Antineoplastic agents. 487. Synthesis and biological evaluation of the antineoplastic agent 3,4-methylenedioxy-5,4′-dimethoxy-3′-amino-Z-stilbene and derived amino acid amides

George Pettit, Collin R. Anderson, Delbert L. Herald, M. Katherine Jung, Debbie J. Lee, Ernest Hamel, Robin Pettit

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

An efficient synthesis of 3,4-methylenedioxy-5,4′-dimethoxy-3′-amino-Z-stilbene (1c) and hydrochloride (1d) is reported. The nitrostilbene intermediate 6a was obtained via a Wittig reaction using phosphonium salt 4 and 3-nitro-4-methoxybenzaldehyde 5. A one-step reduction using zinc in acetic acid produced the synthetic objective amine 1c. The coupling of this amine with various Fmoc amino acids, followed by cleavage of the α-amine protecting group, resulted in a series of new cancer cell growth inhibitory amides. Amine 1c, hydrochloride 1d, glycine amide 3b, and tyrosine amide 3f had the highest level (GI50 = 10-2-10-3 μg/mL) of activity against a panel of six human and one animal (P388) cancer cell lines. Amine 1c and its hydrochloride 1d 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.

Original languageEnglish (US)
Pages (from-to)525-531
Number of pages7
JournalJournal of Medicinal Chemistry
Volume46
Issue number4
DOIs
StatePublished - Feb 13 2003

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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