Screen of pseudopeptidic inhibitors of human sirtuins 1-3: two lead compounds with antiproliferative effects in cancer cells.
In the past few years sirtuins have gained growing attention for their involvement in many biological processes such as cellular metabolism, apoptosis, aging and inflammation. In this contribution, we report the synthesis of a library of thioacetylated pseudopeptides that were screened against human sirtuins 1-3 to reveal their in vitro inhibition activities. Molecular modeling studies were performed to acquire data about the binding modes of the inhibitors. Three sirtuin inhibitors were subjected to cellular studies, and all of them showed an increase in acetylation of Lys382 of p53 after DNA damage. Furthermore, two of the compounds were able to inhibit both A549 lung carcinoma and MCF-7 breast carcinoma cell growth in micromolar concentration with the ability to arrest cancer cell cycle in the G1 phase.
School of Pharmacy and ∥Department of Neurology, Institute of Clinical Medicine , University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
Paolo
P
Mellini
Tarja
T
Kokkola
Tiina
T
Suuronen
Heikki S
HS
Salo
Laura
L
Tolvanen
Antonello
A
Mai
Maija
M
Lahtela-Kakkonen
Elina M
EM
Jarho
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D010455:Peptides / Q000494:pharmacology*; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
D010455:Peptides; D037761:Sirtuins