Part I. Combretastatin A-2 modifications. Part II. Dolastatin 16 synthetic approaches

Combretastatin A-2 represents one of the key antineoplastic and cancer vascular targeting stilbenes that have been isolated from the South African bush willow tree Combretum caffrum. An efficient synthesis of a novel derivative, 3-4-methylenedioxy-5,4′-dimethoxy-3 ′-amino-Z-stilbene, and its hydrochloride salt is reported. The coupling of this amine with various 9-fluorenylmethoxycarbonyl (Fmoc) amino acids, followed by cleavage of the α-amine protecting group, resulted in a series of new cancer cell growth inhibitory amides. The amine, its hydrochloride derivative, and the tyrosine amide had the highest level of activity against a panel of six human and one animal cancer cell lines. The amine and its hydrochloride salt potently inhibited tubulin polymerization by binding at the colchicine site, while the amides had little activity against purified tubulin. Nevertheless, most of the amides caused a marked increase in the mitotic index of treated cells, indicating that tubulin was their intracellular target.; Large scale collections of the shell-less mollusk Dolabella auricularia from Papua New Guinea in 1983 led to the isolation of dolastatin 16, a valuable lead in the dolastatin series of anticancer compounds. The cyclic depsipeptide contains a novel β-amino acid, designated dolamethylleuine (Dml), as well as an unnatural α-amino acid named dolaphenvaline (Dpv). The other six residues consist of three proline units, two α-hydroxyacid components and one N-methylated valine. Dml has been synthesized as the N-Z-protected free acid in four steps. The correct stereochemistry of Dml was confirmed using X-ray crystallography. A hexapeptide portion of dolastatin 16, containing Dml, has been synthesized and biologically evaluated.