oxadiazoles and Neoplasms

Cancer is reported to be one of the most life-threatening diseases. Major limitations of currently used anticancer agents are drug resistance, very small therapeutic index, and severe, multiple side effects.. The current scenario necessitates developing new anticancer agents, acting on novel targets for effectively controlling cancer. The epidermal growth factor receptor is one such target, which is being explored for 1,3,4-oxadiazole and chalcone nuclei.. Findings of different researchers working on these scaffolds have been reviewed and analyzed, and the outcomes were summarized. This review focuses on Structure-Activity Relationship studies (SARs) and computational studies of various 1,3,4-oxadiazole and chalcone hybrids/ derivatives reported as cytotoxic/EGFR-TK inhibitory anticancer activity.. 1,3,4-oxadiazole and chalcone hybrids/derivatives with varied substitutions are found to be effective pharmacophores in obtaining potent anticancer activity. Having done a thorough literature survey, we conclude that this review will surely provide firm and better insights to the researchers to design and develop potent hybrids/derivatives that inhibit EGFR.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Chalcone; Drug Design; Drug Screening Assays, Antitumor; ErbB Receptors; Humans; Molecular Structure; Neoplasms; Oxadiazoles; Structure-Activity Relationship

Cancer is the first or second leading cause of premature death in 134 of 183 countries in the world. 1,3,4-Oxadiazoles are five membered heterocyclic rings containing nitrogen (two atoms) and oxygen (one atom). They show better thermal stability, metabolic stability, aqueous solubility, and lower lipophilicity than the other isomeric oxadiazoles. They are important class of heterocycles present in many drug structures like Raltegravir, Furamizole Tidazosin, Nesapidil, Setileuton (MK-0633) and Zibotentan. The presence of this nucleus in therapeutics has made them an indispensable anchor for drug design and development. Several 1,3,4-oxadiazoles are prepared and reported as anticancer agents by numerous scientists worldwide.. The present review discusses the anticancer potentials together with the molecular targets of 1,3,4-oxadiazoles reported since 2010. The Structure-Activity Relationship (SAR) and molecular docking simulation on different targets have also been discussed herein. Some of the important cancer targets have also been explored.. The most potent 1,3,4-oxadiazoles reported in the literature were highlighted in the manuscript. The anticancer activity was reported in terms of Growth Percent (GP), percent growth inhibition (%GI), GI. 1,3,4-Oxadiazoles are important heterocyclic scaffolds with broad spectrum biological activities. They may be either mono substituted or disubstituted, and they may act as an indispensable anchor for drug design and discovery due to their thermal stability together with low lipophilicity. They exhibited anticancer potentials and showed the inhibitions of various cancer targets.. The discussion outlined herein will prove to be a helpful and vital tool for medicinal chemists investigating and working with 1,3,4-oxadiazoles and anticancer research programs.

Topics: Antineoplastic Agents; Drug Design; Humans; Molecular Docking Simulation; Molecular Structure; Neoplasms; Oxadiazoles; Structure-Activity Relationship

The 1,3,4-oxadiazole nucleus is a biologically imperative scaffold possesses numerous biological activities. The broad and potent activity of 1,3,4-oxadiazole and their derivatives has established them as important pharmacological scaffolds especially in the treatment of cancer disease. Several di-, tri-, aromatic, and heterocyclic substituted 1,3,4-oxadiazole derivatives have been reported to possess potent anticancer activity. These substituted 1,3,4-oxadiazoles had shown different mechanism of action and participated in anticancer drug discovery and development. This review is complementary to earlier reviews and aims to review the work reported on anticancer activities of 1,3,4-oxadiazole derivatives from year 2000 to the beginning of 2020.

Topics: Antineoplastic Agents; Cell Survival; Drug Evaluation, Preclinical; Histone Deacetylases; Humans; Neoplasms; Oxadiazoles; Structure-Activity Relationship; Tubulin; Tubulin Modulators

Nowadays, an increasing number of heterocyclic-based drugs found application in medicinal chemistry and, in particular, as anticancer agents. In this context, oxadiazoles-five-membered aromatic rings-emerged for their interesting biological properties. Modification of oxadiazole scaffolds represents a valid strategy to increase their anticancer activity, especially on 1,2,4 and 1,3,4 regioisomers. In the last years, an increasing number of oxadiazole derivatives, with remarkable cytotoxicity for several tumor lines, were identified. Structural modifications, that ensure higher cytotoxicity towards malignant cells, represent a solid starting point in the development of novel oxadiazole-based drugs. To increase the specificity of this strategy, outstanding oxadiazole scaffolds have been designed to selectively interact with biological targets, including enzymes, globular proteins, and nucleic acids, showing more promising antitumor effects. In the present work, we aim to provide a comprehensive overview of the anticancer activity of these heterocycles, describing their effect on different targets and highlighting how their structural versatility has been exploited to modulate their biological properties.

Topics: Antineoplastic Agents; Cytotoxins; Drug Design; Humans; Neoplasms; Oxadiazoles

The combination of inhibitor of oxidative phosphorylation (OXPHOS) with dimethyl-α-ketoglutarate, a cell-permeable precursor of α-ketoglutarate, is highly efficient in killing human cancer cells in vitro or in vivo, in xenotransplanted mice. This effect involves excessive anaplerosis, as demonstrated by the fact that inhibition of isocitrate dehydrogenase-1, IDH1, reduced the efficacy of cancer cell killing by the combination treatment. However, the signal transduction pathway leading to cell death turned out to be complex because it involved numerous atypical cell death effectors (such as AIF, APEX, MDM2, PARP1), as well as a profound remodeling of the transcriptome resulting in reduced expression of glycolytic enzymes. The combined inhibition of OXPHOS and glycolytic ATP generation culminated in a lethal bioenergetic catastrophe.

Topics: Animals; Antineoplastic Agents; Autophagy; Carcinogenesis; Drug Delivery Systems; Drug Synergism; Energy Metabolism; Humans; Ketoglutaric Acids; Mice; Neoplasms; Oxadiazoles; Oxidative Phosphorylation; Pyrazoles; Tumor Cells, Cultured; Tumor Microenvironment

Cancer is a rapidly growing disease of current era which poses a major life threaten situation to human beings. Continuous research is going on in the direction to develop effective molecules for the treatment of the cancer. These efforts include searching of more active heterocyclic compounds possessing potential anticancer activity. The 1,3,4-Oxadiazole scaffold is a five member heterocyclic ring having versatile activities and created interest for synthetic organic and medicinal chemists for the designing of novel compounds having anticancer activity. The important mechanism behind tumor suppression by 1,3,4-Oxadiazole is related with the inhibition of different growth factors, enzymes and kinases etc. The current literature surveys revealed that 1,3,4-Oxadiazole is a promising lead for anti-cancer agents by the inhibition of telomerase activity. In cancerous cells telomerase enzyme is activated which maintains and restores the telomere which leads to cell proliferation. The telomerase inhibitors with enhanced specificity and improved pharmacokinetics have been considered for design and development of novel anti-cancer agents. This review focuses primarily on telomerase enzyme its function and mechanism of action. It also describes the interaction of telomerase enzyme with 1,3,4-Oxadiazole inhibitors including their structure activity relationships (SARs). With the knowledge of this molecular target, structural insights and SARs, this review may be helpful for (medicinal) chemists to design more potent, safe, selective and cost effective anti-cancer agents.

