NDLI: Synthesis and evaluation of potent, highly-selective, 3-aryl-piperazinone inhibitors of protein geranylgeranyltransferase-I

Content Provider	Royal Society of Chemistry (RSC)
Author	Thai, Van Blaskovich, Michelle Bucher, Cynthia Pusateri, Erin E. Hamilton, Andrew D. Sebti, Said M. Peng, Hairuo Carrico, Dora
Copyright Year	2006
Abstract	A series of compounds based on the carboxyl-terminal CAAL sequence of PGGTase-I substrates was designed and synthesized. Using piperazin-2-one as a semi-rigid scaffold, we have introduced critical pharmacophores in a well-defined arrangement to mimic the CAAL sequence. High potency and exceptional selectivity were obtained for inhibition of PGGTase-I with structures such as 45 and 70. Potency of this series of GGTIs was dependent on the presence of an L-leucine residue with a free carboxyl terminus, as well as an S configuration of the 3-aryl group. The selectivity was significantly enhanced by 5-methyl substitution on the imidazole ring and fluorine substitution on the 3-aryl group. Modification of the 6-position of the piperazinone scaffold was found to be unfavorable. Compounds 44 and 69, the corresponding methyl esters of 45 and 70, were found to selectively block processing of Rap1A by PGGTase-I in whole cells with IC50 values of 0.4 µM and 0.7 µM respectively.
Starting Page	1768
Ending Page	1784
Page Count	17
File Format	HTM / HTML PDF
ISSN	14770520
Volume Number	4
Issue Number	9
Journal	Organic & Biomolecular Chemistry
DOI	10.1039/b517572k
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Open
Subject Keyword	RAP1A Fluorine CAAL Imidazole IC50 Leucine Aryl
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Biochemistry Physical and Theoretical Chemistry

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