Novel cambinol analogs as sirtuin inhibitors: synthesis, biological evaluation, and rationalization of activity.
The tenovins and cambinol are two classes of sirtuin inhibitor that exhibit antitumor activity in preclinical models. This report describes modifications to the core structure of cambinol, in particular by incorporation of substituents at the N1-position, which lead to increased potency and modified selectivity. These improvements have been rationalized using molecular modeling techniques. The expected functional selectivity in cells was also observed for both a SIRT1 and a SIRT2 selective analog.
Medda
Federico
F
School of Chemistry and Centre for Biomolecular Sciences, University of St Andrews, St Andrews, Fife, KY16 9ST, Scotland, UK.
Russell
Rupert J M
RJ
Higgins
Maureen
M
McCarthy
Anna R
AR
Campbell
Johanna
J
Slawin
Alexandra M Z
AM
Lane
David P
DP
Lain
Sonia
S
Westwood
Nicholas J
NJ
D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D006801:Humans; D008969:Molecular Sequence Data; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity
D009281:Naphthalenes; D011744:Pyrimidinones; C510718:cambinol; D037761:Sirtuins