Discovery of salermide-related sirtuin inhibitors: Binding mode studies and antiproliferative effects in cancer cells including cancer stem cells

Dante Rotili, Domenico Tarantino, Angela Nebbioso, Chantal Paolini, Covadonga Huidobro, Ester Lara, Paolo Mellini, Alessia Lenoci, Riccardo Pezzi, Giorgia Botta, Maija Lahtela-Kakkonen, Antti Poso, Christian Steinkühler, Paola Gallinari, Ruggero De Maria, Mario Fraga, Manel Esteller, Lucia Altucci, Antonello Mai

Research output: Contribution to journalArticlepeer-review

Abstract

Chemical changes performed on 1a (sirtinol) led to a series of SIRT1/2 inhibitors, in some cases more potent than 1a mainly against SIRT1. Tested in human leukemia U937 cells, the benzamide and anilide derivatives 1b, 1c, 2b, and 2c as well as the 4-(2-phenylpropyl)thioanalogue 4c showed huge apoptosis induction, while some sulfinyl and sulfonyl derivatives (5b, 5c, and 6a-c) were highly efficient in granulocytic differentiation. When assayed in human leukemia MOLT4 as well as in human breast MDA-MB-231 and colon RKO cancer cell lines, the anilide 2b (salermide) and the phenylpropylthio analogue 4b emerged as the most potent antiproliferative agents. Tested on colorectal carcinoma and glioblastoma multiforme cancer stem cells (CSCs) from patients, 2b was particularly potent against colorectal carcinoma CSCs, while 4b, 6a, and the SIRT2-selective inhibitor AGK-2 showed the highest effect against glioblastoma multiforme CSCs. Such compounds will be further explored for their broad-spectrum anticancer properties.

Original languageEnglish
Pages (from-to)10937-10947
Number of pages11
JournalJournal of Medicinal Chemistry
Volume55
Issue number24
DOIs
Publication statusPublished - Dec 27 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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