Topics: Animals; Antineoplastic Agents; Cell Proliferation; Enzyme Inhibitors; Humans; Molecular Structure; Neoplasms; Oxadiazoles; Telomerase

The 7-nitro-2,1,3-nitrobenzoxadiazole (NBD) derivatives are a series of compounds containing the NBD scaffold that are not glutathione (GSH) peptidomimetics, and result in a strong inhibition of glutathione S-transferases (GSTs). Growing evidences highlight their pivotal roles and outstanding anticancer activity in different tumor models. In particular, 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio) hexanol (NBDHEX) is extensively studied, which is a very efficient inhibitor of GSTP1-1. It triggers apoptosis in several tumor cell lines and this cytotoxic activity is observed at micro and submicromolar concentrations. Importantly, studies have shown that NBDHEX acts as an anticancer drug by inhibiting GSTs catalytic activity, avoiding inconvenience of the inhibitor extrusion from the cell by specific pumps and disrupting the interaction between the GSTP1-1 and key signaling effectors. Additionally, some researchers also have discovered that NBDHEX can act as late-phase autophagy inhibitor, which opens new opportunities to fully exploit its therapeutic potential. In this review, we summarize the advantages, anticancer mechanisms, and analogs of this compound, which will establish the basis on the usage of NBDHEX in clinical applications in future.

Topics: Antineoplastic Agents; Apoptosis; Azoles; Drug Resistance, Neoplasm; Glutathione S-Transferase pi; Hexanols; Humans; Neoplasms; Nitrobenzenes; Oxadiazoles

Compounds containing 1,3,4-oxadiazole ring in their structure are characterised by multidirectional biological activity. Their anti-proliferative effects associated with various mechanisms, such as inhibition of growth factors, enzymes, kinases and others, deserve attention. The activity of these compounds was tested on cell lines of various cancers. In most publications, the most active derivatives of 1,3,4-oxadiazole exceeded the effect of reference drugs, so they may become the main new anti-cancer drugs in the future.

Topics: Animals; Antineoplastic Agents; Cell Proliferation; Humans; Molecular Structure; Neoplasms; Oxadiazoles; Structure-Activity Relationship

In the last few years, a number of important clinical trials have been completed that have investigated the inhibition of the renin-angiotensin system. New drugs, focusing on this system, have now emerged as a result.. The authors review the most relevant information available, reported from the last 5 years, pertaining to the most important clinical trials on renin-angiotensin system blockers (ARBs). The authors' data review includes the trials of aliskiren, telmisartan, olmesartan and azilsartan. The authors also review the possible risk of cancer with ARBs.. The results of ASPIRE and ALTITUDE trials strongly suggested that dual inhibition of aliskiren with either ARBS or angiotensin converting enzyme inhibitors (ACEi) should be avoided. Olmesartan is an effective and safe antihypertensive agent, but special attention should be paid to high-risk patients, such as those with coronary disease, to avoid an excessive reduction in blood pressure. The authors also note that while azilsartan is probably the most potent ARB, there is still a lack of data regarding potential organ damage and the incidence of cardiovascular events. Lastly, recent evidence has shown a lack of a relationship between ARB therapy and the occurrence of cancer.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Blood Pressure; Clinical Trials as Topic; Drug Evaluation; Fumarates; Humans; Imidazoles; Meta-Analysis as Topic; Neoplasms; Oxadiazoles; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Risk Factors; Telmisartan; Tetrazoles

Akt (also known as protein kinase B or PKB) comprises three closely related isoforms Akt1, Akt2 and Akt3 (or PKBα/β/γ respectively). We have a very good understanding of the mechanisms by which Akt isoforms are activated by growth factors and other extracellular stimuli as well as by oncogenic mutations in key upstream regulatory proteins including Ras, PI3-kinase subunits and PTEN. There are also an ever increasing number of Akt substrates being identified that play a role in the regulation of the diverse array of biological effects of activated Akt; this includes the regulation of cell proliferation, survival and metabolism. Dysregulation of Akt leads to diseases of major unmet medical need such as cancer, diabetes, cardiovascular and neurological diseases. As a result there has been substantial investment in the development of small molecular Akt inhibitors that act competitively with ATP or phospholipid binding, or allosterically. In this review we will briefly discuss our current understanding of how Akt isoforms are regulated, the substrate proteins they phosphorylate and how this integrates with the role of Akt in disease. We will furthermore discuss the types of Akt inhibitors that have been developed and are in clinical trials for human cancer, as well as speculate on potential on-target toxicities, such as disturbances of heart and vascular function, metabolism, memory and mood, which should be monitored very carefully during clinical trial.

Topics: Binding Sites; Cardiovascular Diseases; Cell Proliferation; Diabetes Mellitus; Enzyme Activation; Gene Expression Regulation, Enzymologic; Humans; Molecular Structure; Neoplasms; Nervous System Diseases; Oxadiazoles; Phosphorylation; Protein Isoforms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; Transcription Factors

Topics: Analgesics; Animals; Anticonvulsants; Bacteria; Barbiturates; Central Nervous System Stimulants; Diuretics; Drug Synergism; Imines; In Vitro Techniques; Mice; Muscles; Neoplasms; Oxadiazoles; Plasmodium

Topics: Adult; Aged; Antitussive Agents; Asthma; Bronchitis; Child; Clinical Trials as Topic; Cough; Evaluation Studies as Topic; Humans; Infant; Infant, Newborn; Neoplasms; Oxadiazoles; Pneumonia; Tuberculosis, Pulmonary

The spatiotemporal distribution of therapeutic agents in tumors remains an essential challenge of radiation-mediated therapy. Herein, we rationally designed a macrophage microvesicle-inspired nanovehicle of nitric oxide donor-oxaliplatin (FO) conjugate (M-PFO), aiming to promote intratumor permeation and distribution profiles for chemo-radiotherapy. FO was responsively released from M-PFO in intracellular acidic environments, and then be activated by glutathione (GSH) into active oxaliplatin and NO molecules in a programmed manner. M-PFO exhibited notable accumulation, permeation and cancer cell accessibility in tumor tissues. Upon radiation, the reactive peroxynitrite species (ONOO

Topics: Cell Line, Tumor; Chemoradiotherapy; Glutathione; Humans; Neoplasms; Oxadiazoles; Oxaliplatin; Reactive Oxygen Species

In this work, BTEAC (benzyl triethylammonium chloride) was employed as a phase transfer catalyst in an improved synthesis (up to 88% yield) of S-alkylated bromobenzofuran-oxadiazole scaffolds

Topics: Antineoplastic Agents; Catalysis; Cell Line, Tumor; Cell Proliferation; ErbB Receptors; Glycogen Synthase Kinase 3 beta; Humans; Molecular Docking Simulation; Molecular Structure; Neoplasms; Oxadiazoles; Phosphatidylinositol 3-Kinases; Structure-Activity Relationship; TOR Serine-Threonine Kinases; Tubulin; Ultrasonics

Topics: Antineoplastic Agents; Doxorubicin; Humans; Indoles; Molecular Docking Simulation; Neoplasms; Oxadiazoles; Proto-Oncogene Proteins c-mdm2; Tumor Suppressor Protein p53

Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family mainly targeting cytosolic nonhistone substrates, such as α-tubulin, cortactin, and heat shock protein 90 to regulate cell proliferation, metastasis, invasion, and mitosis in tumors. We describe the identification and characterization of a series of 2-(difluoromethyl)-1,3,4-oxadiazoles (DFMOs) as selective nonhydroxamic acid HDAC6 inhibitors. By comparing structure-activity relationships and performing quantum mechanical calculations of the HDAC6 catalytic mechanism, we show that potent oxadiazoles are electrophilic substrates of HDAC6 and propose a mechanism for the bioactivation. We also observe that the inherent electrophilicity of the oxadiazoles makes them prone to degradation in water solution and the generation of potentially toxic products cannot be ruled out, limiting the developability for chronic diseases. However, the oxadiazoles demonstrate high oral bioavailability and low in vivo clearance and are excellent tools for studying the role of HDAC6 in vitro and in vivo in rats and mice.

