Exploration of the Tertiary Amide Chemical Space of Dolastatin 15 Analogs Reveals New Insights into the Structure-Anticancer Activity Relationship.

IF 3.4 4区 医学 Q2 CHEMISTRY, MEDICINAL
ChemMedChem Pub Date : 2025-08-22 DOI:10.1002/cmdc.202500580
Dayana Alonso, Leslie Reguera, Robert Rennert, Ibrahim Morgan, Mohammed Saoud, Manuel G Ricardo, Leslie Valdés, Julieta Coro-Bermello, Ludger A Wessjohann, Daniel G Rivera
{"title":"Exploration of the Tertiary Amide Chemical Space of Dolastatin 15 Analogs Reveals New Insights into the Structure-Anticancer Activity Relationship.","authors":"Dayana Alonso, Leslie Reguera, Robert Rennert, Ibrahim Morgan, Mohammed Saoud, Manuel G Ricardo, Leslie Valdés, Julieta Coro-Bermello, Ludger A Wessjohann, Daniel G Rivera","doi":"10.1002/cmdc.202500580","DOIUrl":null,"url":null,"abstract":"<p><p>Dolastatins are a class of naturally occurring antimitotic peptides that have inspired the development of some of the most active and widely used anticancer agents. Here, we report on the development of synthetic methodologies for the preparation of parallel libraries of small peptides inspired by dolastatin 15 and its analogs cemadotin and tasidotin. The approaches rely on the use of either one or multiple Ugi-multicomponent reactions to generate amide N-substituted dolastatin-like skeletons, which allow the exploration of tertiary amide chemical spaces that have not been assessed previously. Evaluation of the anticancer activity in a variety of cancer cells showed that introducing a tertiary amide at the C-terminal fragment or by replacement of a proline residue does not lead to an increment in the anti-proliferative activity. The microtubule-disrupting capacity of the new dolastatin analogs was studied and compared with other potent antimitotic agents, thereby shedding light on mechanistic details of their anti-proliferative activity.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500580"},"PeriodicalIF":3.4000,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ChemMedChem","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/cmdc.202500580","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0

Abstract

Dolastatins are a class of naturally occurring antimitotic peptides that have inspired the development of some of the most active and widely used anticancer agents. Here, we report on the development of synthetic methodologies for the preparation of parallel libraries of small peptides inspired by dolastatin 15 and its analogs cemadotin and tasidotin. The approaches rely on the use of either one or multiple Ugi-multicomponent reactions to generate amide N-substituted dolastatin-like skeletons, which allow the exploration of tertiary amide chemical spaces that have not been assessed previously. Evaluation of the anticancer activity in a variety of cancer cells showed that introducing a tertiary amide at the C-terminal fragment or by replacement of a proline residue does not lead to an increment in the anti-proliferative activity. The microtubule-disrupting capacity of the new dolastatin analogs was studied and compared with other potent antimitotic agents, thereby shedding light on mechanistic details of their anti-proliferative activity.

Dolastatin 15类似物叔胺化学空间的探索揭示了结构-抗癌活性关系的新见解。
dolastatin是一类天然存在的抗有丝分裂肽,它激发了一些最活跃和广泛使用的抗癌药物的发展。在这里,我们报告了受dolastatin 15及其类似物cemadotin和tasidotin启发的制备小肽平行文库的合成方法的发展。这些方法依赖于使用一个或多个ugi -多组分反应来生成酰胺n取代的dolastatin样骨架,这允许探索以前未评估过的叔酰胺化学空间。对多种癌细胞的抗癌活性评价表明,在c端片段引入叔胺或替换脯氨酸残基不会导致抗增殖活性的增加。研究了新的多拉他汀类似物的微管破坏能力,并将其与其他有效的抗有丝分裂药物进行了比较,从而揭示了其抗增殖活性的机制细节。
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
ChemMedChem
ChemMedChem 医学-药学
CiteScore
6.70
自引率
2.90%
发文量
280
审稿时长
1 months
期刊介绍: Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.
×
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