Spiroindoline-Capped Selective HDAC6 Inhibitors: Design, Synthesis, Structural Analysis, and Biological Evaluation

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2020 Nov 20

PMID 33214839

Citations 9

Authors

A Prasanth Saraswati

Nicola Relitti

Margherita Brindisi

Jeremy D Osko

Giulia Chemi

Stefano Federico

Alessandro Grillo

Simone Brogi

Niamh H McCabe

Richard C Turkington

Ola Ibrahim

Jeffrey OSullivan

Stefania Lamponi

Magda Ghanim

Vincent P Kelly

Daniela Zisterer

Rebecca Amet

Patricia Hannon Barroeta

Francesca Vanni

Cristina Ulivieri

Daniel Herp

Federica Sarno

Antonella Di Costanzo

Fulvio Saccoccia

Giovina Ruberti

Manfred Jung

Lucia Altucci

Sandra Gemma

Stefania Butini

David W Christianson

Giuseppe Campiani

Affiliations

Soon will be listed here.

Abstract

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 . We identified compound as the most potent and selective HDAC6 inhibitor of the series. Biological investigation of compounds , , and 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. induced HDAC6-dependent pSTAT3 inhibition.

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