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

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.

SUBMITTER: Saraswati AP

PROVIDER: S-EPMC7667836 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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

Saraswati A Prasanth AP Relitti Nicola N Brindisi Margherita M Osko Jeremy D JD Chemi Giulia G Federico Stefano S Grillo Alessandro A Brogi Simone S McCabe Niamh H NH Turkington Richard C RC Ibrahim Ola O O'Sullivan Jeffrey J Lamponi Stefania S Ghanim Magda M Kelly Vincent P VP Zisterer Daniela D Amet Rebecca R Hannon Barroeta Patricia P Vanni Francesca F Ulivieri Cristina C Herp Daniel D Sarno Federica F Di Costanzo Antonella A Saccoccia Fulvio F Ruberti Giovina G Jung Manfred M Altucci Lucia L Gemma Sandra S Butini Stefania S Christianson David W DW Campiani Giuseppe G

ACS medicinal chemistry letters 20200929 11

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 t ...[more]

PMID: 33214839

Dataset Information

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

Publications

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

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