Design, synthesis and evaluation of protein prenyltransferase inhibitors as antitumor and antiparasitic agents

Studies encompassing the design, synthesis and structure-activity relationships of inhibitors of mammalian geranylgeranyltransferase-I (GGTase-I) and of parasitic farnesyltransferase (FTase) are described herein. This thesis describes two new series of GGTase-I inhibitors (GGTIs) based on a benzoyleneurea and a piperazine-2-one scaffolds. A series of FTase inhibitors (FTIs) based upon a 5-aminomethyl-2'-methylbiphenyl-2-carboxylic acid scaffold is also described.; Using a benzoyleneurea scaffold as a mimetic for the central dipeptide (AA), CAAX peptidomimetic inhibitors that selectively block the activity of GGTase-I over FTase were synthesized. A small library of benzoyleneurea-based compounds was prepared wherein the C-terminal portion of the peptidomimetics was replaced by a variety of amino acids and simple amine groups, and the Cys residue was substituted by an imidazole zinc-binding moiety. In this series, compound 2.15a displayed the highest inhibition activity against GGTase-I (IC50 = 170 nM). This series of GGTIs represent novel and promising leads for the development of potent inhibitors of GGTase-I for potential application as antitumor agents.; A series of GGTIs based on a piperazine-2-one scaffold was prepared to investigate the effect of imidazole N-substitution on this series' potency and selectivity. Substitution at the N-5 position led to a reversal in selectivity towards FTase, consistent with the strict size limitation of the zinc-binding pocket of GGTase-I. Synthesis and evaluation of non-leucine containing GGTIs revealed the presence of a carboxylate group at the C-terminus is crucial for activity. Computational docking studies with compound 3.67 suggest the existence of a critical interaction between the inhibitor's carboxylate moiety and Arg 173beta of GGTase-I. Compounds 3.62 and 3.67 showed remarkable potency and selectivity in vitro, and compound 3.67 inhibited tumor growth by 64% at a dose of 50 mg kg-1day -1.; Finally, a series of FTI ester derivatives was synthesized in order to investigate the effect of ester structure modification on antiparasitic activity. In this series, the isopropyl ester 4.23 exhibited potent activity against T. brucei (IC50 = 5 nM). Evaluation against P. falciparum showed that benzyl ester derivative 4.29 potently inhibited parasitic growth (ED50 = 150 nM), and showed in vivo antimalarial activity by 46.1% at a daily dose of 50 mg kg -1.