atropisomer[1,1'-对萘]-2,2'-二胺(BINAM)及其类似物在人癌细胞中的细胞毒性:对映体选择性、构效关系及机制

IF 3.4 4区 医学 Q2 CHEMISTRY, MEDICINAL
ChemMedChem Pub Date : 2025-08-27 DOI:10.1002/cmdc.202500426
Malte Eichelbaum, Patrick J Bednarski
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引用次数: 0

摘要

联萘基通常作为不对称合成催化剂的关键手性配体,已在数千个已发表的反应中被报道。本文报道了atropisomer (R)-[1,1'-binaphthalene]-2,2'-diamine (R- binam,1 (R))是一种中等强度的纺锤体毒素,在癌症和正常人类细胞系中引起抗增殖、微管解聚、多极纺锤体、中心周围物质(PCM)断裂、有丝分裂突变、多核细胞和凋亡。此外,导致的异常类似于微管解聚剂(MDAs)如秋水仙碱引起的异常。相反,对映体S- binam (1(S))在所有生物试验中均无活性。此外,还研究了具有关键结构差异的R-和S-BINAM衍生物的构效关系;这些研究显示了与R-BINAM相同的对映体趋势,并为该类化合物抗增殖活性的结构要求提供了见解。这些发现对于开发更具选择性的纺锤体毒素是有用的,特别是由于联苯基及其支架的天然刚性允许各种修饰。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Cytotoxicity of Atropisomeric [1,1'-Binaphthalene]-2,2'-Diamines (BINAM) and Analogs in Human Cancer Cells: Enantioselectivity, Structure-Activity Relationships, and Mechanism.

Binaphthyls usually serve as key chiral ligands in catalysts for asymmetric syntheses, having been reported in thousands of published reactions. Herein, the discovery that atropisomeric (R)-[1,1'-binaphthalene]-2,2'-diamine (R-BINAM, 1(R)) is a moderately potent spindle poison, causing antiproliferation, depolymerization of microtubules, multipolar spindles, pericentriolar material (PCM) fragmentation, mitotic catastrophe, multinucleated cells, and apoptosis in cancer and normal human cell lines, is reported. Furthermore, the resulting abnormalities resemble those induced by microtubule-depolymerizing agents (MDAs) such as colchicine. In contrast, the enantiomer S-BINAM (1(S)) was inactive in all biological assays. Additionally, the structure-activity relationships of a selection of R- and S-BINAM derivatives with key structural differences have been studied; these studies show the same enantiomeric trend as with R-BINAM and provide insight into the structural requirements for the antiproliferative activity of this compound class. These findings should be useful for the development of more selective spindle poisons, especially due to the natural rigidity of binaphthyls and their scaffold that allows for various modifications.

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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.
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