Studies on Oximidine II - Total Synthesis by an Unprecedented Reductive Coupling

Abstract

The benzolactone enamide natural products are identified by three structural characteristics: a salicylate arene, a 12- or 15-membered macrolactone, and an enamide side chain. These natural products exert their biological activity by inhibiting the vacuolar-(H+)-ATPase (V-ATPase) enzyme. The benzolactone enamide oximidine II has been synthesized twice previously with only moderate yields realized for the key macrocyclization step. Following a previous Georg group strategy, we envisioned performing the ring-closure using a Castro-Stephens reaction. While optimizing this copper-mediated macrocyclization, we discovered an unprecedented copper-mediated reductive coupling reaction. The enamide side chain of these natural products is postulated to be critical for biological activity. To probe the importance of this acid-sensitive moiety, we synthesized an allylic amide homolog of oximidine II and tested both oximidine II and this analog in melanoma cancer cells. The bacterial enzyme UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) catalyzes the first committed step of cell wall biosynthesis. Using highthroughput screening, 5 scaffolds were identified with MurA inhibitory activity. Analog development of the pyrrole-benzoic acid scaffold failed to generate compounds with improved potency. We then turned to structure-based drug design to investigate new MurA inhibitors. Using computer-modeling software, low molecular weight molecules were docked into various MurA crystal structures. Evaluation of these docking studies revealed 4 small molecules as potential leads for further optimization. Dioxins are environmental pollutants that cause a range of biological effects in a dose-dependent manner. The exact mechanism of action for dioxins is not fully understood. 2,3,7,8-Tetrachlorophenothiazine (TCPT) was designed to probe potential mechanisms of action and biological effects of dioxin analogs. Utilization of Buchwald-Hartwig coupling methodology produced TCPT in 37% yield. Preliminary biological testing of TCPT has shown favorable pharmacokinetic properties.