Synthesis and biological evaluation of pyrimidine bridged combretastatin derivatives as potential anticancer agents and mechanistic studies

A number of pyrimidine bridged combretastatin derivatives were designed, synthesized and evaluated for anticancer activities against breast cancer (MCF-7) and lung cancer (A549) cell lines using MTT assays. Most of the synthesized compounds displayed good anticancer activity with IC₅₀ values in low micro-molar range. Compounds 4a and 4p were found most potent in the series with IC₅₀ values of 4.67 µM & 3.38 µM and 4.63 µM & 3.71 µM against MCF7 and A549 cancer cell lines, respectively. Biological evaluation of these compounds showed that selective cancer cell toxicity (in vitro using human lung and breast cancer cell lines) might be due to the inhibition of antioxidant enzymes instigating elevated ROS levels which triggers intrinsic apoptotic pathways. These compounds were found nontoxic to the normal human primary cells. Compound 4a, was found to be competitive inhibitor of colchicine and in the tubulin binding assay it showed tubulin polymerization inhibition potential comparable to colchicine. The molecular modeling studies also showed that the synthesized compounds fit well in the colchicine-binding pocket.     

Design,synthesis, and biological evaluation of biotinylated colchicine derivatives as potential antitumor agents

Chemical drug design based on the biochemical characteristics of cancer cells has become an important strategy for discovering new anti-tumour drugs to improve tumour targeting effects and reduce off-target toxicities. Colchicine is one of the most prominent and historically microtubule-targeting drugs, but its clinical applications are hindered by notorious adverse effects. In this study, we presented a novel tumour-specific conjugate 9 that consists of deacetylcolchicine (Deac), biotin, and a cleavable disulphide linker. 9 was found to exhibit potent anti-tumour activity and exerted higher selectivity between tumour and nontarget cells than Deac. The targeting moiety biotin might enhance the transport capability and selectivity of 9 to tumour cells via biotin receptor-mediated endocytosis. The tubulin polymerisation activity of 9 (with DTT) was close to the parent drug Deac. These preliminary results suggested that 9 is a high potency and reduced toxicity antitumor agent and worthy of further investigation.     

Design,synthesis and biological evaluation of 3,5-diaryl isoxazole derivatives as potential anticancer agents

The present study was carried out in the attempt to synthesize a new class of potential anticancer agents comprising eleven compounds (24–34) sharing the 3,5-diarylisoxazole as a core. The chemical structure of the new synthesized compounds was established by IR, ¹H NMR, ¹³C NMR and elemental analysis. Their biological potential towards prostate cancer was evaluated by using cancer PC3 cells and non-tumorigenic PNT1a cells. Interestingly, compound 26 distinguished from others with a quite high selectivity value that is comparable to 5-FU. The binding mode of 26 towards Ribosomal protein S6 kinase beta-1 (S6K1) was investigated at a molecular level of detail by employing docking simulations based on GLIDE standard precision as well as MM-GBSA calculations.     

Design,synthesis and biological evaluation of novel 3-substituted 4-anilino-coumarin derivatives as antitumor agents

Various 3-substituted 4-anilino-coumarin derivatives have been designed, synthesized and their anti-proliferative properties have been studied. The in vitro cytotoxicity screening was performed against MCF-7, HepG2, HCT116 and Panc-1 cancer cell lines by MTT assay. Most of the synthesized compounds exhibited comparable anti-proliferative activity to the positive control 5-Fluorouracil against these four tested cancer cell lines. Among the different substituents at C-3 position of coumarin scaffold, 3-trifluoroacetyl group showed the most promising results. Especially, compounds 33d (IC₅₀ = 16.57, 5.45, 4.42 and 5.16 μM) and 33e (IC₅₀ = 20.14, 6.71, 4.62 and 5.62 μM) showed excellent anti-proliferative activities on MCF-7, HepG2, HCT116 and Panc-1 cell lines respectively. In addition, cell cycle analysis and apoptosis activation revealed that 33d induced G2/M phase arrest and apoptosis in MCF-7 cells in a dose-dependent manner. Low toxicity of compounds 33d and 33e was observed against human umbilical vein endothelial cells (HUVECs), suggesting their acceptable safety profiles in normal cells. Furthermore, the results of in silico ADME studies indicated that both 33d and 33e exhibited good pharmacokinetic properties.     

