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

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

Research output: Contribution to journalArticle

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 M and 0.7 M respectively.

Original languageEnglish (US)
Pages (from-to)1768-1784
Number of pages17
JournalOrganic and Biomolecular Chemistry
Volume4
Issue number9
DOIs
StatePublished - 2006

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Fluorine
Scaffolds
Leucine
inhibitors
Inhibitory Concentration 50
Esters
Substitution reactions
selectivity
substitutes
proteins
leucine
evaluation
synthesis
imidazoles
fluorine
esters
rings
Substrates
Processing
configurations

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)

Cite this

Synthesis and evaluation of potent, highly-selective, 3-aryl-piperazinone inhibitors of protein geranylgeranyltransferase-I. / Peng, Hairuo; Carrico, Dora; Thai, Van; Blaskovich, Michelle; Bucher, Cynthia; Pusateri, Erin E.; Sebti, Said M.; Hamilton, Andrew.

In: Organic and Biomolecular Chemistry, Vol. 4, No. 9, 2006, p. 1768-1784.

Research output: Contribution to journalArticle

Peng, Hairuo ; Carrico, Dora ; Thai, Van ; Blaskovich, Michelle ; Bucher, Cynthia ; Pusateri, Erin E. ; Sebti, Said M. ; Hamilton, Andrew. / Synthesis and evaluation of potent, highly-selective, 3-aryl-piperazinone inhibitors of protein geranylgeranyltransferase-I. In: Organic and Biomolecular Chemistry. 2006 ; Vol. 4, No. 9. pp. 1768-1784.
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AU - Blaskovich, Michelle

AU - Bucher, Cynthia

AU - Pusateri, Erin E.

AU - Sebti, Said M.

AU - Hamilton, Andrew

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