There has been enormous recent interest in the design and synthesis of peptidomimetic compounds as proteolytically stable surrogates for medicinally active peptides. One active area of synthetic interest in this regard is in the design and synthesis of mimics of the terminal amino acid residues of the Ras proteins. Mutated forms of the Ras proteins in which the necessary autohydrolytic function has been impaired have been implicated in the transformation of normal cells into malignant cells and are involved in the etiology of up to 50% of all colon and pancreatic cancers. In so far as the Ras proteins require the presence of a farnesyl group at a terminal residue for activity, it has been found that inhibition of farnesyl transferase, the enzyme responsible for this post- translational modification, is an effective new chemotherapeutic strategy for the treatment of cancer. There is some recent NMR evidence that the terminal four residues of the Ras protein, the so-called CAAX box, adopt a beta-turn conformation in the bound state. An extensive molecular modeling study using the native Ras terminal tetrapeptide constrained into a beta-turn conformation has therefore been undertaken and a series of non-peptide bicyclic compounds has been designed so as to orient the critical recognition elements into the desired turn conformation. These rationally designed molecules will be used both as probes of the natural bound conformation of the Ras substrate and as potential non-peptidic inhibitors of farnesyl transferase and possible new chemotherapeutic agents. The synthesis of the bicyclic ring scaffolds themselves raises some interesting chemical questions as to the control of stereochemistry at one of the ring fusion centers and are of general interest as new type I beta-turn mimics. Biological testing of the compounds will be done in collaboration with researchers at the University of Pittsburg.
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