Cytotoxic Macrolides from a New Species of the Deep-Water Marine Sponge Leiodermatium

• Published in: Journal of organic chemistry 2006-09, Vol.71 (19), p.7245-7251
• Main Authors: Sandler, Joel S, Colin, Patrick L, Kelly, Michelle, Fenical, William
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - isolation & purification; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Survival - drug effects; Chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Macrolides - isolation & purification; Macrolides - pharmacology; Molecular Structure; Organic chemistry; Oxazoles - isolation & purification; Oxazoles - pharmacology; Porifera - chemistry; Preparations and properties; Stereoisomerism
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo060958y

Chemical investigation of a new species of the deep-water marine sponge Leiodermatium, collected by manned submersible at a depth of 740 feet in Palau, resulted in the isolation of two cytotoxic macrolides, leiodolides A (1) and B (2). The leiodolides represent the first members of a new class of 19-membered ring macrolides, incorporating several unique functional groups including a conjugated oxazole ring, a bromine substituent, and an α-hydroxy-α-methyl carboxylic acid side-chain terminus. The structures of these new metabolites were established by spectroscopic analysis, chemical modification, and degradation. The relative and absolute stereochemistries at most chiral centers were assigned on detailed interpretation of spectroscopic data, coupled with chemical degradation and application of the modified Mosher ester method. Leiodolide A showed significant cytotoxicity (average GI50 = 2.0 μM) in the National Cancer Institute's 60 cell line panel with enhanced activity against HL-60 leukemia and OVCAR-3 ovarian cancer cell lines.