title: Simplification of the tetracyclic SIRT1-selective inhibitor MC2141: coumarin- and pyrimidine-based SIRT1/2 inhibitors with different selectivity profile.
abstract: In this report we describe the synthesis and biological characterization of two series of sirtuins' inhibitors (SIRTi), designed as simplification products of the previously reported SIRT1-selective inhibitor MC2141 (4). In the first series (5a-t) we report a number of 2-substituted-1,2-dihydrobenzo[f]chromen-3-ones with a marked selectivity for the inhibition of SIRT2 over SIRT1. Some of such derivatives showed also high pro-apoptotic (5i and 5l) and/or cytodifferentiating (5d, 5i, and 5o) properties in a human leukemia cell line (U937). The second group of SIRTi (6a-q) is characterized by some analogues of cambinol (3), a well known SIRTi active against the Burkitt lymphoma. Such compounds, differently from the unselective prototype, are endowed with a selective inhibition of SIRT1 over SIRT2, and, in some cases (6j, 6k, and 6q), are more efficient than 3 to induce apoptosis in U937 cells.
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: Vincenzo
authors.initials: V
authors.lastname: Carafa
authors.forename: Domenico
authors.initials: D
authors.lastname: Tarantino
authors.forename: Giorgia
authors.initials: G
authors.lastname: Botta
authors.forename: Angela
authors.initials: A
authors.lastname: Nebbioso
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; D045744:Cell Line, Tumor; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors*; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D003374:Coumarins; C562352:MC 2141; D011743:Pyrimidines; D052999:Quinazolinones; C030123:coumarin; D056564:Sirtuin 1; D056565:Sirtuin 2