Renieramycins from the nudibranch Jorunna funebris and chemical modifications of cytotoxic Renieramycin M from the sponge Xestospongia sp.

Abstract

Three new bistetrahydroisoquinolines similar to renieramycins, including jorunnamycins A, B, and C, were isolated from the mantles, the visceral organs, and the egg ribbons of the nudibranch Jorunna funebris pretreated with potassium cyanide. Five known compounds, including renieramycins M, N, O, and Q and mimosamycin were also isolated. Their structures and relative stereochemistries were elucidated on the basis of spectroscopic data and comparison with the literatures. In order to investigate the structure-activity relationships (SAR), chemical modifications on C-22 of renieramycin M obtained from the sponge Xestospongia sp. were performed. New twenty one acyl analogs including acyclic, alicyclic, and aromatic acyl derivatives were prepared by treatment deangeloylrenieramycin M with corresponding acid anhydrides or acid chlorides to provide those derivatives in 25-85 % yields. The cytotoxicity of the renieramycin analogs against 4 tumor cell lines including HCT116 (human colon carcinoma), QG56 (human lung carcinoma), DU145 (human prostate carcinoma), and MDA-MB-435 (human breast carcinoma) were evaluated. The results revealed that a cyano group or a hydroxyl group at C-21 and an ester side chain at C-22 were essential for high cytotoxicity. Replacement of the angelate at C-22 by relatively small aliphatic substituents such as the acetate or the propionate led to a significant increase in potency whereas more bulky substituents (more than five carbons) resulted in a substantial loss in cytotoxicity. Likewise, the substitution of oxygen at C-14 dramatically reduced cytotoxicity. In addition, the small aliphatic esters incorporating an α, β unsaturated carbonyl, the aromatic, and the heteroaromatic esters at C-22 retained potent cytotoxicity. Interestingly, array-based gene expression monitoring of renieramycin M and jorunnamycin C profiles revealed that both compounds showed predominant down-regulated genes and PTPRK was proposed as one of the candidate biomarkers for their cytotoxicity.