Discovery of Salermide-Related Sirtuin Inhibitors: Binding Mode Studies and Antiproliferative Effects in Cancer Cells Including Cancer Stem Cells

• DOI: 10.1021/jm3011614
• Publication Date: 2012-11-29T10:50:08Z
• Authors: Dante Rotili; Domenico Tarantino; Angela Nebbioso; Chantal Paolini; Covadonga Huidobro; Ester Lara; Paolo Mellini; Alessia Lenoci; Riccardo Pezzi; Giorgia Botta; Maija Lahtela-Kak...; Antti Poso; Christian Steinkü...; Paola Gallinari; Ruggero De Maria; Mario Fraga; Manel Esteller; Lucia Altucci; Antonello Mai
• Keywords: Benzamide; SIRT2

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