Topics: Animals; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Mice; Neoplasms; Oxadiazoles; Rats; Tubulin

The infiltration of cytotoxic T lymphocytes (CTLs) in tumors is critically challenged by the intricate intratumor physical barriers, which is emerging as an important issue of anticancer immunotherapy. Herein, a reduction-sensitive nitric oxide donor conjugate of furoxans-oxaliplatin is synthesized and a stroma-cell-accessible bioinspired lipoprotein system (S-LFO) is designed, aiming to facilitate CTL infiltration in tumors for anticancer immunotherapy. S-LFO treatment significantly promotes tumor vessel normalization and eliminates multiple components of tumor stroma, ultimately producing a 2.96-fold, 5.02-fold, and 8.65-fold increase of CD3

Topics: Animals; CD8-Positive T-Lymphocytes; Immunotherapy; Lipoproteins; Mice; Neoplasms; Oxadiazoles; Oxaliplatin

Ultrasound- and microwave-assisted green synthetic strategies were applied to furnish benzofuran-oxadiazole

Topics: A549 Cells; Antineoplastic Agents; Benzofurans; Cell Survival; Chemistry Techniques, Synthetic; Hemolysis; Humans; Microwaves; Molecular Docking Simulation; Neoplasms; Oxadiazoles; Triazoles

Prostate and bladder cancers are commonly diagnosed malignancies in men. Several nitric oxide donor compounds with strong antitumor activity have been reported. Thus, continuing with our efforts to explore the chemical space around bioactive furoxan moiety, multicomponent reactions were employed for the rapid generation of molecular diversity and complexity. We herein report the use of Ugi and Groebke-Blackburn-Bienaymé multicomponent reactions under efficient, safe, and environmentally friendly conditions to synthesize a small collection of nitric-oxide-releasing molecules. The in vitro antiproliferative activity of the synthesized compounds was measured against two different human cancer cell lines, LNCaP (prostate) and T24 (bladder). Almost all compounds displayed antiproliferative activity against both cancer cell lines, providing lead compounds with nanomolar GI

Topics: Humans; Neoplasms; Nitric Oxide; Nitric Oxide Donors; Oxadiazoles

GRPR is over-expressed in cancer cells and is a potential drug target for the treatment of cancer. PD176252, as the most representative non-peptide inhibitor of GRPR, can inhibit the growth of cancer cells, but its low selectivity to cancer cells and normal cells limits its further application.. The aim of this study was to design and synthesize novel GRPR inhibitor with stronger anti-cancer activity and higher affinity with GRPR than the lead compound PD176252.. A series of 1, 3, 4-oxadiazole derivatives as PD176252 analogues (4a-4j, 6a-6q) were synthesized and their cytotoxic activity was investigated on four cancer lines with high expression of GRPR (gastric (HGC-27), colon (HCT- 116), prostate (PC-3), and lung (A549)) and one human cell line (gastric mucosal epithelial (GES-1)) by MTT assay. Flow cytometry analysis and Western Blot were used to determine whether the compound induced programmed apoptosis of cancer cells. Competitive binding experiment was used to verify the affinity between GRPR and the optimal compound.. Compound 6m exhibited significant growth inhibition on all tested cancer cell lines, especially gastric cancer cells (HGC-27 cellular IC. Our results suggested that 6m, as a novel GRPR inhibitor, had a higher affinity with GRPR and potential anti-cancer effect than PD176252, which can be used as a template for further optimization.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Indoles; Male; Neoplasms; Oxadiazoles

Two unknown 1,2,4-oxadiazoles (3-(pyridin-3-yl)-5-(thiophen-3-yl)-1,2,4-oxadiazole and 5-(3-hydroxyphenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole) and one known 1,2,4-oxadiazole (5-(3-methoxyphenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole) were isolated from tubers of Neowerdermannia vorwerkii, collected from the San Juan Huancollo, Ingavi province, La Paz, Bolivia. The chemical structures of these compounds were elucidated through NMR and HRMS spectroscopic analyses. All compounds showed apoptotic capacity against the SK-HEP-1 and Caco-2 tumour cells. 5-(3-methoxyphenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole and 5-(3-hydroxyphenyl)-3-(pyridin-3-yl)-1,2, 4-oxadiazole showed slight apoptotic capacities, with an IC

Topics: Caco-2 Cells; Colon; Humans; Liver; Magnetic Resonance Spectroscopy; Neoplasms; Oxadiazoles; Structure-Activity Relationship

To understand whether previously synthesized novel hydrazone and oxadiazole derivatives have promising anticancer effects, docking studies and in vitro toxicity assays were performed on A-549, MDA-MB-231, and PC-3 cell lines. The antiproliferative properties of the compounds were investigated using molecular docking experiments. Each compound's best-docked poses, binding affinity, and receptor-ligand interaction were evaluated. Compounds' molecular weights, logPs, TPSAs, abilities to pass the blood-brain barrier, GI absorption qualities, and CYPP450 inhibition have been given. When the activities of these molecules were examined in vitro, for the A-549 cell line, hydrazone

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Hydrazones; Molecular Docking Simulation; Molecular Structure; Neoplasms; Oxadiazoles; Structure-Activity Relationship

Topics: Acyclovir; Antineoplastic Agents; Antiviral Agents; Apoptosis; Caspase 3; Cell Line, Tumor; Herpesvirus 3, Human; Humans; Molecular Docking Simulation; Neoplasms; Oxadiazoles; Pyrimidines; Structure-Activity Relationship

The small molecule IACS-010759 has been reported to potently inhibit the proliferation of glycolysis-deficient hypoxic tumor cells by interfering with the functions of mitochondrial NADH-ubiquinone oxidoreductase (complex I) without exhibiting cytotoxicity at tolerated doses in normal cells. Considering the significant cytotoxicity of conventional quinone-site inhibitors of complex I, such as piericidin and acetogenin families, we hypothesized that the mechanism of action of IACS-010759 on complex I differs from that of other known quinone-site inhibitors. To test this possibility, here we investigated IACS-010759's mechanism in bovine heart submitochondrial particles. We found that IACS-010759, like known quinone-site inhibitors, suppresses chemical modification by the tosyl reagent AL1 of Asp

Topics: Animals; Cattle; Cell Hypoxia; Electron Transport Complex I; Glycolysis; Humans; Mitochondria, Heart; Neoplasm Proteins; Neoplasms; Oxadiazoles; Piperidines

Various tetrazole and oxadiazole C-nucleoside analogues were synthesized starting from pure α- or β-glycosyl-cyanide. The synthesis of glycosyl-cyanide as key precursor was optimized on gram-scale to furnish crystalline starting material for the assembly of C-nucleosides. Oxadizole C-nucleosides were synthesized via two independent routes. First,  the glycosyl-cyanide was converted into an amidoxime which upon ring closure offered an alternative pathway for the assembly of 1,2,4-oxadizoles in an efficient manner. Second, both anomers of glycosyl-cyanide were transformed into tetrazole nucleosides followed by acylative rearrangement to furnish 1,3,4-oxadiazoles in high yields. These protocols offer an easy access to otherwise difficult to synthesize C-nucleosides in good yield and protecting group compatibility. These C-nucleosides were evaluated for their antitumor activity. This work paves a path for facile assembly of library of new chemical entities useful for drug discovery.

Topics: Antineoplastic Agents; Cell Line, Tumor; Chemistry Techniques, Synthetic; Humans; Neoplasms; Nucleosides; Oxadiazoles; Stereoisomerism; Tetrazoles

We determined the antiproliferative and nitric oxide (NO)-releasing activity of furoxans and tocopherol analogs-furoxan hybrids by tandem Griess/resazurin/sulforhodamin B assays in HeLa, 253J, T24, and HepG2 cancer cells. In addition, to investigate the NO implications in the inhibition of cell growth, cells were pretreated with the NO scavenger hemoglobin and the genotoxic damage was determined. The compounds 1 and 3 emerged as good anticancer agents for bladder cancer treatment. The NO-releasing activity of these compounds appears to be necessary to obtain the antiproliferative effect. Although compound 1 exerted a DNA damage mechanism of action, compound 3 seemed to act in a different way. The low toxicity levels against normal cell line HaCaT point them out as a very promising scaffold for the further design of new anticancer agents.

Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; DNA Damage; Drug Screening Assays, Antitumor; Humans; Neoplasms; Nitric Oxide; Oxadiazoles; Tocopherols; Tumor Cells, Cultured

The identification of a series of oxadiazole-based compounds, as promising antiproliferative agents, has been previously reported. The aim of this study was to explore the SAR of newly-synthesized oxadiazole derivatives and identify their molecular targets.. A small library of 1,2,5-oxadiazole derivatives was synthetized and their antiproliferative activity was tested by the MTT assay. Their interaction with topoisomerase I was evaluated and a molecular docking study was performed.. Several candidates showed cytotoxicity towards two human tumor cell lines, HCT-116 (colorectal carcinoma) and HeLa (cervix adenocarcinoma). Some derivatives exhibited inhibitory effects on the catalytic activity of topoisomerase I and this effect was supported by docking studies.. The enzyme inhibition results, although not directly related to cytotoxicity, suggest that a properly modified 1,2,5 oxadiazole scaffold could be considered for the development of new anti-topoisomerase agents.

Topics: Cell Proliferation; DNA Topoisomerases, Type I; Drug Screening Assays, Antitumor; HCT116 Cells; HeLa Cells; Humans; Molecular Docking Simulation; Neoplasms; Oxadiazoles; Structure-Activity Relationship

An expanded set of diversely substituted 1,2,4-oxadiazole-containing primary aromatic sulfonamides was synthesized and tested for inhibition of human carbonic anhydrase I, II, IX and XII isoforms. The initial biochemical profiling revealed a significantly more potent inhibition of cancer-related, membrane-bound isoform hCA IX (reaching into submicromolar range), on top of potent inhibition of hCA XII that is another cancer target. The observed structure-activity relationships have been rationalized by molecular modeling. Comparative single-concentration profiling of the carbonic anhydrase inhibitors synthesized for antiproliferative effects against normal (ARPE-19) and cancer (PANC-1) cell lines under chemically induced hypoxia conditions revealed several candidate compounds selectively targeting cancer cells. More in-depth characterization of these leads revealed two structurally related compounds that showed promising selective cytotoxicity against pancreatic cancer (PANC-1) and melanoma (SK-MEL-2) cell lines.

Topics: Carbonic Anhydrase Inhibitors; Carbonic Anhydrase IX; Carbonic Anhydrases; Cell Line; Cell Line, Tumor; Cell Proliferation; Drug Discovery; Humans; Hypoxia; Melanoma; Neoplasms; Oxadiazoles; Pancreatic Neoplasms; Structure-Activity Relationship; Sulfonamides

Replacement of amide moiety with the 1,2,4-oxadiazole core in the scaffold of recently reported efflux pump inhibitors afforded a novel series of oxadiazole/2-imidazoline hybrids. The latter compounds exhibited promising antibacterial activity on both Gram-positive (

Topics: Anti-Bacterial Agents; Bacteria; Cell Death; Cell Line, Tumor; Cell Survival; Communicable Diseases; Humans; Imidazoles; Microbial Sensitivity Tests; Monoamine Oxidase Inhibitors; Neoplasms; Oxadiazoles

To discover CpG island methylator phenotype (CIMP) as a predictor for cancer drug-response mechanism.. CIMP classification of 966 cancer cell lines was determined according to identified copy number alteration and differential methylation by DNA methylation profiles. CIMP-related drugs were analyzed by analysis of variance. Tissue-cell-drug networks were developed to predict drug response of individual samples.. One hundred and thirty-six copy number gain and 142 copy number loss cell lines were classified into CIMP-high and CIMP-low groups, meanwhile 9 and 24 CIMP-associated drugs were identified, respectively. Specially, breast invasive carcinoma samples primarily composed by HCC1419 were predicted to be sensitive to GSK690693. The study provides guidance for drug response in cancer therapy through genome-wide DNA methylation.

Topics: Antineoplastic Agents; Cell Line, Tumor; DNA Copy Number Variations; DNA Methylation; Drug Resistance, Neoplasm; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Oxadiazoles

Topics: Alzheimer Disease; Anti-Infective Agents; Benzoxazoles; Chemistry, Pharmaceutical; Drug Discovery; Humans; Neoplasms; Neuroprotective Agents; Oxadiazoles; Polypharmacology

Two series of novel acylthiosemicarbazide and oxadiazole fused-isosteviol derivatives were synthesized based on the 19-carboxyl modification. The target compounds were evaluated for their cytotoxicities against three cancer cell lines (HCT-116, HGC-27, and JEKO-1) using an MTT assay. Lead compounds from the acylthiosemicarbazides (4) showed IC

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Computer Simulation; Diterpenes, Kaurane; HCT116 Cells; Humans; Inhibitory Concentration 50; Molecular Structure; Neoplasms; Oxadiazoles; Quantitative Structure-Activity Relationship; Semicarbazides

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Drug Design; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Neoplasms; Oxadiazoles; Podophyllotoxin; Quantitative Structure-Activity Relationship; Tubulin; Tubulin Modulators

Topics: Apoptosis; Caspase 3; Cell Line, Tumor; Chaperonin 60; Coordination Complexes; Copper; Humans; Mitochondrial Proteins; Multiprotein Complexes; Neoplasm Proteins; Neoplasms; Oxadiazoles

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Crystallography, X-Ray; Humans; Models, Molecular; Neoplasms; Oxadiazoles; Sirtuin 2; Structure-Activity Relationship

A series of new analogs based on the structure of lead compound 10 were designed, synthesized and evaluated for their in vitro anti-cancer activities against four selected human cancer cell lines (HL-60, Bel-7402, SK-BR-3 and MDA-MB-468). Several synthesized compounds exhibited improved anti-cancer activities comparing with lead compound 10. Among them, 1,3,4-oxadiazole analogs 17o showed highest bioactivity with IC50 values of 1.23, 0.58 and 4.29 μM against Bel-7402, SK-BR-3 and MDA-MB-468 cells, respectively. It is noteworthy that 17o has potent anti-proliferation activity toward a panel of cancer cells with relatively less cytotoxicity to nonmalignant cells. The further mechanistic study showed that it induced apoptosis and cell cycle arrest through disrupting spindle assembly in mitotic progression, indicating these synthesized dithiocarbamates represented a novel series of anti-cancer compounds targeting mitosis.

Topics: Antineoplastic Agents; Cell Cycle Checkpoints; Cell Line; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Humans; Neoplasms; Oxadiazoles; Structure-Activity Relationship; Thiocarbamates

A series of novel 4-chloro-benzamides derivatives containing substituted five-membered heteroaryl ring were designed, synthesized and evaluated as RET kinase inhibitors for cancer therapy. Most of compounds exhibited moderate to high potency in ELISA-based kinase assay. In particular, compound I-8 containing 1,2,4-oxadiazole strongly inhibited RET kinase activity both in molecular and cellular level. In turn, I-8 inhibited cell proliferation driven by RET wildtype and gatekeeper mutation. The results implied that 4-chloro-3-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl)benzamides are promising lead compounds as novel RET kinase inhibitor for further investigation.

Topics: Animals; Benzamides; Cell Line; Cell Line, Tumor; Cell Proliferation; Humans; Mice; Molecular Docking Simulation; Mutation; Neoplasms; Oxadiazoles; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret

Peptide ligand-induced dimerization of the extracellular region of the epidermal growth factor receptor (sEGFR) is central to the signal transduction of many cellular processes. A small molecule microarray screen has been developed to search for non-peptide compounds able to bind to sEGFR. We describe the discovery of nitro-benzoxadiazole (NBD) compounds that enhance tyrosine phosphorylation of EGFR and thereby trigger downstream signaling pathways and other receptor tyrosine kinases in cancer cells. The protein phosphorylation profile in cells exposed to NBD compounds is to some extent reminiscent of the profile induced by the cognate ligand. Experimental studies indicate that the small compounds bind to the dimerization domain of sEGFR, and generate stable dimers providing allosteric activation of the receptor. Moreover, receptor phosphorylation is associated with inhibition of PTP-1B phosphatase. Our data offer a promising paradigm for investigating new aspects of signal transduction mediated by EGFR in cancer cells exposed to electrophilic NBD compounds.

