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

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 Barroeta, Francesca Vanni, Cristina UlivieriDaniel Herp, Federica Sarno, Antonella Di Costanzo, Fulvio Saccoccia, Giovina Ruberti, Manfred Jung, Lucia Altucci, Sandra Gemma, Stefania Butini, David W. Christianson, Giuseppe Campiani*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)2268-2276
Number of pages9
JournalACS Medicinal Chemistry Letters
Issue number11
Early online date29 Sept 2020
Publication statusPublished - 12 Nov 2020

Bibliographical note

Funding Information:
Support from the European Union’s Horizon 2020 (EU) Research and Innovation Programme under the Marie Sklodowska-Curie grant agreement No. 721906-TRACT is acknowledged. Cost Action EPICHEMBIO CM1406 (G.C, M.B.) and the synchrotron beamline staff at the Advanced Photon Source (APS) for assistance, especially David Neau are also gratefully acknowledged. We thank the Northeastern Collaborative Access Team (NE-CAT) funded by the National Institute of General Medical Sciences (NIGMS) from the NIH (P30 GM124165), and US National Institutes of Health grant GM49758. The Pilatus 6M detector on beamline 24-ID-C is funded by a NIH-ORIP HEI grant (S10 RR029205). This research used resources of the Advanced Photon Source (APS), a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. N.R. Tuscany strategic project POR-FSE 2014-2020, ‘Medicina di Precisione e Malattie Rare’(MePreMaRe), (ACE-ESCC). G.R. acknowledges the CNR-CNCCS “Rare, Neglected and Poverty Related Diseases - Schistodiscovery Project” (DSB.AD011.001.003). L.A. acknowledges MIUR20152TE5PK; VALERE: Vanvitelli per la Ricerca; Campania Regional Government Technology Platform Lotta alle Patologie Oncologiche: iCURE and Campania Regional Government FASE2: IDEAL. MIUR, Proof of Concept POC01_00043.

Publisher Copyright:
© 2020 American Chemical Society. All rights reserved.

Copyright 2021 Elsevier B.V., All rights reserved.


  • cancer therapy
  • HDAC inhibitors
  • HDAC6
  • spiroindoline
  • STAT3

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


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