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

Synthesis and evaluation of potent, highly-selective, 3-aryl-piperazinone inhibitors of protein geranylgeranyltransferase-I. Research Abstract Details 

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

Hairuo Peng,Dora Carrico,Van Thai,Michelle Blaskovich,Cynthia Bucher,Erin E Pusateri,Said M Sebti,Andrew D Hamilton,

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 IC(50) values of 0.4 microM and 0.7 microM respectively.

Synthesis and evaluation of potent, highly-selective, 3-aryl-piperazinone inhibitors of protein geranylgeranyltransferase-I. Publishing Authors By Initials

H Peng,D Carrico,V Thai,M Blaskovich,C Bucher,EE Pusateri,SM Sebti,AD Hamilton,

For similar biochemical phenomena, metabolism, and nutrition: biochemical phenomena: structure-activity relationship research abstracts see: biochemical phenomena, metabolism, and nutrition: biochemical phenomena: structure-activity relationship research

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

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Organic & biomolecular chemistry

VOLUME: 4

Page Numbers: 1768-84

Journal Abbreviation: Org. Biomol. Chem.

ISSN: 1477-0520

DAY: 21

MONTH: 03

YEAR: 2006

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

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LANGUAGE: eng

NlmUniqueID: 101154995

Synthesis and evaluation of potent, highly-selective, 3-aryl-piperazinone inhibitors of protein geranylgeranyltransferase-I. Keywords Mesh Terms:

KEYWORDS: Structure-Activity Relationship

MESH TERMS: pharmacology

Chemical & Substance for Abstract: Synthesis and evaluation of potent, highly-selective, 3-aryl-piperazinone inhibitors of protein geranylgeranyltransferase-I. Information

Substance Name: geranylgeranyltransferase type-I

Registry Number: EC 2.5.1.-

Grant and Affiliation Information for Synthesis and evaluation of potent, highly-selective, 3-aryl-piperazinone inhibitors of protein geranylgeranyltransferase-I.

AFFILIATION: Department of Chemistry, Yale University, New Haven, CT 06520, USA.

Country: England

AGENCY: United States NCI

GRANT: CA67771

ACRONYM: CA

MEDLINETA: Org Biomol Chem

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