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.
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Authors | Dante Rotili, Vincenzo Carafa, Domenico Tarantino, Giorgia Botta, Angela Nebbioso, Lucia Altucci, Antonello Mai |
Journal | Bioorganic & medicinal chemistry
(Bioorg Med Chem)
Vol. 19
Issue 12
Pg. 3659-68
(Jun 15 2011)
ISSN: 1464-3391 [Electronic] England |
PMID | 21306905
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2011. Published by Elsevier Ltd. |
Chemical References |
- Antineoplastic Agents
- Coumarins
- MC 2141
- Pyrimidines
- Quinazolinones
- coumarin
- Sirtuin 1
- Sirtuin 2
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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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