Total Synthesis and Biological Evaluation of the Indoleamine 2,3-Dioxygenase Inhibitors Exiguamine A and Iso-Exiguamine A

Abstract

Described in this dissertation are total synthesis and biological evaluation of exiguamine A, an unprecedented alkaloid consisting of a hexacyclic skeleton. This marine natural product possesses potent inhibitory activity against the indoleamine 2,3-dioxygenase (IDO), which catalyzes the first and rate-limiting step of metabolic degradation of the essential amino acid tryptophan (Chapter 1). The immune-regulating enzyme IDO has emerged as a promising target for cancer immunotherapy as it is overexpressed in many human tumors and known to provide cancer cells with a mechanism to evade the immune system. Many endeavors have been made by our group and others to achieve biogenesis and chemical synthesis of exiguamine A (Chapter 2), and several synthetic pathways have been proposed. Our approach was based on the assembly of three domains – tryptamine quinone, dopamine, and hydantoin. Taking advantage of the redox equilibrium between quinone and hydroquinone, all subunits of exiguamine A were tethered in a convergent manner with concomitant construction of the core pyran framework though Mukaiyama-Michael and Claisen rearrangement reactions. After a series of cascade redox processes using hydrogen and oxygen, the efficient synthesis of exiguamine A was accomplished. Our synthetic route also allowed for the synthesis of an isomer of exiguamine A, named iso-exiguamine A (Chapter 3). The synthetic exiguamines were evaluated for IDO inhibitory activity in cell line (Chapter 4).