Design, synthesis, and biological evaluation of novel water-soluble N-mustards as potential anticancer agents

A series of novel water-soluble N-mustard-benzene conjugates bearing a urea linker were synthesized. The benzene moiety contains various hydrophilic side chains are linked to the meta- or para-position of the urea linker via a carboxamide or an ether linkage. The preliminary antitumor studies revealed that these agents exhibited potent cytotoxicity in vitro and therapeutic efficacy against human tumor xenografts in vivo. Remarkably, complete tumor remission in nude mice bearing human breast carcinoma MX-1 xenograft and significant suppression against prostate adenocarcinoma PC3 xenograft were achieved by treating with compound 9aa′ at the maximum tolerable dose with relatively low toxicity. We also demonstrate that the newly synthesized compounds are able to induce DNA cross-linking through alkaline agarose gel shift assay. A pharmacokinetic profile of the representative 9aa′ in rats was also investigated. The current studies suggest that this agent is a promising candidate for preclinical studies.     

Design,synthesis and biological evaluation of matrine derivatives as potential anticancer agents

Using matrine (1) as the lead compound, a series of new 14-(N-substituted-2-pyrrolemethylene) matrine and 14-(N-substituted-indolemethylene) matrine derivatives was designed and synthesized for their potential application as anticancer agents. The structure of these compounds was characterized by ¹H NMR, ¹³C NMR and ESI-MS spectral analyses. The target compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (SMMC-7721, A549 and CNE2). The results revealed that compound A6 and B21 displayed the most significant anticancer activity against three cancer cell lines with IC₅₀ values in range of 3.42–8.05?μM, which showed better activity than the parent compound (Matrine) and positive control Cisplatin. Furthermore, the Annexin V-FITC/PI dual staining assay revealed that compound A6 and B21 could significantly induce the apoptosis of SMMC-7721 and CNE2 cells in a dose-dependent manner. The cell cycle analysis also revealed that compound A6 could cause cell cycle arrest of SMMC-7721 and CNE2 cells at G2/M phase.     

Design,synthesis, biological and in silico evaluation of coumarin-hydrazone derivatives as tubulin targeted antiproliferative agents

Coumarin-based different series of hydrazone derivatives were synthesized and evaluated for anticancer activity against four different human cancer cell lines. The activity of the compounds were compared with doxorubicin as a standard drug and all the compounds exhibited good to moderate cytotoxicity with IC₅₀ values ranging from 6.07 to 60.45 µM against all the examined cancer cell lines. Based on the screening results, it was concluded that the compounds 12a and 18a were the most promising medicinal entities. In vitro tubulin polymerisation inhibition assay was performed for the compounds 12a and 18a and these two compounds displayed good potency when compared with colchicine as the standard drug. The interaction of these compounds with tubulin protein was also studied with the help of molecular docking technique using Discovery studio software. Furthermore, the molecular and ADMET properties of the compounds were computed with Osiris property software and PreADMET server. The compounds exhibited exciting in vitro and in silico results. Hence we propose that the compounds 12a and 18a could be developed as tubulin targeted potential antiproliferative agents.     

Synthesis,biological evaluation and molecular docking studies of trans-indole-3-acrylamide derivatives,a new class of tubulin polymerization inhibitors

In this study, we synthesized a series of trans-indole-3-acrylamide derivatives (3a–k) and investigated their activity for inhibition of cell proliferation against five human cancer cell lines (HeLa, MCF7, MDA-MB-231, Raji and HL-60) by MTT assay. Compound 3e showed significant antiproliferative activity against both the Raji and HL-60 cell lines with IC₅₀ values of 9.5 and 5.1 μM, respectively. Compound 3e also exhibited moderate inhibitory activity on tubulin polymerization (IC₅₀ = 17 μM). Flow cytometric analysis of cultured cells treated with 3e also demonstrated that the compound caused cell cycle arrest at the G2/M phase in HL-60 and HeLa cells. Moreover, 3e, the most active compound, caused an apoptotic cell death through the activation of caspase-3. Docking simulations suggested that 3e binds to the colchicine site of tubulin.     

Synthesis and biological evaluation of novel 4,7-dihydroxycoumarin derivatives as anticancer agents

A series of novel 4,7-dihydroxycoumarin based acryloylcyanohydrazone derivatives were synthesized and evaluated for antiproliferative activity against four different cancer cell lines (A549, HeLa, SKNSH, and MCF7). Most of the compounds displayed potent cytotoxicity with IC₅₀ values ranging from 3.42 to 31.28 µM against all the tested cancer cell lines. The most active compound, 8h was evaluated for pharmacological mechanistic studies on cell cycle progression and tubulin polymerization inhibition assay. The results revealed that the compound 8h induced the cell cycle arrest at G2/M phase and inhibited tubulin polymerization with IC₅₀ = 6.19 µM. Experimental data of the tubulin polymerization inhibition assay was validated by molecular docking technique and the results exhibited strong hydrogen bonding interactions with amino acids (ASN-101, TYR-224, ASN-228, LYS-254) of tubulin.     

