Synthesis of novel inhibitors of farnesyltransferase and geranylgeranyltransferase-I

The focus of this research was to design and synthesize peptidomimetics that inhibit the protein Farnesyltransferase (PFFase) from transferring a farnesyl residue to the sulfhydryl group of the cysteine amino acid found at the C-terminus of the Ras proto-oncogene. Inhibiting PFTase prevents isoprenylation from occurring and oncogenic Ras from becoming localized to the plasma membrane, thus reducing its transforming activity. Most peptidomimetics utilize a cysteine amino acid as a zinc binding residue in the design of PFTase inhibitors which is thought to convey serious disadvantages for use as anti-cancer therapeutics. This work focuses on possible replacements for the cysteine residue by using non-thiol zinc binding residues. It was found that the imidazole group was a viable replacement for the cysteine amino acid. Optimization of the imidazole group in terms of spacer length and substituent effects were evaluated and ultimately lead to potent inhibitors of PFTase. Good selectivity over the closely related enzyme PGGTase-I was observed.; The protein geranylgeranyltransferase-I (PGGTase-I) like PFTase catalyzes the transfer of a geranylgeranyl residue to oncogenic forms of Ras. Designing and inhibiting the enzyme PGGTase-I will help clarify the roles either PFTase or PGGTase-I has in the signaling transformation pathways leading to malignant transformation. Using a dipeptide mimetic a series of hydrophobic modifications were explored utilizing various substituted groups that lead to potent inhibitors of PGGTase-I exhibiting good selectivity of PGGTase-I over PFTase. When these inhibitors were evaluated in whole cells, it was found that they effectively inhibited Rap1A cell processing.; The first proto-oncogene identified from the Rous sarcoma virus, p60 v-src, has been suspected to be involved in a phosphorylation cascade of events leading to malignant transformation. Taking a lead peptide known to inhibit p60v-src a series of dipeptide spacers were synthesized to reduce the peptidic nature of the lead peptide and investigate the structural requirements needed to inhibit p60v-src. The biological activities were evaluated and lead to a compound of only modest potency when evaluated in a Src assay.