Design, synthesis, and bioevaluation of pyrazole-containing tubulin polymerisation inhibitors based on conformational constraint strategy.

IF 5.4 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Zhongqiao Sun, Jiahao Wang, Fengwei Li, Liancheng Huang, Shide Zheng, Qi Guan, Zhaohua Wang, Weige Zhang
{"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.

基于构象约束策略的含吡唑微管蛋白聚合抑制剂的设计、合成和生物评价。
基于SMART类似物的构象偏好和构象约束策略,通过氢键、立体效应(适用于4a - 4k)和五元环和七元环合环(适用于5a - 5h/6a - 6h)设计了两个系列的新型微管蛋白聚合抑制剂(4a - 4k和5a - 5h/6a - 6h),这是SMART类似物设计中首次采用的方法。其中,4k和5a对PC-3细胞的IC50值分别为15 nM和6 nM。机制研究表明,4k和5a可抑制微管蛋白聚合,使细胞周期停留在G2/M期,诱导细胞凋亡,抑制细胞迁移和集落形成。分子对接表明,化合物4k和5a可以以类似dama -秋水仙碱的姿态结合到秋水仙碱的结合位点。Western blot检测显示,4k和5a调节细胞周期和凋亡相关蛋白的表达。理化性质预测显示其具有良好的药物相似度(4k和5a)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
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.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信