Isolation, structure determination, and biological activity of marine natural products.

摘要

Despite new treatment strategies, traditional cancer chemotherapy, which has been strongly influenced by natural products research, remains one of the most important means to treat cancer. The continued study of marine organisms could provide a wealth of unique and diverse secondary metabolites to serve as potential anticancer agents. Several of these marine compounds are at various stages of clinical evaluation, and those isolated from invertebrates in advanced oncological clinical studies are reviewed in Chapter 1.; Chapter 2 reports the discovery of a novel polycyclic alkaloid, perophoramidine from the ascidian Perophora namii. This alkaloid contains an unusual carbon skeleton and is the first reported metabolite from the genus Perophora. In addition, it exhibits cytotoxicity toward the HCT-116 colon carcinoma cell line with an IC₅₀ of 60 μM and induces apoptosis within 24 h.; Chapter 3 compares ubiquitin-isopeptidase inhibition and antineoplastic activity of the punaglandins to A and J series prostaglandins. Punaglandins, cyclopentadienone and cyclopentenone prostaglandins chlorinated at the endocyclic α-carbon position were isolated from the soft coral Telesto riisei. They were then assayed for inhibition of ubiquitin-isopeptidase activity and anti-proliferative effects. As hypothesized the tested punaglandins inhibited isopeptidase activity and exhibited antiproliferative effects more potently than A and J series prostaglandins. Interestingly, the dienone punaglandin 4 was more potent than the enone punaglandin 6.; In Chapter 4 the marine compounds, jaspamide, swinholide A, and latrunculin A, known actin disrupters were isolated from various marine sponges and assayed for pAkt inhibition and p53-dependent activity. Also swinholide A was evaluated for its ability to interrupt Akt translocation. All three compounds showed enhanced cytotoxicity toward the PTEN deficient MDA-MB-468 breast carcinoma cell line and a reduction in pAkt. Also, immunocytochemistry studies of swinholide A showed a similar pattern of actin and Akt disruption. This strongly suggests that Akt is closely associated with actin, most likely accounting for the decrease in pAkt by inhibiting translocation of Akt to the cell membrane. Jaspamide, swinholide A, and latrunculin A may also elicit a p53-dependent mechanism.