ABSTRACT
A novel series of 3,6-diaryl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines were designed, synthesized and biologically evaluated as vinylogous CA-4 analogues, which involved a rigid [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine scaffold to fix the configuration of (Z,E)-butadiene linker of A-ring and B-ring. Among these rigidly vinylogous CA-4 analogues, compounds 4d, 5b, 5i, 6c, 6e, 6g, 6i and 6k showed excellent antiproliferative activities against SGC-7901, A549 and HT-1080 cell lines with IC50 values at the nanomolar level. Compound 6i showed the most highly active antiproliferative activity against the three human cancer cell lines with an IC50 values of 0.011-0.015 µM, which are comparable to those of CA-4 (IC50 = 0.009-0.013 µM). Interestingly, SAR studies revealed that 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3-methoxyphenyl and 4-methoxyphenyl could replace the classic 3,4,5-trimethoxyphenyl in CA-4 structure and keep antiproliferative activity in this series of designed compounds. Tubulin polymerization experiments showed that 6i could effectively inhibit tubulin polymerization, which was corresponded with CA-4, and immunostaining experiments suggested that 6i significantly disrupted microtubule/tubulin dynamics. Furthermore, 6i potently induced cell cycle arrest at G2/M phase in SGC-7901 cells. Competitive binding assays and docking studies suggested that compound 6i binds to the tubulin perfectly at the colchicine binding site. Taken together, these results revealed that 6i may become a promising lead compound for new anticancer drugs discovery.
Subject(s)
Drug Design , Structure-Activity Relationship , Thiadiazines/chemistry , Tubulin Modulators/chemistry , A549 Cells , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , G2 Phase Cell Cycle Checkpoints/drug effects , Humans , Models, Chemical , Molecular Structure , Protein Binding , Thiadiazines/chemical synthesis , Thiadiazines/pharmacology , Tubulin/chemistry , Tubulin Modulators/chemical synthesis , Tubulin Modulators/pharmacologyABSTRACT
A series of 3,6-diaryl-1H-pyrazolo[5,1-c][1,2,4]triazoles (I) and 3,6-diaryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (II) as antitubulin agents were designed, synthesized and bioevaluated. Compounds (II) 4a, 4d, 4f, 4j, 4l and 4n showed potent antiproliferative activity at sub-micromolar or nanomolar concentrations against SGC-7901, A549 and HT-1080 cell lines, indicating that the bioisosteric replacement of the carbonyl group and B-ring of SMART and ABI with a 5,5-fused-heterocycle scaffold successfully maintained potent antiproliferative activity. Compound 4f exhibited the most excellent antiproliferative activity against the three cancer cell lines (IC50 = 0.022-0.029 µM). Consistent with its potent antiproliferative activity, 4f also displayed excellent antitubulin activity (IC50 = 0.77 µM). Furthermore, compound 4f could dramatically affect cell morphology and microtubule networking, while cell cycle studies demonstrated that 4f significantly induced SGC-7901 cells arrest in G2/M phase. In addition, molecular docking studies supported the biological assay data and suggested that 4f may be a potential antitubulin agent.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Tubulin Modulators/pharmacology , Tubulin/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Docking Simulation , Molecular Structure , Polymerization/drug effects , Structure-Activity Relationship , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistryABSTRACT
A series of 3,6-diaryl-[1,2,4]triazolo[4,3-b]pyridazines were designed as a class of vinylogous CA-4 analogues. The easily isomerized (Z,E)-butadiene linker of vinylogous CA-4 was replaced by a rigid [1,2,4]triazolo[4,3-b]pyridazine scaffold. Twenty-one target compounds were synthesized and exhibited moderate to potent antiproliferative activity. The compound 4q with a 3-amino-4-methoxyphenyl moiety as the B-ring, comparable to CA-4 (IC50 = 0.009-0.012 µM), displayed the highly active antiproliferative activity against SGC-7901, A549, and HT-1080 cell lines with IC50 values of 0.014, 0.008, and 0.012 µM, respectively. Tubulin polymerization experiments indicated that 4q effectively inhibited tubulin polymerization, and immunostaining assay revealed that 4q significantly disrupted tubulin microtubule dynamics. Moreover, cell cycle studies revealed that compound 4q dramatically arrested cell cycle progression at G2/M phase in A549 cells. Molecular modeling studies showed that 4q could bind to the colchicine binding site on microtubules.
