THE IN-VITRO BIOLOGICAL-ACTIVITIES OF SYNTHETIC 18-O-METHYL MYCALAMIDE-B, 10-EPI-18-O-METHYL MYCALAMIDE-B AND PEDERIN

Mycalamides A and B, which were originally isolated from a marine spon ge, show close structural similarity to the insect toxin pederin, and exhibit potent cytotoxicity and antitumour activity. Detailed investig ation of the clinical potential of these compounds has been hampered b ecause they are available in only minute quantities from natural sourc es. We now describe the biological activities of 18-O-methyl mycalamid e B, 10-epi-18-O-methyl mycalamide and pederin, all prepared by total synthesis. The activities of 18-O-methyl mycalamide B and pederin were virtually indistinguishable when evaluated in DNA or protein synthesi s assays, and in cytotoxicity assays using human carcinoma cell lines (IC(50)s 0.2-0.6 nM). In all assays, 10-epi-18-O-methyl mycalamide B w as 10(3) times less toxic than its diastereoisomer, demonstrating that the cytotoxicity of 18-O-methyl mycalamide B is inseparable from its ability to inhibit protein synthesis. Short-term exposure of squamous carcinoma cells to 18-O-methyl mycalamide B or pederin caused an irrev ersible inhibition of cellular proliferation and induced cellular necr osis. In contrast, the antiproliferative effects of the compounds on h uman fibroblasts were reversible and there was no evidence of necrosis . Demonstration that 18-O-methyl mycalamide B and the synthetically le ss complex molecule, pederin, show some tumour cell toxicity indicates that this novel class of compounds should be subjected to preclinical evaluation.