Topics: Cell Line, Tumor; Enzyme Activation; Enzyme Inhibitors; ErbB Receptors; Humans; Neoplasms; Nitro Compounds; Oxadiazoles; Phosphorylation; Quinazolines; Signal Transduction; Tyrphostins

New molecules of benzimidazole endowed with oxadiazole were designed and synthesized from 2-(2-((pyrimidin-2-ylthio)methyl)-1H-benzo[d]imidazol-1-yl)acetohydrazide as 1-((5-substituted alkyl/aryl-1,3,4-oxadiazol-2-yl)methyl)-2-((pyrimidin-2-ylthio)methyl)-1H-benzimidazoles (5a-r) with the aim to acquire selective cyclooxygenase (COX-2) inhibitor activity. The synthesized compounds were screened by in vitro cyclooxygenase assays to determine COX-1 and COX-2 inhibitory potency and the results showed that they had good-to-remarkable activity with an IC50 range of 11.6-56.1 µM. The most active compounds were further screened for their in vivo anti-inflammatory activity by using the carrageenan-induced rat paw edema model. In vitro anticancer activities of the hybrid compounds were assessed by the National Cancer Institute (NCI), USA, against 60 human cell lines, and the results showed a good spectrum. Compound 5l exhibited significant COX-2 inhibition with an IC50 value of 8.2 µM and a percent protection of 68.4%. Compound 5b evinced moderate cytotoxicity toward the UO-31 cell line of renal cancer. A docking study was performed using Maestro 9.0, to provide the binding mode into the binding sites of the cyclooxygenase enzyme. Hopefully, in the future, compound 5l could serve as a lead compound for developing new COX-2 inhibitors.

Topics: Animals; Antineoplastic Agents; Benzimidazoles; Carrageenan; Cell Line, Tumor; Cell Survival; Computer-Aided Design; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Humans; Inflammation; Inhibitory Concentration 50; Lipid Peroxidation; Male; Molecular Docking Simulation; Molecular Structure; Neoplasms; Oxadiazoles; Rats, Wistar; Risk Assessment; Stomach Ulcer; Structure-Activity Relationship

The oncogenic bHLH-LZ transcription factor Myc forms binary complexes with its binding partner Max. These and other bHLH-LZ-based protein-protein interactions (PPI) in the Myc-Max network are essential for the physiological and oncogenic activities of Myc. We have generated a genetically determined and highly specific protein-fragment complementation assay based on Renilla luciferase to analyze the dynamic interplay of bHLH-LZ transcription factors Myc, Max, and Mxd1 in vivo. We also applied this PPI reporter to quantify alterations of nuclear Myc-Max complexes in response to mutational events, competitive binding by the transcriptional repressor Mxd1, or perturbations by small-molecule Myc inhibitors, including recently identified potent PPI inhibitors from a Kröhnke pyridine library. We show that the specificity of Myc-Max PPI reduction by the pyridine inhibitors directly correlates with their efficient and highly specific potential to interfere with the proliferation of human and avian tumor cells displaying deregulated Myc expression. In a direct comparison with known Myc inhibitors using human and avian cell systems, the pyridine compounds reveal a unique inhibitory potential even at sub-micromolar concentrations combined with remarkable specificity for the inhibition of Myc-driven tumor cell proliferation. Furthermore, we show in direct comparisons using defined avian cell systems that different Max PPI profiles for the variant members of the Myc protein family (c-Myc, v-Myc, N-Myc, L-Myc) correlate with their diverse oncogenic potential and their variable sensitivity to the novel pyridine inhibitors.

Topics: Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Cell Line, Tumor; Cell Proliferation; HEK293 Cells; Humans; Luciferases, Renilla; Neoplasms; Oxadiazoles; Protein Binding; Protein Multimerization; Proto-Oncogene Proteins c-myc; Pyridines; Repressor Proteins; Thiazoles

Sixteen furoxan-based nitric oxide (NO) releasing coumarin derivatives (6a-c, 8a-g, 10a, 13a,b, 15, and 17a,b) were designed, synthesized, and evaluated against the A549, HeLa, A2780, A2780/CDDP, and HUVEC cell lines. Most derivatives displayed potent antiproliferation activities. Among them, 8b exhibited the strongest antiproliferation activity on the four sensitive cell lines mentioned above and three drug resistant tumor cell lines A2780/CDDP, MDA-MB-231/Gem, and SKOV3/CDDP with IC50 values from 14 to 53 nM and from 62 to 140 nM, respectively. Furthermore, 8b inhibited the growth of A2780 in vivo and displayed lower toxicity on nontumorigenesis T29, showing good selectivity against malignant cells in vitro. Preliminary pharmacological studies showed that 8b induces apoptosis, arrests the cell cycle at the G2/M phase in the A2780 cell line, and disrupts the phosphorylation of MEK1 and ERK1. Overall, the NO-releasing capacity and the inhibition of ERK/MAPK pathway signaling may explain the potent antineoplastic activity of these compounds.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinogenesis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Coumarins; Drug Combinations; Drug Screening Assays, Antitumor; Female; HeLa Cells; Human Umbilical Vein Endothelial Cells; Humans; Inhibitory Concentration 50; MAP Kinase Kinase 1; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase 3; Neoplasms; Nitric Oxide; Oxadiazoles; Signal Transduction

1,3,4-Oxadiazole derivatives have drawn continuing interest over the years because of their varied biological activities. In order to search for novel anticancer agents, we designed and synthesized a series of new 1,3,4-oxadiazole derivatives containing benzotriazole moiety as potential focal adhesion kinase (FAK) inhibitors. All the synthesized compounds were firstly reported. Among the compounds, compound 4 shows the most potent inhibitory activity against MCF-7 and HT29 cell lines with IC50 values of 5.68 μg/ml and 10.21 μg/ml, respectively. Besides, all the compounds were assayed for FAK inhibitory activity using the TRAP-PCR-ELISA assay. The results showed compound 4 exhibited the most potent FAK inhibitory activity with IC50 values of 1.2±0.3 μM. Docking simulation by positioning compound 4 into the FAK structure active site was performed to explore the possible binding mode. Apoptosis which was analyzed by flow cytometry, demonstrated that compound 4 induced apoptosis against MCF-7 cells. Therefore, compound 4 may be a potential anticancer agent against MCF-7 cancer cell.

Topics: Antineoplastic Agents; Focal Adhesion Protein-Tyrosine Kinases; HT29 Cells; Humans; MCF-7 Cells; Molecular Docking Simulation; Neoplasms; Oxadiazoles; Protein Kinase Inhibitors; Structure-Activity Relationship; Triazoles

This study investigated the in vitro and in vivo antitumor effects of 5-[2,3-Dichloro-4-(2-methylene-1-oxobutyl) phenoxymethyl]-3-methyl-1,2,4- oxadiazole (6r), a novel ethacrynic acid (EA) derivative. The in vitro effect of 6r on cell proliferation of human colon, leukemia, prostate, lung, breast, ovarian and cervical tumor cell lines was assessed using MTT assay and the in vivo effect was determined with an SW620 xenografts nude mice model. The effect of 6r on expressions of GST P1-1 and apoptosis-related proteins were measured by western blotting and the effect on cell apoptosis was analysed by Hoechst 33258 nuclear staining as well as by cell surface staining of annexin V/propidium iodide. The effect on cell cycle was assessed by flow cytometry. Results showed that 6r inhibit proliferation of a range of human cancer cells in vitro and growth of SW620 tumor xenografts in vivo. The anti-proliferative effect of 6r is associated with cell apoptosis as a result of increased ratio of cellular Bax/bcl-2 expression and subsequent cytochrome-c and caspase-3 activation. Unlike EA, 6r did not show any influence on cellular GST P1-1 expression and its anti-proliferative action was associated with cell cycle arrest in G1/S-phase. In conclusion, 6r has the potential to be developed as a chemotherapeutic agent by induction of cell apoptosis but not regulating GST P1-1.

