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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.
AuthorsDante Rotili, Vincenzo Carafa, Domenico Tarantino, Giorgia Botta, Angela Nebbioso, Lucia Altucci, Antonello Mai
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 19 Issue 12 Pg. 3659-68 (Jun 15 2011) ISSN: 1464-3391 [Electronic] England
PMID21306905 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2011. Published by Elsevier Ltd.
Chemical References
  • Antineoplastic Agents
  • Coumarins
  • MC 2141
  • Pyrimidines
  • Quinazolinones
  • coumarin
  • Sirtuin 1
  • Sirtuin 2
Topics
  • Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
  • Apoptosis (drug effects)
  • Cell Line, Tumor
  • Coumarins (chemical synthesis, chemistry, pharmacology)
  • Enzyme Activation (drug effects)
  • Humans
  • Inhibitory Concentration 50
  • Molecular Structure
  • Pyrimidines (chemical synthesis, chemistry, pharmacology)
  • Quinazolinones (chemical synthesis, chemistry, pharmacology)
  • Sirtuin 1 (antagonists & inhibitors)
  • Sirtuin 2 (antagonists & inhibitors)

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