New synthetic approach to paullones and characterization of their SIRT1 inhibitory activity

A series of 7,12-dihydroindolo[3,2-d][1]benzazepine-6(5H)-ones (paullones) substituted at C9/C10 (Br) and C2 (Me, CF(3), CO(2)Me) have been synthesized by a one-pot Suzuki-Miyaura cross-coupling of an o-aminoarylboronic acid and methyl 2-iodoindoleacetate followed by intramolecular amide formation....

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Bibliographic Details
Published in:Organic & biomolecular chemistry 2012-03, Vol.10 (10), p.2101-2112
Main Authors: Soto, Sara, Vaz, Esther, Dell'Aversana, Carmela, Álvarez, Rosana, Altucci, Lucia, de Lera, Ángel R
Format: Article
Language:English
Subjects:
Benzazepines - chemical synthesis
Benzazepines - chemistry
Benzazepines - pharmacology
Cell Cycle - drug effects
Cell Line, Tumor
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Humans
Recombinant Proteins - antagonists & inhibitors
Recombinant Proteins - metabolism
Sirtuin 1 - antagonists & inhibitors
Sirtuin 1 - metabolism
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Summary:A series of 7,12-dihydroindolo[3,2-d][1]benzazepine-6(5H)-ones (paullones) substituted at C9/C10 (Br) and C2 (Me, CF(3), CO(2)Me) have been synthesized by a one-pot Suzuki-Miyaura cross-coupling of an o-aminoarylboronic acid and methyl 2-iodoindoleacetate followed by intramolecular amide formation. Other approaches to the paullone scaffold based on Pd-catalyzed C-H activation were unsuccessful. In vitro enzymatic assay with recombinant human SIRT-1 indicated a strong inhibitory profile for the series, in particular the analogue with a methoxycarbonyl group at C2 and a bromine at C9. These compounds are, in general, inducers of granulocyte differentiation of the U937 acute leukemia cell line and cause a marked increase in pre-G1 of the cell cycle.
ISSN:1477-0520
1477-0539
DOI:10.1039/c2ob06695e