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.

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.

Commercially available reagents were used throughout without purification unless otherwise stated. Anhydrous solvents were used as supplied unless otherwise stated. Tetrahydrofuran was distilled from sodium benzophenone ketyl under a nitrogen atmosphere. Toluene was dried by passage through activated alumina. Dichloromethane was distilled from calcium hydride under a nitrogen atmosphere. Light petroleum refers to the fraction with bp 40-60 °C. Ether refers to diethyl ether. Reactions were routinely carried out under a nitrogen or argon atmosphere unless otherwise stated. Analytical thin layer chromatography was carried out on aluminum backed plates coated with silica gel or neutral alumina, and visualized under UV light at 254 and/or 360 nm and/or potassium permanganate or ethanolic vanillin dip. Chromatography was carried out on silica gel or neutral alumina in the case of basic compounds. Fully characterized compounds were chromatographically homogeneous. Infrared spectra were recorded in the range 4000-600 cm-1 as solutions in chloroform. NMR spectra were recorded at the frequencies stated. Chemical shifts are quoted in ppm and J values in Hz. Chemical shift values are referenced against residual protons in the deuterated solvents. In the 13 C NMR spectra, signals corresponding to CH, CH 2 , or CH 3 are assigned from DEPT spectra; all others are quaternary C. High resolution mass spectra were recorded on an ESI time-of-flight spectrometer.