STRUCTURALLY NOVEL BIOCONVERSION PRODUCTS OF THE MARINE NATURAL PRODUCT SARCOPHINE EFFECTIVELY INHIBIT JB6 CELL-TRANSFORMATION

Sarcophytol A (1) and B (2) (see Chart 1) are cembrane-type diterpenes known to inhibit tumor promotion. Indicative of this inhibitory respo nse, we currently report sarcophytol A (1) mediates dose-dependent dim inution of 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced transfor mation of JB6 cells. Moreover, a structurally related furanocembrane d iterpene, sarcophine (3), isolated in good yield from the Red Sea soft coral Sarcophyton glaucum, was also found to serve as an effective in hibitor of JB6 cell transformation. This compound was subjected to pre parative-scale fermentation with Absidia glauca ATCC 22752, Rhizopus a rrhizus ATCC 11145, and Rhizopus stolonifer ATCC 24795, resulting in t he production of 10 new metabolites (5-14) along with the known compou nd 7 beta,8 alpha-dihydroxydeepoxysarcophine (4). Structures were eluc idated primarily on the basis of BD-NMR spectroscopy, with X-ray cryst allography being used to establish the relative stereochemistry of met abolite 5. When evaluated for potential to inhibit TPA-induced JB6 cel l transformation, several of the metabolites mediated inhibitory respo nses greater than sarcophytol A (1) or sarcophine (3), most notably 7 alpha-hydroxy-Delta(8(19))-deepoxysarcophine (6), which was comparable to 13-cis-retinoic acid. These studies provide a basis for further de velopment of novel furanocembranoids as anticancer agents.