Synthesis,biological evaluation and molecular modeling of 1,3,4-thiadiazol-2-amide derivatives as novel antitubulin agents

A series of 1,3,4-thiadiazol-2-amide derivatives (6a–w) were designed and synthesized as potential inhibitors of tubulin polymerization and as anticancer agents. The in vitro anticancer activities of these compounds were evaluated against three cancer cell lines by the MTT method. Among all the designed compounds, compound 6f exhibited the most potent anticancer activity against A549, MCF-7 and HepG2 cancer cell lines with IC₅₀ values of 0.03 μM, 0.06 μM and 0.05 μM, respectively. Compound 6f also exhibited significant tubulin polymerization inhibitory activity (IC₅₀ = 1.73 μM), which was superior to the positive control. The obtained results, along with a 3D-QSAR study and molecular docking that were used for investigating the probable binding mode, could provide an important basis for further optimization of compound 6f as a novel anticancer agent.     

Design,synthesis and biological evaluation of a series of pyrano chalcone derivatives containing indole moiety as novel anti-tubulin agents

A new series of pyrano chalcone derivatives containing indole moiety (3–42, 49a–49r) were synthesized and evaluated for their antiproliferative activities. Among all the compounds, compound 49b with a propionyloxy group at the 4-position of the left phenyl ring and N-methyl-5-indoly on the right ring displayed the most potent cytotoxic activity against all tested cancer cell lines including multidrug resistant phenotype, which inhibits cancer cell growth with IC₅₀ values ranging from 0.22 to 1.80 μM. Furthermore, 49b significantly induced cell cycle arrest in G2/M phase and inhibited the polymerization of tubulin. Molecular docking analysis demonstrated the interaction of 49b at the colchicine binding site of tubulin. In experiments in vivo, 49b exerted potent anticancer activity in HepG2 human liver carcinoma in BALB/c nude mice. These results indicated these compounds are promising inhibitors of tubulin polymerization for the potential treatment of cancer.     

Synthesis,molecular properties prediction and biological evaluation of indole-vinyl sulfone derivatives as novel tubulin polymerization inhibitors targeting the colchicine binding site

Twenty-two novel indole-vinyl sulfone derivatives were designed, synthesized and evaluated as tubulin polymerization inhibitors. The physicochemical and drug-likeness properties of all target compounds were predicted by Osiris calculations. All compounds were evaluated for their antiproliferative activities, among them, compound 7f exhibited the most potent activity against a panel of cancer cell lines, which was 2–7 folds more potent than our previously reported compound 4. Especially, 7f displayed about 8-fold improvement of selective index as compared with compound 4, indicating that 7f might have lower toxicity. Besides, 7f inhibited the microtubule polymerization by binding to the colchicine site of tubulin. Further investigations showed that compound 7f effectively disrupted microtubule network, caused cell cycle arrest at G2/M phase and induced cell apoptosis in K562 cells. Moreover, 7f reduced the cell migration and disrupted capillary-like tube formation in HUVEC cells. Importantly, the in vivo anti-tumor activity of 7f was validated in H22 liver cancer xenograft mouse model without apparent toxicity, suggesting that 7f is a promising anti-tubulin agent for cancer therapy.     

The discovery of colchicine-SAHA hybrids as a new class of antitumor agents

A novel class of colchicine-SAHA hybrids were designed and synthesised based on the synergistic antitumor effect of tubulin inhibitors and histone deacetylases (HDAC) inhibitors. To the best of our knowledge, this is the first design of molecules that are dual inhibitors of tubulin and HDAC. Biological evaluations of these compounds included the inhibitory activity of HDAC, in vitro cell cycle analysis in BEL-7402 cells as well as cytotoxicity in five cancer cell lines.     

Design,synthesis and biological evaluation of novel glyoxalase I inhibitors possessing diazenylbenzenesulfonamide moiety as potential anticancer agents

The enzyme glyoxalase-I (Glo-I) is an essential therapeutic target in cancer treatment. Significant efforts have been made to discover competitive inhibitors of Glo-I as potential anticancer agents. Herein, we report the synthesis of a series of diazenylbenzenesulfonamide derivatives, their in vitro evaluation against Glo-I and the resulting structure–activity relationships. Among the compounds tested, compounds 9h and 9j exhibited the highest activity with IC₅₀ 1.28 µM and 1.13 µM, respectively. Docking studies to explore the binding mode of the compounds identified key moieties that may contribute to the observed activities. The active compounds will serve as suitable leads for further chemical optimization.     

Design,synthesis and biological studies of novel tubulin inhibitors

A series of compounds originally derived from the vascular endothelial growth factor receptor tyrosine kinase inhibitor, SU5416, were synthesized and evaluated. The most potent compound in this series, compound 3, which structurally resembles the potent anti-microtubule agent combretastatin A-4, inhibited tubulin polymerization and showed potent growth inhibitory activities on both prostate and breast cancer lines with IC₅₀ values in the low nanomolar range.     

