STRUCTURAL ELUCIDATION OF THE CYTOTOXIC COMPOUNDS FROM CENTAUREA REPENS AND PIPTOCARPHA CHONTALENSIS
Abstract
Part I. Centaurea repens. A crystalline compound from Centaurea repens was determined to be the known sesquiterpene lactone centaurepensin on the basis of IR, mass, NMR, and CMR spectral data. Centaurepensin shows significant (ED 50 = 0.4 (mu)g/ml) cytotoxic activity in KB tissue culture but is inactive against P-388 leukemia, B-16 melanoma, and C-6 colon carcinoma. The kinetic rate constant of the reaction of centaurepensin with cysteine was determined to be 1463 liter/mole-min, and the angle strain energy associated with the (gamma)-lactone ring was calculated (4.66 kcal/mole) from the literature X-ray coordinates. These results upset a correlation of cytotoxicity, kinetic rate constant, and angle strain previously observed for three other sesquiterpene lactones. Part II. Piptocarpha chontalensis. Using in vitro activity against 9KB cells to guide the fractionation procedure, the leaf material of P. chontalensis was extracted and fractionated in order to isolate the constituents accounting for the borderline cytotoxicity of the crude ethanol extract. Repetitive chromatography accomplished the separation of six cytotoxic natural products, piptocarphins A-F. Spectral analysis using UV, IR, MS, PMR, and CMR spectroscopy allowed the structural elucidation of these six compounds as a series of closely related germacranolide sesquiterpene lactones possessing an unusual conjugated enol lactone and an intramolecular hemiketal functionality. The differences among these compounds occur in the alcohol, ester, and ether functionalities attached to the parent lactone alcohol. Piptocarphin A, the major component, shows toxicity and borderline antitumor activity against P-388 murine leukemia. It has been submitted for additional testing in the B-16 melanoma and C-8 colon tumor systems.
Degree
Ph.D.
Subject Area
Pharmacology
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