Discovery of long-chain salicylketoxime derivatives as monoacylglycerol lipase (MAGL) inhibitors

Giulia Bononi; Carlotta Granchi; Margherita Lapillo; Massimiliano Giannotti; Daniela Nieri; Serena Fortunato; Maguie El Boustani; Isabella Caligiuri; Giulio Poli; Kathryn E. Carlson; Sung Hoon Kim; Marco Macchia; Adriano Martinelli; Flavio Rizzolio; Andrea Chicca; John A. Katzenellenbogen; Filippo Minutolo; Tiziano Tuccinardi

doi:10.1016/j.ejmech.2018.08.038

Discovery of long-chain salicylketoxime derivatives as monoacylglycerol lipase (MAGL) inhibitors

Giulia Bononi, Carlotta Granchi, Margherita Lapillo, Massimiliano Giannotti, Daniela Nieri, Serena Fortunato, Maguie El Boustani, Isabella Caligiuri, Giulio Poli, Kathryn E. Carlson, Sung Hoon Kim, Marco Macchia, Adriano Martinelli, Flavio Rizzolio, Andrea Chicca, John A. Katzenellenbogen, Filippo Minutolo, Tiziano Tuccinardi

Centro di Riferimento Oncologico

Research output: Contribution to journal › Article

Abstract

Monoacylglycerol lipase (MAGL) is the enzyme hydrolyzing the endocannabinoid 2-arachidonoylglycerol (2-AG) to free arachidonic acid and glycerol. Therefore, MAGL is implicated in many physiological processes involving the regulation of the endocannabinoid system and eicosanoid network. MAGL inhibition represents a potential therapeutic target for many diseases, including cancer. Nowadays, most MAGL inhibitors inhibit this enzyme by an irreversible mechanism of action, potentially leading to unwanted side effects from chronic treatment. Herein, we report the discovery of long-chain salicylketoxime derivatives as potent and reversible MAGL inhibitors. The compounds herein described are characterized by a good target selectivity for MAGL and by antiproliferative activities against a series of cancer cell lines. Finally, modeling studies suggest a reasonable hypothetical binding mode for this class of compounds.

Original language	English
Pages (from-to)	817-836
Number of pages	20
Journal	European Journal of Medicinal Chemistry
Volume	157
DOIs	https://doi.org/10.1016/j.ejmech.2018.08.038
Publication status	Published - Sep 5 2018

Keywords

Cancer
Ketoxime
MAGL
Monoacylglycerol lipase inhibitors

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

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Bononi, G., Granchi, C., Lapillo, M., Giannotti, M., Nieri, D., Fortunato, S., Boustani, M. E., Caligiuri, I., Poli, G., Carlson, K. E., Kim, S. H., Macchia, M., Martinelli, A., Rizzolio, F., Chicca, A., Katzenellenbogen, J. A., Minutolo, F., & Tuccinardi, T. (2018). Discovery of long-chain salicylketoxime derivatives as monoacylglycerol lipase (MAGL) inhibitors. European Journal of Medicinal Chemistry, 157, 817-836. https://doi.org/10.1016/j.ejmech.2018.08.038

Discovery of long-chain salicylketoxime derivatives as monoacylglycerol lipase (MAGL) inhibitors. / Bononi, Giulia; Granchi, Carlotta; Lapillo, Margherita; Giannotti, Massimiliano; Nieri, Daniela; Fortunato, Serena; Boustani, Maguie El; Caligiuri, Isabella; Poli, Giulio; Carlson, Kathryn E.; Kim, Sung Hoon; Macchia, Marco; Martinelli, Adriano; Rizzolio, Flavio; Chicca, Andrea; Katzenellenbogen, John A.; Minutolo, Filippo; Tuccinardi, Tiziano.

In: European Journal of Medicinal Chemistry, Vol. 157, 05.09.2018, p. 817-836.

Research output: Contribution to journal › Article

Bononi, G, Granchi, C, Lapillo, M, Giannotti, M, Nieri, D, Fortunato, S, Boustani, ME, Caligiuri, I, Poli, G, Carlson, KE, Kim, SH, Macchia, M, Martinelli, A, Rizzolio, F, Chicca, A, Katzenellenbogen, JA, Minutolo, F & Tuccinardi, T 2018, 'Discovery of long-chain salicylketoxime derivatives as monoacylglycerol lipase (MAGL) inhibitors', European Journal of Medicinal Chemistry, vol. 157, pp. 817-836. https://doi.org/10.1016/j.ejmech.2018.08.038

Bononi, Giulia ; Granchi, Carlotta ; Lapillo, Margherita ; Giannotti, Massimiliano ; Nieri, Daniela ; Fortunato, Serena ; Boustani, Maguie El ; Caligiuri, Isabella ; Poli, Giulio ; Carlson, Kathryn E. ; Kim, Sung Hoon ; Macchia, Marco ; Martinelli, Adriano ; Rizzolio, Flavio ; Chicca, Andrea ; Katzenellenbogen, John A. ; Minutolo, Filippo ; Tuccinardi, Tiziano. / Discovery of long-chain salicylketoxime derivatives as monoacylglycerol lipase (MAGL) inhibitors. In: European Journal of Medicinal Chemistry. 2018 ; Vol. 157. pp. 817-836.

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abstract = "Monoacylglycerol lipase (MAGL) is the enzyme hydrolyzing the endocannabinoid 2-arachidonoylglycerol (2-AG) to free arachidonic acid and glycerol. Therefore, MAGL is implicated in many physiological processes involving the regulation of the endocannabinoid system and eicosanoid network. MAGL inhibition represents a potential therapeutic target for many diseases, including cancer. Nowadays, most MAGL inhibitors inhibit this enzyme by an irreversible mechanism of action, potentially leading to unwanted side effects from chronic treatment. Herein, we report the discovery of long-chain salicylketoxime derivatives as potent and reversible MAGL inhibitors. The compounds herein described are characterized by a good target selectivity for MAGL and by antiproliferative activities against a series of cancer cell lines. Finally, modeling studies suggest a reasonable hypothetical binding mode for this class of compounds.",

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AU - Nieri, Daniela

AU - Fortunato, Serena

AU - Boustani, Maguie El

AU - Caligiuri, Isabella

AU - Poli, Giulio

AU - Carlson, Kathryn E.

AU - Kim, Sung Hoon

AU - Macchia, Marco

AU - Martinelli, Adriano

AU - Rizzolio, Flavio

AU - Chicca, Andrea

AU - Katzenellenbogen, John A.

AU - Minutolo, Filippo

AU - Tuccinardi, Tiziano

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AB - Monoacylglycerol lipase (MAGL) is the enzyme hydrolyzing the endocannabinoid 2-arachidonoylglycerol (2-AG) to free arachidonic acid and glycerol. Therefore, MAGL is implicated in many physiological processes involving the regulation of the endocannabinoid system and eicosanoid network. MAGL inhibition represents a potential therapeutic target for many diseases, including cancer. Nowadays, most MAGL inhibitors inhibit this enzyme by an irreversible mechanism of action, potentially leading to unwanted side effects from chronic treatment. Herein, we report the discovery of long-chain salicylketoxime derivatives as potent and reversible MAGL inhibitors. The compounds herein described are characterized by a good target selectivity for MAGL and by antiproliferative activities against a series of cancer cell lines. Finally, modeling studies suggest a reasonable hypothetical binding mode for this class of compounds.

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