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 response, we currently report sarcophytol A (1) mediates dose-dependent diminution of 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced transformation of JB6 cells. Moreover, a structurally related furanocembrane diterpene, sarcophine (3), isolated in good yield from the Red Sea soft coral Sarcophyton glaucum, was also found to serve as an effective inhibitor of JB6 cell transformation. This compound was subjected to preparative-scale fermentation with Absidia glauca ATCC 22752, Rhizopus arrhizus ATCC 11145, and Rhizopus stolonifer ATCC 24795, resulting in the production of 10 new metabolites (5-14) along with the known compound 7beta,8alpha-dihydroxydeepoxysarcophine (4). Structures were elucidated primarily on the basis of 2D-NMR spectroscopy, with X-ray crystallography being used to establish the relative stereochemistry of metabolite 5. When evaluated for potential to inhibit TPA-induced JB6 cell transformation, several of the metabolites mediated inhibitory responses greater than sarcophytol A (1) or sarcophine (3), most notably 7alpha-hydroxy-Delta(8(19))-deepoxysarcophine (6), which was comparable to 13-cis-retinoic acid. These studies provide a basis for further development of novel furanocembranoids as anticancer agents.
El Sayed
Khalid A.
KA
Program for Collaborative Research in the Pharmaceutical Sciences and Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, 833 South Wood Street, Chicago, Illinois 60612-7231.
Hamann
Mark T.
MT
Waddling
Christopher A.
CA
Jensen
Craig
C
Lee
Sang Kook
SK
Dunstan
Christina Andersson
CA
Pezzuto
John M.
JM