111394-55-9Relevant academic research and scientific papers
Antineoplastic agents. 578. synthesis of stilstatins 1 and 2 and their water-soluble prodrugs
Pettit, George R.,Thornhill, Andrew,Melody, Noeleen,Knight, John C.
experimental part, p. 380 - 388 (2009/12/04)
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)and2(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.
