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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.
AuthorsGeorge R Pettit, Andrew Thornhill, Noeleen Melody, John C Knight
JournalJournal of natural products (J Nat Prod) Vol. 72 Issue 3 Pg. 380-8 (Mar 27 2009) ISSN: 1520-6025 [Electronic] United States
PMID19228038 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Prodrugs
  • Stilbenes
  • stilstatin 1
  • stilstatin 2
  • Water
Topics
  • Animals
  • Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Leukemia P388
  • Male
  • Mice
  • Molecular Structure
  • Prodrugs (chemical synthesis, chemistry)
  • Solubility
  • Stereoisomerism
  • Stilbenes (chemical synthesis, chemistry, pharmacology)
  • Water (chemistry)

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