Development of triazolothiadiazine derivatives as highly potent tubulin polymerization inhibitors: Structure-activity relationship, in vitro and in vivo study

• Published in: European journal of medicinal chemistry 2020-12, Vol.208, p.112847-112847, Article 112847
• Main Authors: Ma, Weifeng, Chen, Peng, Huo, Xiansen, Ma, Yufeng, Li, Yanhong, Diao, Pengcheng, Yang, Fang, Zheng, Shengquan, Hu, Mengjin, You, Wenwei, Zhao, Peiliang
• Format: Article
• Language: English
• Subjects: Antiproliferative activity; Structure-activity relationship; Triazolothiadiazine derivatives; Tubulin
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112847

Based on our prior work, we reported the design, synthesis, and biological evaluation of fifty-two new triazolothiadiazine-based analogues of CA-4 and their preliminary structure-activity relationship. Among synthesized compounds, Iab was found to be the most potent derivative possessing IC50 values ranging from single-to double-digit nanomolar in vitro, and also exhibited excellent selectivity over the normal human embryonic kidney HEK-293 cells (IC50 > 100 μM). Further mechanistic studies revealed that Iab significantly blocked tubulin polymerization and disrupted the intracellular microtubule network of A549 cells. Moreover, Iab induced G2/M cell cycle arrest by regulation of p-cdc2 and cyclin B1 expressions, and caused cell apoptosis through up-regulating cleaved PARP and cleaved caspase-3 expressions, and down-regulating of Bcl-2. Importantly, in vivo, Iab effectively suppressed tumor growth of A549 lung cancers in a xenograft mouse model without obvious signs of toxicity, confirming its potential as a promising candidate for cancer treatment. [Display omitted] •52 new triazolothiadiazine-based analogues of CA-4 and their SAR were reported.•Iab possessed IC50 values ranging from single-to double-digit nanomolar.•Iab blocked tubulin polymerization and disrupted microtubule network.•Iab concentration dependently induced G2/M cell cycle arrest and apoptosis.•Iab suppressed tumor growth of A549 lung cancers in a xenograft mouse model.