Topics: Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Female; Flow Cytometry; G1 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Glutathione S-Transferase pi; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Oxadiazoles; S Phase Cell Cycle Checkpoints; Xenograft Model Antitumor Assays

The fluorescence-labeled closo-dodecaborane lipid (FL-SBL) was synthesized from (S)-(+)-1,2-isopropylideneglycerol as a chiral starting material. FL-SBL was readily accumulated into the PEGylated DSPC liposomes prepared from DSPC, CH, and DSPE-PEG-OMe by the post insertion protocol. The boron concentrations and the fluorescent intensities of the FL-SBL-labeled DSPC liposomes increased with the increase of the additive FL-SBL, and the maximum emission wavelength of the liposomes appeared at 531 nm. A preliminary in vivo imaging study of tumor-bearing mice revealed that the FL-SBL-labeled DSPC liposomes were delivered to the tumor tissue but not distributed to hypoxic regions.

Topics: Animals; Boron; Boron Compounds; Drug Delivery Systems; Female; Fluorescence; Liposomes; Mice; Neoplasms; Oxadiazoles; Phosphatidylcholines; Phosphatidylethanolamines; Polyethylene Glycols; Stearates; Tissue Distribution

The phosphoinositide specific-phospholipase C-γ (PLC-γ1 and 2) enzymes are plausible anticancer targets implicated in cell motility important to invasion and dissemination of tumour cells. A host of known PLC-γ2 inhibitors were tested against the NCI60 panel of human tumour cell lines as well as their commercially available structural derivatives. A class of thieno[2,3-b]pyridines showed excellent growth arrest with derivative 3 giving GI(50) = 58 nM for the melanoma MDA-MB-435 cell line. The PLC-γ2 is uniquely expressed in haematopoietic cells and the leukaemia tumour cell lines were growth restricted on average GI(50) = 275 nM by derivative 3 indicating a specific interaction with this isoform. Furthermore, a moderate growth inhibition was found for compound classes of indoles and 1H-pyrazoles. It is likely that the active compounds do not only inhibit the PLC-γ2 isoform but other PLCs as well due to their conserved binding site. The compounds tested were identified by applying the tools of chemoinformatics, which supports the use of in silico methods in drug design.

Topics: Binding Sites; Cell Line, Tumor; Cell Proliferation; Enzyme Inhibitors; Humans; Indoles; Molecular Docking Simulation; Neoplasms; Oxadiazoles; Phospholipase C gamma; Protein Conformation; Pyrazoles; Structure-Activity Relationship; Thienopyridines

Neutropenia, which may develop as a consequence of chemotherapy, increases the risk of bacterial infection. Similarly, increased risk of bacterial infection appears in disorders of phagocytic functions, such as the genetic disorder chronic granulomatous disease. To elucidate the organizing principles behind these distinct immunodeficiency conditions, we investigated the interaction between in vitro bacteria and human neutrophils by experiments and mathematical modeling. The model and the experiments showed that the in vitro bacterial dynamics exhibit bistability for a certain range of neutrophil concentration and function. Thus, there is a critical bacterial concentration above which infection develops, and below which neutrophils defeat the bacteria. Whereas with normal neutrophil concentration and function, an infection may develop when the initial bacterial concentration is very high, under neutropenic conditions or when there is neutrophil dysfunction, the critical bacterial concentration can be lower, within the clinically relevant range. We conclude that critical bacterial concentration has clinically relevant implications. The individual maximum bearable bacterial concentration depended on neutrophil concentration, phagocytic activity, and patient barrier integrity; thus, the resulting maximal bearable bacterial concentration may vary by orders of magnitude between patients. Understanding the interplay between neutrophils and bacteria may enhance the development of new therapeutic approaches to bacterial infections.

Topics: Bacteria; Bacterial Infections; Bacterial Physiological Phenomena; Blood Bactericidal Activity; Host-Pathogen Interactions; Humans; In Vitro Techniques; Neoplasms; Neutropenia; Neutrophils; Oxadiazoles; Phagocytosis; Staphylococcus aureus

Two new series of benzimidazole bearing oxadiazole[1-(1H-benzo[d]imidazol-2-yl)-3-(5-substituted-1,3,4-oxadiazol-2-yl)propan-1-ones (4a-l)] and triazolo-thiadiazoles[1-(1H-benzo[d]imidazol-2-yl)-3-(6-(substituted)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)propan-1-one (7a-e)] have been synthesized successfully from 4-(1H-benzo[d]imidazol-2-yl)-4-oxobutanehydrazide (3) with an aim to produce promising anticancer agents. In vitro anticancer activities of synthesized compounds were screened at the National Cancer Institute (NCI), USA, according to their applied protocol against full NCI 60 human cell lines panel; results showed good to remarkable anticancer activity. Among them, compound (4j, NCS: 761980) exhibited significant growth inhibition and further screened at 10-fold dilutions of five different concentrations (0.01, 0.1, 1, 10 and 100 μM) with GI(50) values ranging from 0.49 to 48.0 μM and found superior for the non-small cell lung cancer cell lines like HOP-92 (GI(50) 0.49, TGI 19.9,LC(50) >100 and Log(10)GI(50) -6.30, Log(10)TGI -4.70, Log(10)LC(50) >-4.00).

Topics: Antineoplastic Agents; Benzimidazoles; Cell Line, Tumor; Drug Design; Drug Screening Assays, Antitumor; Humans; Neoplasms; Oxadiazoles; Thiadiazoles; Triazoles

Six novel platinum(II) complexes 1-6 bearing different furoxan moieties as nitric oxide (NO) donors have been designed, synthesized, and characterized by elemental analysis and (1)H NMR, IR, and ESI-MS spectroscopy. The furoxan groups were introduced to the platinum complexes to release NO, which may take synergic action with the platinum-based moieties on the tumor cells. It was found that all compounds exhibited considerable cytotoxicity against human HCT-116 and SGC-7901 cell lines via DNA binding together with NO-releasing features, especially for compound 3. This finding is in accordance with the previous reports that NO hybrids show higher cytotoxicity against colon cancer cell lines compared with their parent compounds.

Topics: Antineoplastic Agents; Cell Line, Tumor; DNA; Drug Screening Assays, Antitumor; Humans; Neoplasms; Nitric Oxide Donors; Organoplatinum Compounds; Oxadiazoles

A recipe for potency: A novel series of bis(indolyl)-1,3,4-oxadiazoles was prepared from the corresponding hydrazide-hydrazones via iodobenzene diacetate-promoted oxidative cyclization. Evaluation against a panel of human cancer cell lines revealed that some derivatives possess potent cytotoxicity with tunable selectivity for different cancer types.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cytotoxins; Drug Screening Assays, Antitumor; Humans; Indoles; Neoplasms; Oxadiazoles

Two monofunctional platinum(II) complexes, cis-[PtL(NH(3))(2)Cl]NO(3) (1) and cis-[PtL'(NH(3))(2)Cl]NO(3) (2) {L = N-methyl-7-nitro-N-(2-(pyridin-2-yl)ethyl)benzo[c][1,2,5]-oxadiazol-4-amine, L' = 7-nitro-N-(2-(pyridin-2-yl)ethyl)benzo[c][1,2,5] oxadiazol-4-amine}, have been synthesized and characterized. The X-ray single crystal structure of complex 1 shows that platinum(II) is coordinated in a square-planar geometry with a [PtN(3)Cl] setting. Fluorescence profiles of the complexes show that complex 1 is more suitable for cellular imaging than complex 2. The cellular uptake and distribution of complex 1 in the human cervical cancer HeLa cells were studied using confocal microscopy. Complex 1 enters the cells slowly, induces cytoplasmic vacuolations, and accumulates in the nucleoli. These results suggest that monofunctional platinum(II) complexes can stimulate tumour cells to undergo a nonapoptotic death process, which is distinct from the apoptosis induced by cisplatin.

