Synthetic Studies toward Analogues of Manassantin A

Abstract

In response to oxygen deprivation, tumor cells express a transcription factor, hypoxia inducible factor 1 (HIF-1). HIF-1 regulates the expression of genes involved in erythropoiesis, angiogenesis, and other adaptive responses to hypoxia, which encourage cell survival and proliferation. Overexpression of HIF-1 causes increased vascularization and tumor growth, while HIF-1 inhibition reverses these processes. The natural products manassantins A and B are potent HIF-1 down-regulators whose molecular mechanisms are unknown. This research aims to establish structure-activity relationships which will aid in both the identification of the chemical moieties necessary for down regulation of HIF-1 and synthesis of manassantin A analogues with reduced structural complexity and increased synthetic accessibility. Preparation and biological characterization of manassantin A analogues is described. A few analogues have been identified with promising lead development potential. Further establishment of their pharmacological profiles will provide insight into the HIF-1 signaling pathway. Our efforts to elucidate the mode of action of manassantin A are described that will aid in the development of these natural products into probes of cancer biology.