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 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

doi:10.1021/acsmedchemlett.0c00395

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

Patrick G Johnston Centre for Cancer Research

Research output: Contribution to journal › Article › peer-review

5 Citations (Scopus)

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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.

Original language	English
Pages (from-to)	2268-2276
Number of pages	9
Journal	ACS Medicinal Chemistry Letters
Volume	11
Issue number	11
Early online date	29 Sep 2020
DOIs	https://doi.org/10.1021/acsmedchemlett.0c00395
Publication status	Published - 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:
Copyright 2021 Elsevier B.V., All rights reserved.

Keywords

cancer therapy
HDAC inhibitors
HDAC6
spiroindoline
STAT3

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Novel Spiroindoline-Capped Selective HDAC6 Inhibitors: Design, Synthesis, Structural Analysis, and Biological Evaluation
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Saraswati, A. P., Relitti, N., Brindisi, M., Osko, J. D., Chemi, G., Federico, S., Grillo, A., Brogi, S., McCabe, N. H., Turkington, R. C., Ibrahim, O., O'Sullivan, J., Lamponi, S., Ghanim, M., Kelly, V. P., Zisterer, D., Amet, R., Hannon Barroeta, P., Vanni, F., ... Campiani, G. (2020). Spiroindoline-Capped Selective HDAC6 Inhibitors: Design, Synthesis, Structural Analysis, and Biological Evaluation. ACS Medicinal Chemistry Letters, 11(11), 2268-2276. https://doi.org/10.1021/acsmedchemlett.0c00395

@article{5bed77f32eb84bef8802360242d740c1,

title = "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.",

keywords = "cancer therapy, HDAC inhibitors, HDAC6, spiroindoline, STAT3",

author = "Saraswati, {A. Prasanth} and Nicola Relitti and Margherita Brindisi and Osko, {Jeremy D.} and Giulia Chemi and Stefano Federico and Alessandro Grillo and Simone Brogi and McCabe, {Niamh H.} and Turkington, {Richard C.} and Ola Ibrahim and Jeffrey O'Sullivan and Stefania Lamponi and Magda Ghanim and Kelly, {Vincent P.} and Daniela Zisterer and Rebecca Amet and {Hannon Barroeta}, Patricia and Francesca Vanni and Cristina Ulivieri and Daniel Herp and Federica Sarno and {Di Costanzo}, Antonella and Fulvio Saccoccia and Giovina Ruberti and Manfred Jung and Lucia Altucci and Sandra Gemma and Stefania Butini and Christianson, {David W.} and Giuseppe Campiani",

note = "Funding Information: Support from the European Union{\textquoteright}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, {\textquoteleft}Medicina di Precisione e Malattie Rare{\textquoteright}(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: {\textcopyright} 2020 American Chemical Society. All rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2020",

month = nov,

day = "12",

doi = "10.1021/acsmedchemlett.0c00395",

language = "English",

volume = "11",

pages = "2268--2276",

journal = "ACS Medicinal Chemistry Letters",

issn = "1948-5875",

publisher = "American Chemical Society",

number = "11",

}

Saraswati, AP, Relitti, N, Brindisi, M, Osko, JD, Chemi, G, Federico, S, Grillo, A, Brogi, S, McCabe, NH, Turkington, RC, Ibrahim, O, O'Sullivan, J, Lamponi, S, Ghanim, M, Kelly, VP, Zisterer, D, Amet, R, Hannon Barroeta, P, Vanni, F, Ulivieri, C, Herp, D, Sarno, F, Di Costanzo, A, Saccoccia, F, Ruberti, G, Jung, M, Altucci, L, Gemma, S, Butini, S, Christianson, DW & Campiani, G 2020, 'Spiroindoline-Capped Selective HDAC6 Inhibitors: Design, Synthesis, Structural Analysis, and Biological Evaluation', ACS Medicinal Chemistry Letters, vol. 11, no. 11, pp. 2268-2276. https://doi.org/10.1021/acsmedchemlett.0c00395

TY - JOUR

T1 - Spiroindoline-Capped Selective HDAC6 Inhibitors: Design, Synthesis, Structural Analysis, and Biological Evaluation

AU - Saraswati, A. Prasanth

AU - Relitti, Nicola

AU - Brindisi, Margherita

AU - Osko, Jeremy D.

AU - Chemi, Giulia

AU - Federico, Stefano

AU - Grillo, Alessandro

AU - Brogi, Simone

AU - McCabe, Niamh H.

AU - Turkington, Richard C.

AU - Ibrahim, Ola

AU - O'Sullivan, Jeffrey

AU - Lamponi, Stefania

AU - Ghanim, Magda

AU - Kelly, Vincent P.

AU - Zisterer, Daniela

AU - Amet, Rebecca

AU - Hannon Barroeta, Patricia

AU - Vanni, Francesca

AU - Ulivieri, Cristina

AU - Herp, Daniel

AU - Sarno, Federica

AU - Di Costanzo, Antonella

AU - Saccoccia, Fulvio

AU - Ruberti, Giovina

AU - Jung, Manfred

AU - Altucci, Lucia

AU - Gemma, Sandra

AU - Butini, Stefania

AU - Christianson, David W.

AU - Campiani, Giuseppe

N1 - 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: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2020/11/12

Y1 - 2020/11/12

N2 - 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.

AB - 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.

KW - cancer therapy

KW - HDAC inhibitors

KW - HDAC6

KW - spiroindoline

KW - STAT3

U2 - 10.1021/acsmedchemlett.0c00395

DO - 10.1021/acsmedchemlett.0c00395

M3 - Article

AN - SCOPUS:85096385397

VL - 11

SP - 2268

EP - 2276

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

SN - 1948-5875

IS - 11

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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