Spiroindoline-Capped Selective HDAC6 Inhibitors: Design, 2 Synthesis, Structural Analysis, and Biological Evaluation

Zisterer, Daniela; Kelly, Vincent; O'Sullivan, Jeffrey

doi:https://dx.doi.org/10.1021/acsmedchemlett.0c00395

Spiroindoline-Capped Selective HDAC6 Inhibitors: Design, 2 Synthesis, Structural Analysis, and Biological Evaluation

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proof-ACSml_HDAC_Spiro.pdf (4.32 MB)

Date

2020

Authors

Zisterer, Daniela

Kelly, Vincent

O'Sullivan, Jeffrey

Access

openAccess

Citation

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 O Sullivan, Stefania Lamponi, Magda Ghanim, Vincent P. Kelly, Daniela Zisterer, Rebecca Amet, Patricia Hannon, 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, and Giuseppe Campiani, Spiroindoline-Capped Selective HDAC6 Inhibitors: Design, 2 Synthesis, Structural Analysis, and Biological Evaluation, ACS Medicinal Chemistry Letters, 2020

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.