{"title":"Design, synthesis, and bioevaluation of pyrazole-containing tubulin polymerisation inhibitors based on conformational constraint strategy.","authors":"Zhongqiao Sun, Jiahao Wang, Fengwei Li, Liancheng Huang, Shide Zheng, Qi Guan, Zhaohua Wang, Weige Zhang","doi":"10.1080/14756366.2025.2545004","DOIUrl":null,"url":null,"abstract":"<p><p>Based on conformational preference of SMART analogues and conformational constraint strategy, two series of new tubulin polymerisation inhibitors (<b>4a </b>-<b> 4k</b> and <b>5a </b>-<b> 5h</b>/<b>6a </b>-<b> 6h</b>) were designed <i>via</i> hydrogen bonding, steric effect (for <b>4a </b>-<b> 4k</b>) and ring-closing approach by fused five- and seven-membered ring (for <b>5a </b>-<b> 5h</b>/<b>6a </b>-<b> 6h</b>) which was first adopted in the design of new SMART analogues. Among these compounds, <b>4k</b> and <b>5a</b> showed potent activities with IC<sub>50</sub> values of 15 nM and 6 nM against PC-3 cell line. Mechanism studies indicated that <b>4k</b> and <b>5a</b> could inhibit tubulin polymerisation, arrest cell cycle at G<sub>2</sub>/M phase, induce cell apoptosis, and inhibit cell migration and colony formation. Molecular docking suggested that compounds <b>4k</b> and <b>5a</b> could bind into the colchicine binding site at the pose similar to DAMA-colchicine. Western blot assays revealed that <b>4k</b> and <b>5a</b> regulated the expression of cell cycle and apoptosis-related proteins. Prediction of physicochemical properties indicated good drug-likeness of <b>4k</b> and <b>5a</b>.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2545004"},"PeriodicalIF":5.4000,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12459184/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Enzyme Inhibition and Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/14756366.2025.2545004","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/9/23 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Based on conformational preference of SMART analogues and conformational constraint strategy, two series of new tubulin polymerisation inhibitors (4a - 4k and 5a - 5h/6a - 6h) were designed via hydrogen bonding, steric effect (for 4a - 4k) and ring-closing approach by fused five- and seven-membered ring (for 5a - 5h/6a - 6h) which was first adopted in the design of new SMART analogues. Among these compounds, 4k and 5a showed potent activities with IC50 values of 15 nM and 6 nM against PC-3 cell line. Mechanism studies indicated that 4k and 5a could inhibit tubulin polymerisation, arrest cell cycle at G2/M phase, induce cell apoptosis, and inhibit cell migration and colony formation. Molecular docking suggested that compounds 4k and 5a could bind into the colchicine binding site at the pose similar to DAMA-colchicine. Western blot assays revealed that 4k and 5a regulated the expression of cell cycle and apoptosis-related proteins. Prediction of physicochemical properties indicated good drug-likeness of 4k and 5a.
期刊介绍:
Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents.
Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research.
The journal’s focus includes current developments in:
Enzymology;
Cell biology;
Chemical biology;
Microbiology;
Physiology;
Pharmacology leading to drug design;
Molecular recognition processes;
Distribution and metabolism of biologically active compounds.