THE ACTIVE-CENTERS OF AGELASTATIN-A, A STRONGLY CYTOTOXIC ALKALOID OFTHE CORAL SEA AXINELLID SPONGE AGELAS-DENDROMORPHA, AS DETERMINED BY COMPARATIVE BIOASSAYS WITH SEMISYNTHETIC DERIVATIVES

Agelastatin A (1), an unusual alkaloid of the axinellid sponge Agelas dendromorpha from the Coral Sea, can be selectively acetylated (--> 7) or methylated at OH-C(8a) (--> 4), peracetylated (--> 8) or permethyl ated at OH-C(8a), NH(5), and NH(6) (--> 5), or, finally, subjected to C(9)-C(8a) (--> 14) or C(5b)-C(8a) beta-elimination (--> 11-13), in a regiospecific manner or not, depending on the reaction conditions. Und er acidic conditions, compound 12 adds H2O or MeOH, regioselectively t hough not endo/exo stereoselectively, giving transoid/cisoid mixtures 1/18 or 4/19, respectively. Similarly 11 or 13 add MeOH to give mixtur es (-)-2/20 or 15/16, respectively. Compound 13 also adds AcOH giving mixture 8/17. The intermediate cisoid form obtained on treatment of 21 with H3O+ undergoes N(5)-N(6) bridging affording pentacyclic 22 which constitutes a proof for the cisoid configuration. From conformational studies, rules are devised that allow assigning the configuration of these compounds from NMR data. Iii vitro comparative cytotoxicity assa ys of these compounds show that for high cytotoxic activity, such as o f 1 in vivo, unsubstituted OH-C(8a), H-N(5), H-N(6) moieties are neede d in the natural B/D transoid configuration.