title: New synthetic approach to paullones and characterization of their SIRT1 inhibitory activity.
abstract: 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.
authors.affiliation: Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Soto
authors.forename: Esther
authors.initials: E
authors.lastname: Vaz
authors.forename: Carmela
authors.initials: C
authors.lastname: Dell'Aversana
authors.forename: Rosana
authors.initials: R
authors.lastname: Álvarez
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
authors.forename: Ángel R
authors.initials: ÁR
authors.lastname: de Lera
mesh_terms: D001552:Benzazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001552:Benzazepines; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; C547599:paullone; C447939:SIRT1 protein, human; D056564:Sirtuin 1