Hemithioindigo-based histone deacetylase inhibitors induce a light-dependent anticancer effect,European Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › Eur. J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Hemithioindigo-based histone deacetylase inhibitors induce a light-dependent anticancer effect
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2024-09-06 , DOI: 10.1016/j.ejmech.2024.116846
Laia Josa-Culleré ₁ , Carla Aira Rodríguez ₁ , Amadeu Llebaria ₁

Affiliation

Photoswitchable molecules exhibit light-dependent biological activity which allow us to control the therapeutic effect of drugs with high precision. Such molecules could solve some of the limitations of anticancer drugs by providing a localised effect in the tumour. Histone deacetylase inhibitors (HDACis) constitute a promising drug class for oncology whose application is often limited by a lack of selectivity. Herein, we developed photoswitchable HDACis based on a hemithioindigo scaffold. We established synthetic routes to access them and determined the optimal conditions for isomerisation and their thermal stability. We then optimised their enzyme activity through three rounds of re-design to identify examples that are up to 6-fold more active under illumination than in the dark. We also confirmed that our best derivative reduces the viability of HeLa cells only under illumination. All in all, we disclose a series of derivatives containing a hemithioindigo moiety, which display a light-dependent effect on both HDAC inhibition and cancer cell viability.

中文翻译：

基于半硫靛蓝的组蛋白脱乙酰酶抑制剂诱导光依赖性抗癌作用

光开关分子表现出光依赖性生物活性，这使我们能够高精度地控制药物的治疗效果。这种分子可以通过在肿瘤中提供局部作用来解决抗癌药物的一些局限性。组蛋白脱乙酰酶抑制剂（HDACis）是一类很有前途的肿瘤药物，其应用通常受到缺乏选择性的限制。在此，我们开发了基于 hemithioindigo 支架的光开关 HDACis。我们建立了合成途径来获取它们，并确定了异构化的最佳条件及其热稳定性。然后，我们通过三轮重新设计优化了它们的酶活性，以确定在光照下比在黑暗中活性高 6 倍的示例。我们还证实，我们的 Best 衍生物仅在光照下降低 HeLa 细胞的活力。总而言之，我们公开了一系列含有半硫靛蓝部分的衍生物，这些部分对 HDAC 抑制和癌细胞活力均显示出光依赖性作用。

更新日期：2024-09-06

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南