Synthesis of structural analogues of GGT1-DU40, a potent GGTase-1 inhibitor

Abstract

A series of new substituted pyrazoles 2-12 have been synthesized. The synthesized compounds are structural analogues of GGT1-DU40 1, a highly potent and selective inhibitor of protein geranylgeranyltransferase I (GGTase-I) both in vitro and in vivo. The implications of GGTase-I in oncogenesis have highlighted its potential as a cancer therapeutic target. Accordingly, the development of GGTase-I inhibitors has been a subject of much interest. The synthesis of 2-12 stemmed from the acetylation or acylation of N-function of amino acids to produce suitably modified amino acids. Meanwhile, the substituted pyrazole subunit originated from the reaction of ethyl nicotinate with γ-butyrolactone followed by condensation of the resultant β-keto lactone with (3,4-dichlorophenyl) hydrazine. The operations of O-alkylation and thioetherification on the resultant intermediate eventually produced the substituted pyrazole fragment. The amidation of the latter with amino acid derivatives finally rendered 2-12 in good to excellent yields.