tsitsikammamine-a and wakayin

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.

Topics: Alkaloids; Animals; Anti-Infective Agents; Antineoplastic Agents; Biological Products; Humans; Indole Alkaloids; Indoles; Pyrroles; Quinolines; Quinones

Two aza-analogues of the marine pyrroloquinoline alkaloids wakayin and tsitsikammamines A and B have been synthesized. The strategy used was based on a 1,3-dipolar cycloaddition reaction between indole 4,7-dione and a diazo-aminopropane derivative. One of the two analogues partially inhibits human topoisomerase I, whereas synthetic intermediates inhibit the enzyme DNA cleavage activity at a concentration comparable to that of the control drug camptothecin.

Topics: Animals; Aza Compounds; Cyclization; Humans; Indole Alkaloids; Molecular Structure; Pyrroles; Quinolines; Structure-Activity Relationship; Topoisomerase I Inhibitors

A series of aza analogues of the marine alkaloids wakayin and tsitsikammamines A and B have been synthesized. The strategy used was based on [3 + 2] cycloaddition reactions involving 3-ethylamine-indole-4,7-dione and different diazo reagents. All the compounds were evaluated in vitro for antiproliferative activity against five distinct cancer cell lines and for their inhibitory effect on topoisomerase isoenzymes I and II. Some of the compounds inhibited the topoisomerase I and/or II catalyzed relaxation of supercoiled DNA at a concentration comparable to the drugs camptothecin and etoposide. Only a few of them exhibited cytotoxic activity with IC50 values in the micromolar range.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Indole Alkaloids; Pyrazoles; Pyrroles; Quinolines; Structure-Activity Relationship; Topoisomerase I Inhibitors; Topoisomerase II Inhibitors