Topics: Antineoplastic Agents; Cell Line, Tumor; Coordination Complexes; Crystallography, X-Ray; Humans; Isomerism; Microscopy, Confocal; Molecular Conformation; Neoplasms; Oxadiazoles; Platinum; Spectrometry, Fluorescence

The enzymatic inhibition of histone deacetylase activity has come out as a novel and effectual means for the treatment of cancer. Two novel series of 2-[5-(4-substitutedphenyl)-[1,3,4]-oxadiazol/thiadiazol-2-ylamino]-pyrimidine-5-carboxylic acid (tetrahydro-pyran-2-yloxy)-amides were designed and synthesized as novel hydroxamic acid based histone deacetylase inhibitors. The antiproliferative activities of the compounds were investigated in vitro using histone deacetylase inhibitory assay and MTT assay. The synthesized compounds were also tested for antitumor activity against Ehrlich ascites carcinoma cells in Swiss albino mice. The efforts were also made to establish structure-activity relationships among synthesized compounds. The results of the present studying indicates 2,5-disubstituted 1,3,4-oxadiazole/thiadiazole as promising surface recognition moiety for development of newer hydroxamic acid based histone deacetylase inhibitor.

Topics: Animals; Antineoplastic Agents; Carcinoma, Ehrlich Tumor; Cell Proliferation; Drug Design; Drug Evaluation, Preclinical; Drug Screening Assays, Antitumor; Histone Deacetylase Inhibitors; Hydroxamic Acids; Mice; Neoplasms; Oxadiazoles; Structure-Activity Relationship; Surface Properties; Thiadiazoles; Zinc

Ethacrynic acid (EA) is a glutathione S-transferase P1-1 (GST P1-1) inhibitor with weak antiproliferative ability in tumor cells. By use of the principle of bioisosterism, a series of novel EA oxadiazole analogues were designed and synthesized. The structure-activity relationships of inhibiting GST P1-1 activity and cell proliferation of those EA analogues were investigated in human leukemia HL-60 cells. Our data revealed that those EA oxadiazole analogues had improved antiproliferative activity and most of them had similar or better inhibitory effects on GST P1-1 activity than EA. Compound 6u was one of the potent antiproliferative agents without inhibition of GST P1-1 activity. Compounds 6r and 6s were two potent cell growth inhibitors in several solid tumor cell lines with the concentrations inhibiting half of cell growth of less than 5 microM. Our data suggest that these EA oxadiazole analogues are promising antitumor agents that may act through GST P1-1 inhibition-dependent and/or -independent pathways.

Topics: Antineoplastic Agents; Cell Proliferation; Ethacrynic Acid; Glutathione S-Transferase pi; Humans; Molecular Structure; Neoplasms; Oxadiazoles; Structure-Activity Relationship; Tumor Cells, Cultured

Akt plays a central role in regulating tumor cell survival and cell cycle progression and is regarded as a promising therapeutic target. We used genetically defined mouse models that develop spontaneous tumors exhibiting activated Akt to determine if Akt inhibition by GSK690693 is effective in the treatment of cancer. The broad long-term objective of this project was to use preclinical cancer models with precisely defined genetic lesions to elucidate the efficacy of targeting Akt with GSK690693.. We tested the in vivo effects of GSK690693 in Lck-MyrAkt2 transgenic mice that develop lymphomas, heterozygous Pten(+/-) knockout mice that exhibit endometrial tumors, and TgMISIIR-TAg-DR26 mice that develop ovarian carcinomas, all of which exhibit hyperactivation of Akt. In addition to standard disease onset and histology, tumors arising in treated animals were examined by immunohistochemistry to verify downregulated Akt signaling relative to placebo-treated mice. When possible, drug response was evaluated in tumor cell cultures by standard proliferation and apoptosis assays and by immunoblotting with various phosphospecific antibodies.. GSK690693 exhibited efficacy irrespective of the mechanism of Akt activation involved. Interestingly, GSK690693 was most effective in delaying tumor progression in Lck-MyrAkt2 mice expressing a membrane-bound, constitutively active form of Akt. Both tumors and primary cell cultures displayed downregulation of the Akt pathway, increased apoptosis, and primarily decreased cell proliferation.. These results suggest that GSK690693 or other Akt inhibitors might have therapeutic efficacy in human cancers with hyperactivated Akt and/or a dependence on Akt signaling for tumor progression.

Topics: Animals; Antineoplastic Agents; Cell Transformation, Neoplastic; Disease Models, Animal; Disease Progression; Drug Evaluation, Preclinical; Enzyme Activation; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Mice; Mice, Transgenic; Neoplasm Transplantation; Neoplasms; Oncogene Protein v-akt; Oxadiazoles; Protein Kinase Inhibitors; Tumor Cells, Cultured

A series of 2,5-diaryloxadiazole linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates have been prepared and evaluated for their anticancer activity. These conjugates have shown promising activity with GI50 values ranging from <0.1 to 0.29 microM. It is observed that some of these conjugates particularly 4a, 4d, 4i and 4l exhibit significant anticancer activity. Some detailed biological assays relating to the cell cycle aspects associated to Bax and caspases have been examined with a view to understand the mechanism of action of these conjugates.

Topics: Animals; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Benzodiazepines; Caspases; Cell Cycle; Cell Line, Tumor; Cyclin-Dependent Kinase 2; Humans; Male; Mice; Mice, Inbred NOD; Mitochondria; Neoplasms; Oxadiazoles; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

GSK690693 is a small molecule ATP-competitive inhibitor of the pro-survival kinase Akt. Since Akt regulates multiple downstream targets including transcription factors, glycogen synthase 3, the pro-apoptotic protein Bad, as well as MDM2 and mTORC1, it was tested against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP).. GSK690693 was tested in vitro at concentrations from 1 nM to 10 µM, and against the in vivo panel of xenografts at a dose of 30 mg/kg daily × 5 for 6 consecutive weeks. Three measures of in vivo antitumor activity were used: (1) an objective response measure modeled after the clinical setting; (2) a treated to control (T/C) tumor volume measure; and (3) a time to event measure based on the median event-free survival (EFS) of treated and control animals for each xenograft.. GSK690693 inhibited cell growth in vitro with IC(50) values between 6.5 nM and >10 µM. In vivo, GSK690693 significantly increased EFS in 11 of 34 (32%) solid tumor xenografts, most notably in all 6 osteosarcoma models, but not in any of the 8 ALL xenografts tested. No objective responses were observed and only one solid tumor met EFS T/C criteria for intermediate activity.. GSK690693 demonstrated broad activity in vitro, however our results against both the solid tumor and ALL PPTP in vivo panels demonstrate that, as single agent at the dose and schedule used, GSK690693 has only modest antitumor activity.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Female; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, Nude; Mice, SCID; Neoplasms; Oxadiazoles; Proto-Oncogene Proteins c-akt; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

The c-Myc oncoprotein is overexpressed in many tumors and is essential for maintaining the proliferation of transformed cells. To function as a transcription factor, c-Myc must dimerize with Max via the basic helix-loop-helix leucine zipper protein (bHLH-ZIP) domains in each protein. The small molecule 7-nitro-N-(2-phenylphenyl)-2,1,3-benzoxadiazol-4-amine (10074-G5) binds to and distorts the bHLH-ZIP domain of c-Myc, thereby inhibiting c-Myc/Max heterodimer formation and inhibiting its transcriptional activity. We report in vitro cytotoxicity and in vivo efficacy, pharmacodynamics, pharmacokinetics, and metabolism of 10074-G5 in human xenograft-bearing mice. In vitro, 10074-G5 inhibited the growth of Daudi Burkitt's lymphoma cells and disrupted c-Myc/Max dimerization. 10074-G5 had no effect on the growth of Daudi xenografts in C.B-17 SCID mice that were treated with 20 mg/kg 10074-G5 intravenously for 5 consecutive days. Inhibition of c-Myc/Max dimerization in Daudi xenografts was not seen 2 or 24 h after treatment. Concentrations of 10074-G5 in various matrices were determined by high-performance liquid chromatography-UV, and metabolites of 10074-G5 were identified by liquid chromatography/tandem mass spectrometry. The plasma half-life of 10074-G5 in mice treated with 20 mg/kg i.v. was 37 min, and peak plasma concentration was 58 μM, which was 10-fold higher than peak tumor concentration. The lack of antitumor activity probably was caused by the rapid metabolism of 10074-G5 to inactive metabolites, resulting in tumor concentrations of 10074-G5 insufficient to inhibit c-Myc/Max dimerization. Our identification of 10074-G5 metabolites in mice will help design new, more metabolically stable small-molecule inhibitors of c-Myc.

