Secondary metabolites from the New Zealand marine sponge Mycale hentscheli

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.