Cytotoxic bistetrahydroisoquinoline alkaloids from the Thai marine sponge, Xestospongia sp.

Abstract

A group of bistetrahydroisoquinoline alkaloids, including renieramycin M as a major component, together with five minor derivatives, renieramycins N, O, Q, R, and S, were isolated from the Thai sponge, Xestospongia sp., pretreated with potassium cyanide. Their structures and relative stereochemistries were elucidated on the basis of spectroscopic data. Replacement of the carbinolamine by the cyanoamine dramatically increased the stability of renieramycins. Therefore, the KCN-pretreated strategy is the first example to provide an important solution to increase large-scale supply of renieramycins for further chemical and biological investigations. Ten new additional renieramycins were obtained by several chemical transformations of renieramycin M, including allylic oxidation by selenium dioxide in alcoholic solvents, reductive deangelation and reductive acetylation. The transformations of renieramycin M into known renieramycins including renieramycins Eand J and jorumycin were achieved. The oxidative degradations of renieramycin E and jorumycin to generate simple isoquinolinequinone alkaloids were also demonstrated and the degradation mechanism was proposed. The cytotoxicity and structure-activity relationship (SAR) of the isolated and semisynthetic renieramycins against carcinoma cell lines revealed that the cyano or hydroxyl groups at C-21 position was essential for the activity. Moreover, the deangeloyl compounds displayed higher potent cytotoxicity than the parent compounds. In addition, the presence of the oxygen containing functionality at C-14 caused less cytotoxic activity. The O-acetyl hydroquinone derivatives displayed equipotent cytotoxicity to the parent quinone compounds. The important impact of this discovery is the opening for new biomedical research collaborations to develop renieramycins as first anticancer agent from Thai marine natural resources.