Discovery of Salermide-Related Sirtuin Inhibitors: Binding Mode Studies and Antiproliferative Effects in Cancer Cells Including Cancer Stem Cells
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- 作者：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 Steink眉hler ; Paola Gallinari ; Ruggero De Maria ; Mario Fraga ; Manel Esteller ; Lucia Altucci ; Antonello Mai
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：December 27, 2012
- 年：2012
- 卷：55
- 期：24
- 页码：10937-10947
- 全文大小：551K
- 年卷期：v.55,no.24(December 27, 2012)
- ISSN：1520-4804
文摘
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鈥?b>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.