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Spiroindoline-Capped Selective HDAC6 Inhibitors: Design, Synthesis, Structural Analysis, and Biological Evaluation
ACS Medicinal Chemistry Letters ( IF 4.2 ) Pub Date : 2020-09-29 , DOI: 10.1021/acsmedchemlett.0c00395
A Prasanth Saraswati 1 , Nicola Relitti 1 , Margherita Brindisi 1 , Jeremy D Osko 2 , Giulia Chemi 1 , Stefano Federico 1 , Alessandro Grillo 1 , Simone Brogi 3 , Niamh H McCabe 4 , Richard C Turkington 4 , Ola Ibrahim 5 , Jeffrey O'Sullivan 5 , Stefania Lamponi 1 , Magda Ghanim 6 , Vincent P Kelly 6 , Daniela Zisterer 6 , Rebecca Amet 6 , Patricia Hannon Barroeta 6 , Francesca Vanni 7 , Cristina Ulivieri 7 , Daniel Herp 8 , Federica Sarno 9 , Antonella Di Costanzo 9 , Fulvio Saccoccia 10 , Giovina Ruberti 10 , Manfred Jung 8 , Lucia Altucci 9 , Sandra Gemma 1 , Stefania Butini 1 , David W Christianson 2 , Giuseppe Campiani 1
Affiliation  

Histone deacetylase inhibitors (HDACi) have emerged as promising therapeutics for the treatment of neurodegeneration, cancer, and rare disorders. Herein, we report the development of a series of spiroindoline-based HDAC6 isoform-selective inhibitors based on the X-ray crystal studies of the hit 6a. We identified compound 6j as the most potent and selective hHDAC6 inhibitor of the series. Biological investigation of compounds 6b, 6h, and 6j demonstrated their antiproliferative activity against several cancer cell lines. Western blotting studies indicated that they were able to increase tubulin acetylation, without significant variation in histone acetylation state, and induced PARP cleavage indicating their apoptotic potential at the molecular level. 6j induced HDAC6-dependent pSTAT3 inhibition.

中文翻译:

螺吲哚啉封端的选择性 HDAC6 抑制剂:设计、合成、结构分析和生物学评价

组蛋白去乙酰化酶抑制剂 (HDACi) 已成为治疗神经退行性疾病、癌症和罕见疾病的有前途的疗法。在此,我们报告了基于命中6a的 X 射线晶体研究的一系列基于螺二氢吲哚的 HDAC6 异构体选择性抑制剂的开发。我们确定化合物6j是该系列中最有效和最具选择性的h HDAC6 抑制剂。化合物6b6h6j的生物学研究证明了它们对几种癌细胞系的抗增殖活性。蛋白质印迹研究表明,它们能够增加微管蛋白乙酰化,而组蛋白乙酰化状态没有显着变化,并诱导 PARP 裂解,表明它们在分子水平上具有凋亡潜力。6j诱导 HDAC6 依赖性 pSTAT3 抑制。
更新日期:2020-11-12
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