Synthesis of N-heterocycle-based phosphonates as inhibitors of protein prenylation

My research goal is to synthesize organic molecules as inhibitors of some downstream enzymes of a metabolic pathway in mammals known as isoprenoid biosynthetic pathway (IBP). Previous studies demonstrated that targeting those enzymes could lead to a novel therapeutic strategy for the treatment of multiple myeloma. Multiple myeloma is a disorder of malignant plasma cells, characterized by the overproduction of monoclonal proteins. The over-secreted protein can have devastating effects on the kidneys. Despite advances in treatment options over the past decade, multiple myeloma remains an incurable disease. For this reason, development of a novel therapeutic strategy for multiple myeloma is highly desirable.

To achieve that goal, we have used two lines of approach: develop inhibitors of the IBP enzyme GGTase-II or deplete cellular supplies of the substrate for GGTase-II. As a direct approach, various compounds based on nitrogen heterocycles have been synthesized and biologically evaluated. Structure activity relationship studies of these compounds demonstrated the importance of the functional groups, nature and geometry of the carbon chains, and the type of heterocycles to selectively target GGTase-II. Unfortunately, the cellular potency of those compounds needs further improvement to be clinically relevant.

As an indirect approach, depletion of the isoprenoid substrate of GGTase-II, that is GGPP can be achieved by inhibition of another IBP enzyme GGDPS. In recent past, a family of GGDPS inhibitors based on triazole bisphosphonates has been developed in the Wiemer lab, and through collaboration their bioactivity was evaluated. These compounds have shown potency against myeloma cells and GGDPS which is relevant from a therapeutic perspective. My research goal was to develop derivatives of those potent inhibitors so that they can be linked to a biopolymer and delivered selectively into a target organ. This would provide better therapeutic index and less off-target effects.

To explore this area, we have synthesized ω-hydroxy triazole bisphosphonates. Through collaboration, the biological activity of those novel compounds has been evaluated and then linked to biopolymer hyaluronic acid (HA). Preliminary biological studies demonstrate enhanced cellular activity of the newly developed drug-HA conjugates compared to their corresponding free drugs. Evaluation of the biodistribution and toxicity profile of the HA-GGDPS inhibitor conjugates is currently in progress.