Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12779/7314
Title: Spiroindoline-Capped Selective HDAC6 Inhibitors: Design, Synthesis, Structural Analysis, and Biological Evaluation
Authors: Saraswati, A Prasanth
Relitti, Nicola 
Brindisi, Margherita 
Osko, Jeremy D
Chemi, Giulia 
Federico, Stefano 
Grillo, Alessandro
Brogi, Simone
McCabe, Niamh H
Turkington, Richard C
Ibrahim, Ola
O'Sullivan, Jeffrey
Lamponi, Stefania 
Ghanim, Magda
Kelly, Vincent P
Zisterer, Daniela
Amet, Rebecca
Hannon Barroeta, Patricia
Vanni, Francesca
Ulivieri, Cristina
Herp, Daniel
Sarno, Federica
Di Costanzo, Antonella
Saccoccia, Fulvio
Ruberti, Giovina
Jung, Manfred
Altucci, Lucia
Gemma, Sandra 
Butini, Stefania 
Christianson, David W
Campiani, Giuseppe 
Issue Date: 2020
Project: None 
Journal: ACS MEDICINAL CHEMISTRY LETTERS
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 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.
Description: 
227168
URI: http://hdl.handle.net/20.500.12779/7314
ISSN: 1948-5875
DOI: 10.1021/acsmedchemlett.0c00395
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