization; Tubulin

2014
Rational design, synthesis, and biological evaluation of third generation α-noscapine analogues as potent tubulin binding anti-cancer agents.
    PloS one, 2013, Volume: 8, Issue:10

    Systematic screening based on structural similarity of drugs such as colchicine and podophyllotoxin led to identification of noscapine, a microtubule-targeted agent that attenuates the dynamic instability of microtubules without affecting the total polymer mass of microtubules. We report a new generation of noscapine derivatives as potential tubulin binding anti-cancer agents. Molecular modeling experiments of these derivatives 5a, 6a-j yielded better docking score (-7.252 to -5.402 kCal/mol) than the parent compound, noscapine (-5.505 kCal/mol) and its existing derivatives (-5.563 to -6.412 kCal/mol). Free energy (ΔG bind ) calculations based on the linear interaction energy (LIE) empirical equation utilizing Surface Generalized Born (SGB) continuum solvent model predicted the tubulin-binding affinities for the derivatives 5a, 6a-j (ranging from -4.923 to -6.189 kCal/mol). Compound 6f showed highest binding affinity to tubulin (-6.189 kCal/mol). The experimental evaluation of these compounds corroborated with theoretical studies. N-(3-brormobenzyl) noscapine (6f) binds tubulin with highest binding affinity (KD, 38 ± 4.0 µM), which is ~ 4.0 times higher than that of the parent compound, noscapine (KD, 144 ± 1.0 µM) and is also more potent than that of the first generation clinical candidate EM011, 9-bromonoscapine (KD, 54 ± 9.1 µM). All these compounds exhibited substantial cytotoxicity toward cancer cells, with IC50 values ranging from 6.7 µM to 72.9 µM; compound 6f showed prominent anti-cancer efficacy with IC50 values ranging from 6.7 µM to 26.9 µM in cancer cells of different tissues of origin. These compounds perturbed DNA synthesis, delayed the cell cycle progression at G2/M phase, and induced apoptotic cell death in cancer cells. Collectively, the study reported here identified potent, third generation noscapinoids as new anti-cancer agents.

    Topics: Antineoplastic Agents; Apoptosis; Cell Division; Cell Proliferation; Crystallography, X-Ray; Drug Design; G2 Phase; Humans; Magnetic Resonance Spectroscopy; Models, Molecular; Neoplasms; Noscapine; Protein Binding; Tubulin; Tumor Cells, Cultured

2013
In silico inspired design and synthesis of a novel tubulin-binding anti-cancer drug: folate conjugated noscapine (Targetin).
    Journal of computer-aided molecular design, 2012, Volume: 26, Issue:2

    Our screen for tubulin-binding small molecules that do not depolymerize bulk cellular microtubules, but based upon structural features of well known microtubule-depolymerizing colchicine and podophyllotoxin, revealed tubulin binding anti-cancer property of noscapine (Ye et al. in Proc Natl Acad Sci USA 95:2280-2286, 1998). Guided by molecular modelling calculations and structure-activity relationships we conjugated at C9 of noscapine, a folate group-a ligand for cellular folate receptor alpha (FRα). FRα is over-expressed on some solid tumours such as ovarian epithelial cancers. Molecular docking experiments predicted that a folate conjugated noscapine (Targetin) accommodated well inside the binding cavity (docking score -11.295 kcal/mol) at the interface between α- and β-tubulin. The bulky folate moiety of Targetin is extended toward lumen of microtubules. The binding free energy (ΔG (bind)) computed based on molecular mechanics energy minimization was -221.01 kcal/mol that revealed favourable interaction of Targetin with the receptor. Chemical synthesis, tubulin-binding experiments, and anti-cancer activity in vitro corroborate fully well with the molecular modelling experiments. Targetin binds tubulin with a dissociation constant (K (d) value) of 149 ± 3.0 μM and decreases the transition frequencies between growth and shortening phases of microtubule assembly dynamics at concentrations that do not alter the total polymer mass. Cancer cells in general were more sensitive to Targetin compared with the founding compound noscapine (IC(50) in the range of 15-40 μM). Quite strikingly, ovarian cancer cells (SKOV3 and A2780), known to overexpress FRα, were much more sensitive to targetin (IC(50) in the range of 0.3-1.5 μM).

