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

Abstract

Natural quinones,o ften linked with cellular oxidation processes,e xhibit pronounced biological activity.I n particular,t he structurally unique isothiazolonaphthoquinone aulosirazole,isolated from blue-green alga, possesses selective antitumor cytotoxicity,a lthough its mechanism of action is unknown. The first synthesis of aulosirazole uses ar oute centered upon alate-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,a nd at lower doses have the potential to alter the ratio of intracellular oxidized to reduced pyridine nucleotides.

Inhibition Mechanisms of Indoleamine 2,3-Dioxygenase 1 (IDO1)

“…In a cellular environment, some of these quinones have been shown to be efficient substrates of the human quinone reductase NQO1 and to undergo NQO1-dependent redox cycling, leading to antitumor cytotoxicity through the generation of reactive oxygen species. 55 Anticipating our results, we will call these types of redox-based IDO1 inhibitors that do not bind to the IDO1 active site type X inhibitors.…”

Recent Advances in the Synthesis and Reactivity of Isothiazoles

“…Moody and co‐workers reported a direct condensation to afford the desired isothiazoles in their total synthesis of pronqodine A and aulosirazole, naturally occurring isothiazole‐containing quinones with potential anticancer activity (Scheme ) . In the total synthesis of pronqodine A (Scheme , top ), ortho ‐lithiation of a cyclic acetal, trapping with dimethyl disulfide and hydrolysis provided the aldehyde starting material (not shown).…”

Phenyl Benzenesulfonylhydrazides Exhibit Selective Indoleamine 2,3-Dioxygenase Inhibition with Potent in Vivo Pharmacodynamic Activity and Antitumor Efficacy

“…Chlorosulfonic acid (2.5 mL) was added slowly to 3-(morpholin-4-yl)-N-phenylpropanamide (5) (0.270 g, 1.00 mmol) at room temperature, and the reaction mixture was stirred for 6 h. The resulting mixture was added to ice with NaCl (s) carefully and extracted with ethyl acetate. The organic layer was dried over MgSO 4 and concentrated in vacuo to give 4-{[3-(morpholin-4yl)propanoyl]amino}benzenesulfonyl chloride (23), which was used directly in the next step. To a solution of 23 (0.100 g, 0.250 mmol) in 7 mL of dichloromethane and 0.5 mL of DMF was added 4bromophenyl hydrazine g, 0.85 mmol), and the mixture was stirred at room temperature for 17 h. The resulting mixture was poured into water and extracted with ethyl acetate.…”