Our practical synthetic solutions to natural products have enabled us to access analog collections for meaningful structure-function and mode-of-action studies to investigate their biological effects in vitro and in vivo, and for optimization of potency and pharmacological properties.
Previously, we had discovered that the natural product salicylihalamide targets the mammalian Vacuolar ATPase, and demonstrated its use as effective anticancer and antiviral agent. We designed and executed a gram-scale synthesis of a synthetic analog (SaliPhe) that was selected based on its potent inhibitory activity (
During the past five years, we have showed that SaliPhe has not only been useful to study the function of V-ATPase in a variety of normal and pathogenic cellular processes, but also enabled in vivo modulation of V-ATPase activity as a means to inhibit the growth of human lung cancer xenografts, to attenuate wear particle-induced osteolysis in a mouse calvarial model (for the potential treatment of peri-implant osteolysis), or to protect mice against a lethal challenge of a mouse-adapted influenza strain. SaliPhe is now viewed as the most selective V-ATPase inhibitor available.
To discover the mode-of-action of the potent anticancer natural product psymberin, we performed a C. elegans mutant screen (with M. Roth) that identified a dominant drug resistant worm for which the mutation was mapped to a ribosomal protein. An efficient second-generation total synthesis provided gram-scale quantities that enabled a collaborative study with Seattle Genetics for incorporation into antibody drug conjugates.