The in vitro biological activities of synthetic 18-O-methyl mycalamide B, 10-epi-18-O-methyl mycalamide B and pederin

Authors: Richter A.¹; Kocienski P.²; Raubo P.²; Davies D.

Source: Anti-Cancer Drug Design, Volume 12, Number 3, 1997 , pp. 217-227(11)

Publisher: Cognizant Communication Corporation

Buy & download fulltext article:

Price: $79.00 plus tax (Refund Policy)

Abstract:

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 (IC_50s 0.2-0.6 nM). In all assays, 10-epi-O-methyl mycalamide B was 10³ times less toxic than its diastereoisomoer, 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.

Keywords: carcinoma/cytotoxicity/mycalamide/pederin/protein synthesis inhibitors/therapy

Document Type: Research article

Affiliations: 1: Corresponding author 2: Department of Chemistry, University of Southampton, Southampton SO17 1BJ, UK

Publication date: 1997-04-01