Recent advances in isolation, synthesis, and evaluation of bioactivities of bispyrroloquinone alkaloids of marine origin

Abstract

The ocean continues to provide a plethora of unique scaffolds capable of remarkable biological applications. A large number of pyrroloiminoquinone alkaloids, including discorhabdins, epinardins, batzellines, makaluvamines, and veiutamine, have been isolated from various marine organisms. A class of pyrroloiminoquinone-related alkaloids, known as bispyrroloquinones, is the focus of this review article. This family of marine alkaloids, which contain an aryl substituted bispyrroloquinone ring system, includes three subclasses of alkaloids namely, wakayin, tsitsikammamines A-B, and zyzzyanones A-D. Both wakayin and the tsitsikammamines contain a tetracyclic fused bispyrroloiminoquinone ring system, while zyzzyanones contain a fused tricyclic bispyrroloquinone ring system. The unique chemical structures of these marine natural products and their diverse biological properties, including antifungal and antimicrobial activity, as well as the potent, albeit generally nonspecific and universal cytotoxicities, have attracted great interest of synthetic chemists over the past three decades. Tsitsikammamines, wakayin, and several of their analogs show inhibition of topoisomerases. One additional possible mechanism of anticancer activity of tsitsikammamines analogs that has been discovered recently is through the inhibition of indoleamine 2, 3-dioxygenase, an enzyme involved in tumoral immune resistance. This review discusses the isolation, synthesis, and evaluation of bioactivities of bispyrroloquinone alkaloids and their analogs.

Keywords: Anticancer; Antimicrobial; Bispyrroloquinones; Topoisomerase; Tsitsikammamines; Wakayin; Zyzzyanones.

Figure 1. Marine derived drugs

Figure 2. Representative bispyrroloquinone alkaloids isolated from marine sources

Scheme 1. Oxidative formation of the pyrrole ring D of wakayin

Scheme 2. Formation of bispyrroloquinone ring system of wakayin

Scheme 3. Synthesis of 3-ethylamine-indole- 4,7-dione derivative

Scheme 4. Synthesis of pyrazolic analogues of wakayin

Scheme 5. Synthesis of diimidazole analogues of wakayin

Scheme 6. Synthesis of an open analogue of wakayin

Scheme 7. Synthesis of tsitsikammamine A

Scheme 8. Synthesis of regioisomer of tsitsikammamine A

Scheme 9. Synthesis of aza analogues of tsitsikammamines

Scheme 10. Synthesis of zyzzyanone A

Scheme 11. Synthesis of zyzzyanone B

Scheme 12. Synthesis of zyzzyanone C

Scheme 13. Synthesis of zyzzyanone D