Synthesis, biological characterization and molecular modeling insights of spirochromanes as potent HDAC inhibitors

Florian Thaler; Loris Moretti; Raffaella Amici; Agnese Abate; Andrea Colombo; Giacomo Carenzi; Maria Carmela Fulco; Roberto Boggio; Giulio Dondio; Stefania Gagliardi; Saverio Minucci; Luca Sartori; Mario Varasi; Ciro Mercurio

doi:10.1016/j.ejmech.2015.11.010

Synthesis, biological characterization and molecular modeling insights of spirochromanes as potent HDAC inhibitors

Florian Thaler, Loris Moretti, Raffaella Amici, Agnese Abate, Andrea Colombo, Giacomo Carenzi, Maria Carmela Fulco, Roberto Boggio, Giulio Dondio, Stefania Gagliardi, Saverio Minucci, Luca Sartori, Mario Varasi, Ciro Mercurio

Istituto Europeo di Oncologia

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

Abstract

In the last decades, inhibitors of histone deacetylases (HDAC) have become an important class of anti-cancer agents. In a previous study we described the synthesis of spiro[chromane-2,4′-piperidine]hydroxamic acid derivatives able to inhibit histone deacetylase enzymes. Herein, we present our exploration for new derivatives by replacing the piperidine moiety with various cycloamines. The goal was to obtain highly potent compounds with a good in vitro ADME profile. In addition, molecular modeling studies unravelled the binding mode of these inhibitors.

Original language	English
Pages (from-to)	53-67
Number of pages	15
Journal	European Journal of Medicinal Chemistry
Volume	108
DOIs	https://doi.org/10.1016/j.ejmech.2015.11.010
Publication status	Published - Jan 27 2016

Keywords

Antiproliferation
Epigenetics
Histone deacetylases
Molecular modeling
Privileged structures

ASJC Scopus subject areas

Drug Discovery
Organic Chemistry
Pharmacology

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10.1016/j.ejmech.2015.11.010

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Thaler, F., Moretti, L., Amici, R., Abate, A., Colombo, A., Carenzi, G., Fulco, M. C., Boggio, R., Dondio, G., Gagliardi, S., Minucci, S., Sartori, L., Varasi, M., & Mercurio, C. (2016). Synthesis, biological characterization and molecular modeling insights of spirochromanes as potent HDAC inhibitors. European Journal of Medicinal Chemistry, 108, 53-67. https://doi.org/10.1016/j.ejmech.2015.11.010

Thaler, F, Moretti, L, Amici, R, Abate, A, Colombo, A, Carenzi, G, Fulco, MC, Boggio, R, Dondio, G, Gagliardi, S, Minucci, S, Sartori, L, Varasi, M & Mercurio, C 2016, 'Synthesis, biological characterization and molecular modeling insights of spirochromanes as potent HDAC inhibitors', European Journal of Medicinal Chemistry, vol. 108, pp. 53-67. https://doi.org/10.1016/j.ejmech.2015.11.010

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AU - Thaler, Florian

AU - Moretti, Loris

AU - Amici, Raffaella

AU - Abate, Agnese

AU - Colombo, Andrea

AU - Carenzi, Giacomo

AU - Fulco, Maria Carmela

AU - Boggio, Roberto

AU - Dondio, Giulio

AU - Gagliardi, Stefania

AU - Minucci, Saverio

AU - Sartori, Luca

AU - Varasi, Mario

AU - Mercurio, Ciro

PY - 2016/1/27

Y1 - 2016/1/27

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AB - In the last decades, inhibitors of histone deacetylases (HDAC) have become an important class of anti-cancer agents. In a previous study we described the synthesis of spiro[chromane-2,4′-piperidine]hydroxamic acid derivatives able to inhibit histone deacetylase enzymes. Herein, we present our exploration for new derivatives by replacing the piperidine moiety with various cycloamines. The goal was to obtain highly potent compounds with a good in vitro ADME profile. In addition, molecular modeling studies unravelled the binding mode of these inhibitors.

KW - Antiproliferation

KW - Epigenetics

KW - Histone deacetylases

KW - Molecular modeling

KW - Privileged structures

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JO - European Journal of Medicinal Chemistry

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Synthesis, biological characterization and molecular modeling insights of spirochromanes as potent HDAC inhibitors

Abstract

Keywords

ASJC Scopus subject areas

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