Isolation, structure, and synthesis of combretastatins A-1 and B-1, potent new inhibitors of microtubule assembly, derived from Combretum caffrum

George Pettit, Sheo Bux Singh, Margaret L. Niven, Ernest Hamel, Jean M. Schmidt

Research output: Contribution to journalArticle

286 Citations (Scopus)

Abstract

The principal antineoplastic constituent of the South African tree Combretum caffrum has been isolated and designated combretastatin A-1. The structure of this new cis-stilbene [1a] was unequivocally established by X-ray crystal structure determination and total synthesis. A Wittig reaction sequence [5d and 6] in THF comprised the synthetic key step (92.5% yield) and provided a very favorable 9:1 ratio of the cis:trans [1c:2c, geometrical isomers]. Selective hydrogenation of combretastatin A-1 [1a] afforded combretastatin B-1 [3], a companion cell growth inhibitory constituent of C. caffrum, Combretastatin A-1 [1a] provided 26-29% life extension at 2.75-11 mg/kg dose levels with ED50 0.99 μg/ml against the murine P-388 lymphocytic leukemia in vivo and in vitro systems. Both combretastatin A-1 and combretastatin B-1 are potent inhibitors of microtubule assembly in vitro and among the most potent inhibitors of the binding of colchicine to tubulin yet described. The structural simplicity and ready synthesis of combretastatin A-1 and combretastatin B-1 suggest that these new biosynthetic products will become useful in a variety of biological endeavors.

Original languageEnglish (US)
Pages (from-to)119-131
Number of pages13
JournalJournal of Natural Products
Volume50
Issue number1
StatePublished - 1987

Fingerprint

Combretum caffrum
Combretum
Microtubules
microtubules
lymphocytic leukemia
synthesis
stilbenes
hydrogenation
colchicine
crystal structure
tubulin
isomers
cell growth
X-radiation
mice
Lymphoid Leukemia
dosage
Stilbenes
Hydrogenation
Colchicine

ASJC Scopus subject areas

  • Plant Science
  • Chemistry (miscellaneous)
  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

Isolation, structure, and synthesis of combretastatins A-1 and B-1, potent new inhibitors of microtubule assembly, derived from Combretum caffrum. / Pettit, George; Singh, Sheo Bux; Niven, Margaret L.; Hamel, Ernest; Schmidt, Jean M.

In: Journal of Natural Products, Vol. 50, No. 1, 1987, p. 119-131.

Research output: Contribution to journalArticle

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