Abstract:
The New Zealand marine sponge Mycale hentscheli is the source of three classes of biologically active secondary metabolites, each with a different activity profile. Mycalamides A, B and D (102-104) inhibit the elongation stage of protein synthesis, where 102 and 103 have also been shown to reverse the morphology of ras-transformed T-cells to normal. The dilactone macrolide pateamine (105) is also a protein synthesis inhibitor, but at the initiation stage of translation. The polyoxygenatcd macrolide peloruside A (106) has been shown to cause cells to accumulate in the G2-M phase of mitosis by promoting microtubule polymerisation much like the highly successful antitumor drug paclitaxel (Taxol) (1) and thus has become a promising pharmaceutical candidate and a popular synthetic target.
A study of a wild sample of M. hentscheli collected from Kapiti Island initiated by West and continued in this study resulted in the isolation of 104, 106 and also revealed a new compound, peloruside B (141). Large-scale extractions of wild and aquacultured Pelorus Sound specimens of M. hentscheli using a combination of normal- and reversed-phase chromatographic methods and standard spectroscopic techniques resulted in the isolation of 102, 106 and three new compounds, mycalamide E (107). and pelorusides C-D (142-143). Mycalamide E (107), the 6-des-O-methyl analogue of mycalamide A (102) was found to be 30 times less cytotoxic than 102 across four cell lines. Peloruside B (141), the 3-des-O-methyl analogue of peloruside A (106) was found to be approximately three times less cytotoxic than 106, yet still arrested cells at the G2-M phase of mitosis. Peloruside C (142), identified as the 3,7-des-0-methyl-8,9-didehydroxy-8-ene analogue of peloruside A (106), was found to be cytotoxic at nanomolar concentrations 15 times less than 106 but showed no antimitotic activity. Peloruside D (143), containing the 16-membered macrolide ring but with an unusual cyclisation about the C-7 to C-l I region and deoxygenation at the C-8 position, was found to be inactive at micromolor concentrations against the HL-60 cell line.
