Efficient syntheses of 3,4-methylenedioxy-4',5-dimethoxy-2',3'-dihydroxy-Z-stilbene (
stilstatin 1, 2), 3,4,4'-trimethoxy-2',3',5-trihydroxy-Z-stilbene (
stilstatin 2, 5), and respective
phosphate prodrugs have been summarized. Both 2 and 5 were accessed via a convergent step synthesis using phosphonium
bromides 6 and 21 in Wittig reactions with 2,3-bis(tert-butyldimethylsilyloxy)-4'-methoxybenzaldehyde 14. Deprotection of silyl
ethers 15 and 26 with TBAF furnished 2 and 5, respectively. Phosphorylation of 2 and 5 afforded the
phosphoric acid intermediates 17 and 28 for
prodrug development. These
phosphoric acid precursors were employed in parallel series of reactions to produce a selection of
metal cation prodrug candidates. The
biological activities of stilstatins 1 (2) and 2 (5) and their respective
prodrugs were evaluated against a panel of one murine (P388) and six human
cancer cell lines. Compared to
combretastatin A-2 (1),
stilstatin 1 (2) has an additional vicinal hydroxy group on the B ring, the presence of which was detrimental to the
cancer cell line potency; in vivo, however, compound 2 would be predicted to have greater anticancer activity resulting from the o-
quinone mechanism of action analogous to that of
combretastatin A-1 (4). The substitution of a hydroxy group for a methoxy group on the A ring of
combretastatin A-1 (4), resulting in
stilstatin 2 (5), gave rise to a modest level of inhibition consistent with that found for 4 against
cancer cell lines.