Topics: Animal Structures; Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Blood Proteins; Cell Line, Tumor; Cell Survival; Doxorubicin; Feces; Female; Glucuronates; Glucuronidase; HL-60 Cells; Humans; Inhibitory Concentration 50; Liver; Mice; Mice, SCID; Neoplasms; Oxadiazoles; Plasma; Protein Binding; Protein Multimerization; Proto-Oncogene Proteins c-myc; Tandem Mass Spectrometry; Thiazoles; Treatment Outcome; Urine; Xenograft Model Antitumor Assays

A facile, convenient and high yielding synthesis of a series of novel 5-(3'-indolyl)-2-(substituted)-1,3,4-oxadiazoles from readily available starting materials has been described. The key step of this protocol is oxidative cyclization of N-acylhydrazones 1 using [bis(trifluoroacetoxy)iodo]benzene under solvent-free condition. The 5-(3'-indolyl)-2-(substituted)-1,3,4-oxadiazoles were screened for their in vitro anticancer activity against various human cancer cell lines. Compounds 3c, 3d and 3j exhibited potent cytotoxicity (IC(50) approximately 1microM) and selectivity against human cancer cell lines.

Topics: Antineoplastic Agents; Cell Line, Tumor; Chemistry, Pharmaceutical; Drug Design; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Indoles; Inhibitory Concentration 50; Iodine; Models, Chemical; Molecular Structure; Neoplasms; Oxadiazoles; Solvents; Structure-Activity Relationship

Activated protein C (APC) has both anticoagulant activity and direct cell-signaling properties. APC has been reported to promote cancer cell migration/invasion and to inhibit apoptosis and therefore may exacerbate metastasis. Opposing these activities, APC signaling protects the vascular endothelial barrier through sphingosine-1-phosphate receptor-1 (S(1)P(1))activation, which may counteract cancer cell extravasation. Here, we provide evidence that endogenous APC limits cancer cell extravasation, with in vivo use of monoclonal antibodies against APC. The protective effect of endogenous APC depends on its signaling properties. The MAPC1591 antibody that only blocks anticoagulant activity of APC does not affect cancer cell extravasation as opposed to MPC1609 that blocks anticoagulant and signaling properties of APC. Combined administration of anti-APC antibodies and S(1)P(1) agonist (SEW2871) resulted in a similar number of pulmonary foci in mice in presence and absence of APC, indicating that the protective effect of APC depends on the S(1)P(1) pathway. Moreover, endogenous APC prevents cancer cell-induced vascular leakage as assessed by the Evans Blue Dye assay, and SEW2871 treatment reversed MPC1609-dependent vascular leakage. Finally, we show that cancer cells combined with MPC1609 treatment diminished endothelial VE-cadherin expression. In conclusion, endogenous APC limits cancer cell extravasation because of S(1)P(1)-mediated VE-cadherin-dependent vascular barrier enhancement.

Topics: Animals; Antibodies, Monoclonal; Anticoagulants; Antigens, CD; Cadherins; Endothelium, Vascular; Evans Blue; Female; Melanoma, Experimental; Mice; Models, Biological; Neoplasms; Oxadiazoles; Protein C; Receptors, Lysosphingolipid; Signal Transduction; Thiophenes

Akt kinases 1, 2, and 3 are important regulators of cell survival and have been shown to be constitutively active in a variety of human tumors. GSK690693 is a novel ATP-competitive, low-nanomolar pan-Akt kinase inhibitor. It is selective for the Akt isoforms versus the majority of kinases in other families; however, it does inhibit additional members of the AGC kinase family. It causes dose-dependent reductions in the phosphorylation state of multiple proteins downstream of Akt, including GSK3 beta, PRAS40, and Forkhead. GSK690693 inhibited proliferation and induced apoptosis in a subset of tumor cells with potency consistent with intracellular inhibition of Akt kinase activity. In immune-compromised mice implanted with human BT474 breast carcinoma xenografts, a single i.p. administration of GSK690693 inhibited GSK3 beta phosphorylation in a dose- and time-dependent manner. After a single dose of GSK690693, >3 micromol/L drug concentration in BT474 tumor xenografts correlated with a sustained decrease in GSK3 beta phosphorylation. Consistent with the role of Akt in insulin signaling, treatment with GSK690693 resulted in acute and transient increases in blood glucose level. Daily administration of GSK690693 produced significant antitumor activity in mice bearing established human SKOV-3 ovarian, LNCaP prostate, and BT474 and HCC-1954 breast carcinoma xenografts. Immunohistochemical analysis of tumor xenografts after repeat dosing with GSK690693 showed reductions in phosphorylated Akt substrates in vivo. These results support further evaluation of GSK690693 as an anticancer agent.

Topics: Animals; Antineoplastic Agents; Female; Humans; Mice; Mice, Nude; Mice, SCID; Neoplasms; Oxadiazoles; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Xenograft Model Antitumor Assays

Some 3-acetyl-2-substituted phenyl-5-(3,4,5-trimethoxyphenyl)-2,3-dihydro-1,3,4-oxadiazole derivatives were synthesized by cyclization reaction of N'-substituted benzylidene-3,4,5-trimethoxybenzohydrazide in acetic anhydride. Their structures were verified by elemental analysis, IR, (1)H NMR, and (13)C NMR. Compound 3i was provided with X-ray crystallographic data. The compounds were evaluated for their antiproliferative activities against some cancer cells in vitro by MTT method. Among them, 2a, 2b, 2c, 2f, 3l, and 3m were highly effective against PC3 cells and 2a, 2c, and 2f showed moderate activities against Bcap37 and BGC823 cells. The IC(50) values of high active compounds 2a, 2b, 2c, 2f, 3l, and 3m against PC3 cells were 0.2, 1.8, 0.2, 1.2, 1.7, and 0.3muM, respectively.

Topics: Antineoplastic Agents; Benzylidene Compounds; Cell Line, Tumor; Cell Proliferation; Cell Survival; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; Molecular Structure; Neoplasms; Oxadiazoles; Prohibitins; Spectrum Analysis; Structure-Activity Relationship

In reaching a regulatory decision on the use of pesticides with carcinogenic potential, it is of great importance to investigate the extent of dermal exposure and absorption of a pesticide to users and field workers. By applying this information, along with the appropriate carcinogenicity categorization of a pesticide, a reasonably sound regulatory decision can be derived. Seven pesticides were selected, based on adequacy of tumor data, and were taken through the tumor evaluation system as reported in Part I 1984, Regul. Toxicol. Pharmacol. 4, 355-360). A step-by-step analysis on how a regulatory decision is reached on each pesticide by the EPA and CDFA was discussed.

Topics: Agricultural Workers' Diseases; Allyl Compounds; Animals; Benzilates; California; Carcinogens; Decision Making; Ethylene Dibromide; Hexachlorocyclohexane; Humans; Hydrocarbons, Chlorinated; Insecticides; Legislation, Drug; Neoplasms; Oxadiazoles; Pesticides; Risk; Skin Absorption; Toluidines; Toxaphene

Topics: Animals; Carcinogens; Carcinoma; Carcinoma, Squamous Cell; Dogs; Neoplasms; Neoplasms, Experimental; Oxadiazoles; Pathology; Rats; Research; Toxicology; Urinary Bladder Neoplasms