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 sponge, show close structural similarity to the insect toxin pederin, and exhibit potent cytotoxicity and antitumour activity. Detailed investigation of the clinical potential of these compounds has been hampered because they are available in only minute quantities from natural sources. We now describe the biological activities of 18-O-methyl mycalamide 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 synthesis assays, and in cytotoxicity assays using human carcinoma cell lines (IC50s 0.2-0.6 nM). In all assays, 10-epi-18-O-methyl mycalamide B was 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 irreversible inhibition of cellular proliferation and induced cellular necrosis. In contrast, the antiproliferative effects of the compounds on human fibroblasts were reversible and there was no evidence of necrosis. Demonstration that 18-O-methyl mycalamide B and the synthetically less complex molecule, pederin, show some tumour cell toxicity indicates that this novel class of compounds should be subjected to preclinical evaluation.
Richter
A
A
CRC Wessex Medical Oncology Unit, Southampton General Hospital, Tremona Road, Southampton, UK.
Kocienski
P
P
Raubo
P
P
Davies
D E
DE
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D011161:Porifera / Q000737:chemistry; D011714:Pyrans / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C106002:10-epi-18-O-methylmycalamide B; C106001:18-O-methylmycalamide B; D000970:Antineoplastic Agents; D011714:Pyrans; C100127:pederin