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Antineoplastic agents 440. Asymmetric synthesis and evaluation of the combretastatin A-1 SAR probes (1S,2S)- and (1R,2R)-1, 2-dihydroxy- 1-(2',3'-dihydroxy-4'-methoxyphenyl)-2-(3' ',4' ',5' '-trimethoxyphenyl)-ethane.

Abstract
The synthetic (E)-isomer (3b) of natural combretastatin A-1 (1a) isolated from the African bushwillow Combretum caffrum was the focus of chiral hydroxylation (Sharpless) reactions as part of a structure-activity relationship study. The resulting (R,R)- and (S,S, )-diols (6 and 7) and synthetic intermediates were evaluated against a series of cancer cell lines, microorganisms, and tubulin. Chiral diols 6 and 7 showed increased activity against the P-388 murine lymphocytic leukemia cell line with ED(50) values of 3.9 and 2.9 microg/mL, respectively, when compared to the precursor (E)-stilbene 3b. In contrast, (E)-stilbene 3b exhibited more potent antibiotic activity than the chiral diols (6 and 7). Both diols, (R,R)-6 and (S, S)-7, displayed less cancer cell growth inhibition and less antibiotic activity than did natural combretastatin A-1 (1a) (P-388 ED(50) 0.25 microg/mL).
AuthorsG R Pettit, J W Lippert 3rd, D L Herald, E Hamel, R K Pettit
JournalJournal of natural products (J Nat Prod) Vol. 63 Issue 7 Pg. 969-74 (Jul 2000) ISSN: 0163-3864 [Print] United States
PMID10924176 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • 1,2-dihydroxy-1-(2',3'-dihydroxy-4'-methoxyphenyl)-2-(3'',4'',5''-trimethoxyphenyl)ethane
  • Antineoplastic Agents, Phytogenic
  • Ethylene Glycols
  • Molecular Probes
  • Stilbenes
  • combretastatin A-1
  • Guaiacol
Topics
  • Animals
  • Antineoplastic Agents, Phytogenic (chemical synthesis, chemistry, pharmacology)
  • Drug Screening Assays, Antitumor
  • Ethylene Glycols (chemical synthesis, chemistry, pharmacology)
  • Guaiacol (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
  • Humans
  • Mice
  • Microbial Sensitivity Tests
  • Molecular Probes
  • Stereoisomerism
  • Stilbenes (chemistry)
  • Structure-Activity Relationship
  • Trees (chemistry)
  • Tumor Cells, Cultured

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