    Topics: Anticarcinogenic Agents; Binding Sites; Cell Line, Tumor; Cell Proliferation; Computer Simulation; Folate Receptor 1; Folic Acid; Gene Expression Regulation, Neoplastic; Humans; Ligands; Microtubules; Models, Molecular; Neoplasms; Noscapine; Protein Binding; Protein Conformation; Structure-Activity Relationship; Tubulin

2012
Synthesis and biological evaluation of N-substituted noscapine analogues.
    ChemMedChem, 2012, Volume: 7, Issue:12

    Noscapine is a phthalideisoquinoline alkaloid isolated from the opium poppy Papaver somniferum. It has long been used as an antitussive agent, but has more recently been found to possess microtubule-modulating properties and anticancer activity. Herein we report the synthesis and pharmacological evaluation of a series of 6'-substituted noscapine derivatives. To underpin this structure-activity study, an efficient synthesis of N-nornoscapine and its subsequent reduction to the cyclic ether derivative of N-nornoscapine was developed. Reaction of the latter with a range of alkyl halides, acid chlorides, isocyanates, thioisocyanates, and chloroformate reagents resulted in the formation of the corresponding N-alkyl, N-acyl, N-carbamoyl, N-thiocarbamoyl, and N-carbamate derivatives, respectively. The ability of these compounds to inhibit cell proliferation was assessed in cell-cycle cytotoxicity assays using prostate cancer (PC3), breast cancer (MCF-7), and colon cancer (Caco-2) cell lines. Compounds that showed activity in the cell-cycle assay were further evaluated in cell viability assays using PC3 and MCF-7 cells.

    Topics: Antineoplastic Agents, Phytogenic; Antitussive Agents; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Humans; Neoplasms; Noscapine; Papaver

2012
Molecular modelling and competition binding study of Br-noscapine and colchicine provide insight into noscapinoid-tubulin binding site.
    Journal of molecular graphics & modelling, 2011, Volume: 29, Issue:7

    We have previously discovered the tubulin-binding anti-cancer properties of noscapine and its derivatives (noscapinoids). Here, we present three lines of evidence that noscapinoids bind at or near the well studied colchicine binding site of tubulin: (1) in silico molecular docking studies of Br-noscapine and noscapine yield highest docking score with the well characterised colchicine-binding site from the co-crystal structure; (2) the molecular mechanics-generalized Born/surface area (MM-GB/SA) scoring results ΔΔG(bind-cald) for both noscapine and Br-noscapine (3.915 and 3.025 kcal/mol) are in reasonably good agreement with our experimentally determined binding affinity (ΔΔG(bind-Expt) of 3.570 and 2.988 kcal/mol, derived from K(d) values); and (3) Br-noscapine competes with colchicine binding to tubulin. The simplest interpretation of these collective data is that Br-noscapine binds tubulin at a site overlapping with, or very close to colchicine-binding site of tubulin. Although we cannot rule out a formal possibility that Br-noscapine might bind to a site distinct and distant from the colchicine-binding site that might negatively influence the colchicine binding to tubulin.

    Topics: Animals; Antineoplastic Agents; Antitussive Agents; Binding Sites; Colchicine; Goats; Humans; Models, Chemical; Molecular Dynamics Simulation; Molecular Structure; Neoplasms; Noscapine; Protein Conformation; Tubulin

2011
Determination of noscapine's localization and interaction with the tubulin-α/β heterodimer.
    Chemical biology & drug design, 2011, Volume: 78, Issue:4

    Noscapine, the benzylisoquinoline alkaloid, 5-(4,5-Dimethoxy-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-6-ium, has been extensively used as a cough-suppressing medication with low toxicity. It has been recently shown to also have anti-cancer activity in mice and humans. In this work, using in silico analyses, the most probable binding site for noscapine is identified to be at the intradimer region of the α and β subunits of the tubulin heterodimer. By utilization of small molecule docking techniques, and an analysis of the thermodynamically favorable binding modes of noscapine in its binding site, the key residues of tubulin monomers interacting with noscapine are determined. Upon noscapine binding, the conformational change in the tubulin heterodimer along with a potential long-range allosteric effect on both the N and E sites is studied by means of molecular dynamics simulations. Noscapine is found to function as a tubulin-stabilizing agent that interacts strongest with the lateral and longitudinal segments of the tubulin dimer, impacting the interaction between monomers in neighboring protofilaments. We infer that this may act as a depolymerization inhibitor of microtubules. As a result of this study, we have designed novel analogues of noscapine with the ultimate goal of finding agents with increased anti-tumor activity and lower inhibitory concentrations than that of noscapine.

    Topics: Antineoplastic Agents; Antitussive Agents; Binding Sites; Humans; Models, Molecular; Neoplasms; Noscapine; Protein Binding; Protein Multimerization; Tubulin

2011
[Chemotherapy of cancer. I. 2,3-Dichloro-4-(2,3,4-trimethoxyphenyl)-crotonic acid gamma-lactone 2,3-dichloro-4-(p-methoxyphenyl)-crotonic acid gamma-lactone].
    Casopis lekaru ceskych, 1954, Feb-19, Volume: 93, Issue:8

    Topics: Acids; Crotonates; Humans; Lactones; Neoplasms; Noscapine

1954