Synthesis and Intracellular Redox Cycling of Natural Quinones and Their Analogues and Identification of Indoleamine-2,3-dioxygenase (IDO) as Potential Target for Anticancer Activity

Natural Quinones, often linked with cellular oxidation processes, exhibit pronounced biological activity. In particular, the structurally unique isothiazolonaphthoquinone aulosirazole, isolated from blue-green alga, possesses selective antitumor cytotoxicity, although its mechanism of action is unknown. The first synthesis of aulosirazole uses a route centered upon a late-stage regioselective Diels-Alder reaction. The structurally related natural product pronqodine A, an inhibitor of prostaglandin release, and analogues thereof, were also prepared for comparison. Biological evaluation of the compounds identified one potential target as the immunoregulatory enzyme indoleamine-2,3-dioxygenase (IDO). The isothiazoloquinones are also efficient substrates for the human Quinone Reductase NQO1, and undergo intracellular NQO1-dependent redox cycling resulting in the generation of Reactive Oxygen Species, and at lower doses have the potential to alter the ratio of intracellular oxidized to reduced pyridine nucleotides.

Diels-Alder reaction; oxidoreductases; quinones; redox chemistry; sulfur/nitrogen heterocycles.