title: Antineoplastic agents. 578. Synthesis of stilstatins 1 and 2 and their water-soluble prodrugs.
abstract: 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.
authors.affiliation: Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, P.O. Box 871604, Tempe, Arizona 85287-1604, USA. bpettit@asu.edu
authors.forename: George R
authors.initials: GR
authors.lastname: Pettit
authors.forename: Andrew
authors.initials: A
authors.lastname: Thornhill
authors.forename: Noeleen
authors.initials: N
authors.lastname: Melody
authors.forename: John C
authors.initials: JC
authors.lastname: Knight
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007941:Leukemia P388; D008297:Male; D051379:Mice; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry; D012995:Solubility; D013237:Stereoisomerism; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014867:Water / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D013267:Stilbenes; C548739:stilstatin 1; C548740:stilstatin 2; D014867:Water