N(epsilon)-Modified lysine containing inhibitors for SIRT1 and SIRT2

Bioorganic & Medicinal Chemistry
Tero HuhtiniemiElina Jarho

Abstract

Sirtuins catalyze the NAD(+) dependent deacetylation of N(epsilon)-acetyl lysine residues to nicotinamide, O'-acetyl-ADP-ribose (OAADPR) and N(epsilon)-deacetylated lysine. Here, an easy-to-synthesize Ac-Ala-Lys-Ala sequence has been used as a probe for the screening of novel N(epsilon)-modified lysine containing inhibitors against SIRT1 and SIRT2. N(epsilon)-Selenoacetyl and N(epsilon)-isothiovaleryl were the most potent moieties found in this study, comparable to the widely studied N(epsilon)-thioacetyl group. The N(epsilon)-3,3-dimethylacryl and N(epsilon)-isovaleryl moieties gave significant inhibition in comparison to the N(epsilon)-acetyl group present in the substrates. In addition, the studied N(epsilon)-alkanoyl, N(epsilon)-alpha,beta-unsaturated carbonyl and N(epsilon)-aroyl moieties showed that the acetyl binding pocket can accept rather large groups, but is sensitive to even small changes in electronic and steric properties of the N(epsilon)-modification. These results are applicable for further screening of N(epsilon)-acetyl analogues.

References

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Citations

Feb 23, 2012·Journal of the American Chemical Society·Blair C R DancyPhilip A Cole
Sep 8, 2011·Journal of Medicinal Chemistry·Tero HuhtiniemiMaija Lahtela-Kakkonen
Jun 1, 2011·Cancer Management and Research·Nadine Martinet, Philippe Bertrand
Sep 29, 2012·Current Pharmaceutical Design·Santina BruzzoneAlessio Nencioni
Apr 22, 2014·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Piia KokkonenMaija Lahtela-Kakkonen
Jun 26, 2014·Future Medicinal Chemistry·Jing HuHening Lin
May 27, 2016·Clinical Epigenetics·Vincenzo CarafaLucia Altucci
Aug 24, 2016·Bioconjugate Chemistry·Noémie ScornetDelphine Joseph
Oct 30, 2012·Current Opinion in Chemical Biology·Anthony A Sauve, Dou Yeon Youn
Apr 1, 2014·FEBS Letters·Tarja KokkolaMaija Lahtela-Kakkonen
Sep 16, 2010·Molecular BioSystems·Brett M Hirsch, Weiping Zheng
Nov 17, 2011·Journal of Biomolecular Screening·Walter Stünkel, Robert M Campbell
Dec 13, 2012·ACS Medicinal Chemistry Letters·Piia KokkonenMaija Lahtela-Kakkonen
Sep 17, 2019·Journal of the American Chemical Society·Jeffrey E MontgomeryRaymond E Moellering

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