3,5-Diaryl-1H-pyrazolo[3,4-b]pyridines as potent tubulin polymerization inhibitors: Rational design, synthesis and biological evaluation

• Published in: European journal of medicinal chemistry Vol. 168; pp. 426 - 435
• Main Authors: Zhai, Min'an, Liu, Shiyuan, Gao, Meiqi, Wang, Long, Sun, Jun, Du, Jianan, Guan, Qi, Bao, Kai, Zuo, Daiying, Wu, Yingliang, Zhang, Weige
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.04.2019; Elsevier
• Subjects: Chemistry, Medicinal; Colchicine site; Conformational analysis; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Pyrazolo[3,4-b]pyridine; Ring tethering; Science & Technology; Colchicine site; Ring tethering; Conformational analysis; Pyrazolo[3,4-b]pyridine; PHARMACOKINETICS; ANALOGS; AGENTS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.12.053

A series of novel 3,5-diaryl-1H-pyrazolo[3,4-b]pyridines as tubulin polymerization inhibitors targeting the colchicine site were designed via ring tethering strategy, which was supported by conformational analysis. The general, chemically unstable and rotational linker, carbanyl group, was locked by 1H-pyrazolo[3,4-b]pyridine to avoid carbonyl reduction and restrict the instability of molecular conformation caused by the rotation of the carbon-carbon single bond beside carbonyl group. All of target compounds were synthesized and evaluated for their antiproliferative activities against three human cancer lines (SGC-7901, A549 and HeLa) by MTT assay. Most of these compounds showed prominent in vitro potency and the most potent compound in this scaffold 13d (SGC-7901: IC50 = 13 nM) could significantly inhibit tubulin polymerization and strongly disrupt cytoskeleton. The results of molecular modeling study revealed that 13d interacts with tubulin by binding to the colchicine site. [Display omitted] •Conformations of SMART analogues were analyzed based on DFT calculation.•Target compounds were design rationally via ring tethering strategy.•Most of the target compounds showed significant antiproliferative activities.•Compound 13d inhibited tubulin polymerization and caused cells arrest in G2/M phase.•The binding mode of 13d was determined by docking studies.