'Heads and tails': The design and synthesis of novel RAS farnesyl protein transferase inhibitors

摘要

In the past decade, a major goal in cancer research has been the development of chemotherapeutic agents that are more specific and less toxic than those in current use. While traditional cancer chemotherapy has involved cytotoxic compounds that are often of limited selectivity, new approaches are focusing more on the primary disease mechanisms that underlie the development and maintenance of human cancer. One such target is a guanosine triphosphate-binding protein known as RAS that plays an essential role in the signal transduction pathways which regulate cell proliferation. Mutations in RAS genes are associated with approximately 30% of all human cancers. The demonstration that RAS farnesylation is essential for RAS-induced cellular transformations has aroused an intense interest in farnesyl pyrophosphate analogues as potential chemotherapeutic agents.;We have developed two novel strategies for the design of farnesyl pyrophosphate mimetics. The recent publication of a crystal structure for farnesyl protein transferase, the enzyme that catalyzes reaction of farnesyl pyrophosphate with RAS, revealed a hydrophobic pocket lined with ten aromatic amino acid residues that presumably accepts the terpenoid chain. This crystal data lends credibility to the design of novel farnesyl "tails" incorporating aromatic rings, compounds that may illuminate the importance of non-bonding interactions in recognition of the farnesyl tail. The synthesis of a family of these compounds has been achieved in high yields through the development of a novel allylic tetrahydropyranyl ether/organometallic coupling reaction.;With methods established for the preparation of farnesol analogues, diphosphate "head" mimetics were desired that could be used in conjunction with these novel terpenoid tails. A new cyclic phosphonate head was synthesized that, unlike the natural substrate, would not readily lose a phosphate group when covalently attached to RAS. RAS proteins modified in this way should be substantially more polar than normally farnesylated RAS. It is anticipated that this increased polarity will impair the normal signal transducing functions of RAS by disrupting subsequent post-translational modifications and/or by keeping the proteins from localizing into the cellular membranes.