title: Discovery of salermide-related sirtuin inhibitors: binding mode studies and antiproliferative effects in cancer cells including cancer stem cells.
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.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma La Sapienza, P.le A. Moro 5, 00185 Roma, Italy.
authors.forename: Dante
authors.initials: D
authors.lastname: Rotili
authors.forename: Domenico
authors.initials: D
authors.lastname: Tarantino
authors.forename: Angela
authors.initials: A
authors.lastname: Nebbioso
authors.forename: Chantal
authors.initials: C
authors.lastname: Paolini
authors.forename: Covadonga
authors.initials: C
authors.lastname: Huidobro
authors.forename: Ester
authors.initials: E
authors.lastname: Lara
authors.forename: Paolo
authors.initials: P
authors.lastname: Mellini
authors.forename: Alessia
authors.initials: A
authors.lastname: Lenoci
authors.forename: Riccardo
authors.initials: R
authors.lastname: Pezzi
authors.forename: Giorgia
authors.initials: G
authors.lastname: Botta
authors.forename: Maija
authors.initials: M
authors.lastname: Lahtela-Kakkonen
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
authors.forename: Christian
authors.initials: C
authors.lastname: Steinkühler
authors.forename: Paola
authors.initials: P
authors.lastname: Gallinari
authors.forename: Ruggero
authors.initials: R
authors.lastname: De Maria
authors.forename: Mario
authors.initials: M
authors.lastname: Fraga
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects; D006801:Humans; D062105:Molecular Docking Simulation; D009284:Naphthols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects*; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors*; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C539427:N-(3-((2-hydroxynaphthalen-1-ylmethylene)amino)phenyl)-2-phenylpropionamide; D009284:Naphthols; D010666:Phenylpropionates; D056564:Sirtuin 1; D056565:Sirtuin 2