Farnesyl Protein Transferase Inhibitor Design, Synthesis And Activity Evaluation

The recent development of farnesyltransferase (FTase) inhibitors impairing the growth of Ras-transformed cells demonstrates that membrane association of Ras is important for its biological functions. In the late 1980s, it was established that Ras is modified at the C-terminus, leading to its membrane association and tumorigenicity. The first step in this modification is to add a 15-carbon farnesyl group to Ras by the farnesylation reaction, which is catalyzed by FTase, providing cytosolic Ras with hydrophobic residue for membrane attachment.In this dissertation, two series of novel FTase inhibitors, which were designed by computer aid and synthesized, were present.1, One class is CAAX-mimetic compounds with an imidazolyl residue on one end and a carboxylic group on the other connected by benzodiazepine scaffold at different positions.2, The other class is alkylthiol benzoate compounds with linear or benzodiazepine skeleton at para position of benzene, and with different length linear alkyi groups connected by the sulfur atom, alkylthiol benzoate compounds were considered either as CAAX analogs when the alkyl groups were methyl or ethyl, or as bisubstrate analogs of CAAX and FPP when a long linear alkyl group was linked to the sulfur atom.By means of Molecular modeling a comparison of minimized conformation of the designed compounds with crystal structure of CAAX and FPP stripped from FTase-ligand complex were performed, and the perfectly aligned compounds were defined to be synthesized.As CAAX-mimetics, l,3-dihydro-5-phenyl-2-H-1,4-benzodiazepin-2-one was modified by linking carboxyl groups with various carbon through N-1 and C-3, 3-(imidazol-4-yl)propion amido group with different substituents was connected at C-7; In the synthesis of bisubstrate analogues, thiocarbamido compounds was alkylated by alkyl iodide and then hydrolyzed to...