Synthesis of combretastatin A-2 prodrugs and cephalostatin 1 structural modifications

Natural products from both marine and terrestrial sources provide a vast and extremely important array of medicinally valuable compounds. Illustrative of this are the stilbenes, designated combretastatins, isolated from the South African willow tree Combretum caffrum and the trisdecacyclic disteroidal alkaloids, designated cephalostatins, isolated from the tiny Indian Ocean marine worm Cephalodiscus gilchristi.; The original synthesis of combretastatin A-2, reported in 1987 from the root bark of C. caffrum, was modified to provide a more practical scale-up protocol for this antineoplastic stilbene. The major synthetic advancements achieved include an increase in the overall yield of the final product and a vast improvement in the cis/trans ratio of the product from the key Wittig coupling step. Additionally, the production of numerous water-soluble metal and amine prodrug derivatives of the parent stilbene was accomplished in an effort to afford additional bioseiectivity for neoplastic cells, which proved to possess potent antineoplastic behavior against a broad spectrum of human tumor cancer cells.; The scarcity, complex molecular architecture and incredible cytotoxicity associated with the cephalostatins has generated great interest in the development of structurally simpler synthetic analogues with comparable bioactivity. To this end, construction of a symmetric pyrazine from a modified steroidal monomer of the antineoplastic bufadienolide bufalin was accomplished to provide important structure-activity relationship insights into the pharmacore of the cephalostatins. Unfortunately, unremarkable cytotoxicity against the P388 lymphocytic leukemia cell strain was observed from the synthetic derivatives obtained.; In an effort to provide adducts with more closely related structures to that of the cephalostatins, a symmetric trisdecacyclic pyrazine analogue was sought. Hecogenin acetate was synthetically transformed to give in an overall yield of 19% a dihydroxylated intermediate. Subsequent spirocyclization to yield the key monomeric unit for future symmetric trisdecacyclic pyrazine formation has been accomplished in seven synthetic transformations with an overall yield from hecogenin acetate of 4.6%. Additionally, none of the synthetic intermediates screened thus far against the P388 cell strain have demonstrated potent cytotoxicity.