PROTEIN-TYROSINE KINASE INHIBITORY PROPERTIES OF PLANAR POLYCYCLICS OBTAINED FROM THE MARINE SPONGE XESTOSPONGIA CF CARBONARIA AND FROM TOTAL SYNTHESIS

Nine related polycyclic quinones and hydroquinones of the halenaquinon e class were isolated from two Indo-Pacific collections of the sponge Xestospongia cf. carbonaria. The halenaquinone family appears not to b e of polyketide origin but can be biogenetically derived by the union of a sesquiterpene and a quinone. Four new metabolites were characteri zed including tetrahydrohalenaquinone B (8a), 14-methoxyhalenaquinone (9), xestoquinolide A (10), and xestoquinolide B (11). These were acco mpanied by five known compounds, halenaquinone (3), halenaquinol (4), halenaquinol sulfate (5), xestoquinone (6), and tetrahydrohalenaquinon e A (7a). The new structures were established from 2D NMR data, and th e absolute stereochemistry of the chiral centers in 7 and 8 was determ ined by the formation of 7b and 7c, the bis esters of O-methylmandelic acid. A series of polycyclic models of natural products 3 and 6 were synthesized and included 16-23. The more complex members of this group were assembled via a 4 + 2 cycloaddition between an o-quinodimethane and a functionalized enone. The marine natural products plus two known fungal metabolites, viridin (13) and wortmannin (14), along with hale naquinone synthetic model compounds, were each tested for their abilit y to inhibit the activity of pp60v-src protein tyrosine kinase (PTK). Halenaquinone and 14-methoxyhalenaquinone were the most potent with IC 50 values <10 muM. The other compounds were either less potent or inac tive, and a rationalization for this SAR (structure activity relations hip) pattern is presented.