Regioselective synthesis and evaluation of 2-amino 3-cyano chromene-chrysin hybrids as potential anticancer agents

The first example of Ca(OH)₂-activated p-regioselective synthesis of chrysin-fused chromene was reported through a cascade Michael/cyclization of chrysin and arylidenemalononitrile. The newly synthesized structurally diverse 2-amino 3-cyano chromene-chrysin hybrids 3 were evaluated for their in vitro anticancer activity, and some of the compounds showed stronger anti-proliferative activity against K562, PC-3, A549 and NCI-H1299 than parent compound chrysin, and demonstrated equipotent potency compared with the reference drug of cisplatin. In particular, compound 3h had the highest cytotoxicity towards K562 cells (IC₅₀ = 6.41 µM). Furthermore, compound 3h induced apoptosis of K562 cells in a concentration-dependent manner, as well as induced the apoptosis possibly through promoting the formation of apoptotic DNA of cancer cell via the intrinsic apoptotic pathway. Thus, our results provide in vitro evidence that compound 3h may be a potential candidate for the development of new anti-tumour drugs.     

Design, synthesis and biological evaluation of N-phenylsulfonylnicotinamide derivatives as novel antitumor inhibitors

A series of novel N-phenylsulfonylnicotinamide derivatives (1-24) have been synthesized and evaluated as potential EGFR tyrosine kinase (TK) inhibitors. Among all the compounds, compound 10 (5-bromo-N-(4-chlorophenylsulfonyl)nicotinamide) showed the most potent growth inhibitory activity against EGFR TK and antiproliferative activity of MCF-7 cancer cell line in vitro, with IC(50) value of 0.09 and 0.07 μM. Docking simulation was performed to insert compound 10 into the EGFR TK active site to determine the probable binding model. Based on the preliminary results, compound 10 with potent inhibitory activity to tumor growth may be a potential anticancer agent.     

Design,synthesis and evaluation of novel levoglucosenone derivatives as promising anticancer agents

A series of levoglucosenone-derived 1,2,3-triazoles and isoxazoles featuring a flexible spacer between the heteroaromatic and anhydropyranose cores have been designed and synthesized following an hetero Michael // 1,3-dipolar cycloaddition path. The use of a design of experiments approach allowed the optimization of the oxa-Michael reaction with propargyl alcohol as nucleophile, a key step for the synthesis of the target compounds. All of the compounds were tested for their anticancer activity on MDA-MB-231 cells, featuring mutant p53. The results highlighted the importance of the introduction of the flexible spacer as well as the higher activity of oxa-Michael isoxazole-derivatives. The most prominent compounds also showed anti-proliferative activities against lung and colon cancer cell lines. The compounds showed enhanced cytotoxic effects in the presence of mutant p53, determined both by endogenous mutant p53 knock down (R280K) and by reintroducing p53 R280K in cells lacking p53 expression.     

Design,synthesis, molecular modeling and biological evaluation of novel 1H-pyrazolo[3,4-b]pyridine derivatives as potential anticancer agents

In trying to develop new anticancer agents, a series of 1H-pyrazolo[3,4-b]pyridine derivatives was designed and synthesized. Fifteen compounds were evaluated in vitro for their anti-proliferative activity against HePG-2, MCF-7, HCT-116, and PC-3 cell lines. Additionally, DNA binding affinity of the synthesized derivatives was investigated as a potential mechanism for the anticancer activity using DNA/methyl green assay and association constants assay. Compounds 19, 20, 21, 24 and 25 exhibited good activity against the four cancer cells comparable to that of doxorubicin. Interestingly, DNA binding assay results were in agreement with that of the cytotoxicity assays where the most potent anticancer compounds showed good DNA binding affinity comparable to that of doxorubicin and daunorubicin. Furthermore, a molecular docking of the tested compounds was carried out to investigate their binding pattern with the prospective target, DNA (PDB-code: 152d).     

Design,synthesis and biological evaluation of novel indole-based oxalamide and aminoacetamide derivatives as tubulin polymerization inhibitors

A series of novel indole-based oxalamide and aminoacetamide derivatives were designed, synthesized, and evaluated for antiproliferative activities. Preliminary results revealed that compound 8g exhibited significant antiproliferative effect against PC-3, HeLa and HCT-116 cell lines. Flow cytometric analysis of the cell cycle demonstrated the compound 8g induced the cell cycle arrest at G2/M phase in HeLa cell lines. Immunocytochemistry revealed loss of intact microtubule structure in cells treated with 8g and inhibition of tubulin polymerization. Additionally, molecular docking analysis suggested that 8g formed stable interactions in the colchicine-binding site of tubulin. These preliminary results demonstrated that a new class of novel indole-based oxalamide and aminoacetamide derivatives described in the investigation could be developed as potential scaffolds to new anticancer agents.