支架重新定位方法:二氢苯并咪唑三嗪二酮 (BITD) 衍生物作为 ALDH1A1 的选择性抑制剂。

IF 3.9 2区 化学 Q2 CHEMISTRY, APPLIED
Bianca Laura Bernardoni, Ilaria D'Agostino, Sonia Siragusa, Mattia Mori, Silvia Garavaglia, Concettina La Motta
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引用次数: 0

摘要

醛脱氢酶1A亚家族(aldh1a)在多种疾病,特别是癌症中的过表达,使其成为治疗应用的重要靶点。有趣的是,1A1同工酶在肿瘤的发生和发展中发挥作用,被确定为癌症干细胞的生物标志物。然而,尽管前景看好,目前的ALDH1A1抑制剂缺乏异构体选择性和脱靶毒性。本研究旨在通过开发一类新的aldh1a1选择性抑制剂来解决这些限制。通过利用与isatin基ALDH1A1抑制剂的结构相似性,我们设计了含有二氢苯并[4,5]咪唑[2,1-c][1,2,4]三嗪-3,4-二酮(BITD)核心的化合物,该化合物从重新定位方法中产生。利用微波辅助方法,合成了一个小的衍生物文库,酶分析显示ALDH1A1在ALDH1As中具有很好的异构体特异性,其中同类最佳化合物5显示对ALDH1A1酶活性的抑制作用为86%,对1A2和1A3同工酶无抑制作用。硅实验进一步阐明了5的结合模式,为观察到的选择性提供了合理的依据。这些发现为开发更具选择性的ALDH1A1抑制剂提供了一个有希望的策略,为进一步优化过程奠定了基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A scaffold repositioning approach: dihydroBenzoImidazoTriazineDione (BITD) derivatives as selective ALDH1A1 inhibitors.

The overexpression of the Aldehyde Dehydrogenases 1A subfamily (ALDH1As) in various diseases, particularly in cancer, has made it an important target for therapeutic applications. Interestingly, the 1A1 isoenzyme plays a role in tumor initiation and progression, being identified as a biomarker for cancer stem cells. However, although promising, current ALDH1A1 inhibitors suffer from a lack of isoform selectivity and off-target toxicity. This study aims to address these limitations by developing a new class of ALDH1A1-selective inhibitors. By leveraging structural analogies with Isatin-based ALDH1A1 inhibitors, we designed compounds containing a dihydrobenzo[4,5]imidazo[2,1-c][1,2,4]triazine-3,4-dione (BITD) core, that emerged from a repositioning approach. Using a microwave-assisted protocol, a small library of derivatives was synthesized, and enzymatic assays highlighted a promising isoform specificity for ALDH1A1 among ALDH1As, with the best-in-class compound 5, showing an inhibition of the enzyme activity of 86% for ALDH1A1 and no inhibition for 1A2 and 1A3 isoenzymes. In silico studies further elucidated the binding mode of 5, providing a rational basis for the observed selectivity. These findings represent a promising strategy for the development of more selective ALDH1A1 inhibitors, laying the foundation for further optimization processes.

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来源期刊
Molecular Diversity
Molecular Diversity 化学-化学综合
CiteScore
7.30
自引率
7.90%
发文量
219
审稿时长
2.7 months
期刊介绍: Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;
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