Design, synthesis, and biological evaluation of novel alkylsulfanyl-1,2,4-triazoles as cis-restricted combretastatin A-4 analogues

• Published in: European journal of medicinal chemistry Vol. 125; pp. 1098 - 1106
• Main Authors: Li, Yan-Hong, Zhang, Bei, Yang, Hai-Kui, Li, Qiu, Diao, Peng-Cheng, You, Wen-Wei, Zhao, Pei-Liang
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 05.01.2017; Elsevier
• Subjects: Alkylsulfanyl-1,2,4-triazoles; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferative activity; Bibenzyls - chemistry; Bibenzyls - pharmacology; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Drug Screening Assays, Antitumor; Humans; Life Sciences & Biomedicine; Neoplasms - drug therapy; Neoplasms - metabolism; Pharmacology & Pharmacy; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Synthesis; Triazoles - chemistry; Triazoles - pharmacology; Antiproliferative activity; Alkylsulfanyl-1,2,4-triazoles; Synthesis; POTENT; MOIETY; TUBULIN POLYMERIZATION INHIBITORS; NATURAL-PRODUCTS; ANTICANCER AGENTS; DRUG DISCOVERY; ANTINEOPLASTIC AGENTS; MODEL; DERIVATIVES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.10.051

Thirty-two novel 3-alkylsulfanyl-1,2,4-triazole derivatives, designed as cis-restricted combretastatin A-4 analogues, were synthesized and evaluated for their antiproliferative activities. The results indicated that analogue 20 showed more potent antiproliferative activities against PC-3 cell lines than positive control CA-4. Particularly, the most promising compound 25 displayed 5-fold improvement compared to CA-4 in inhibiting HCT116 cell proliferation with IC50 values of 1.15 μM. Further flow-activated cell sorting analysis revealed that compound 20 displayed a significant effect on G2/M cell-cycle arrest in a dose-dependent manner in PC-3 cells. From this study, analogues 20 and 25 were the most potent anti-cancer agents in this structural class, and were considered lead compounds for further development as anti-cancer drugs. [Display omitted] •32 novel 1,2,4-triazole derivatives were designed and synthesized as cis-restricted combretastatin A-4 analogues.•Antiproliferative activity of these compounds was evaluated.•Analogues 20 and 25 exhibited much stronger antitumor activity than CA-4.•Flow-activated cell sorting analysis suggested that compound 20 mainly arrested PC-3 cells in G2/M stage.