Experimental and Computational Study of Bisphosphonates Targeting Isoprenoid Biosynthesis Pathway

180 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2008.Bisphosphonates are a class of drugs widely used to treat bone resorption diseases. Recently, bisphosphonates have been found to have anti-cancer, anti-parasitic, anti-bacterial and herbicidal activity. They also have the unexpected property of activating human gammadelta T cells to kill tumor cells. In this work, I used experimental, mainly x-ray crystallography and computational methods to understand the structure activity relationships of these bisphosphonates with their targets, farnesyl diphosphate synthase, geranylgeranyl diphosphate synthase, and undecaprenyl diphosphate synthase. New bisphosphonates have been developed and optimized based on these findings. In particular, new lipophilic bisphosphonates targeting multiple prenyl-transferases are developed and far more potent than current commercially available bisphosphonate drugs in tumor cell killing, and gammadelta T cell activation.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD