Date of Award

1980

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Abstract

Investigations of the antineoplastic crude extracts of Melampodium cinereum No. 2015B provided low yields of four new cis, cis-germacranolide sesquiterpene lactones which were named melcanthin D (83), E (84), F (87), and G (88). The separations of these closely related compounds were accomplished by reverse phase high pressure liquid chromatography. Structure elucidation of melcanthins D to G utilized infrared, ultraviolet, circular dichroism, mass, and proton nuclear magnetic resonance spectroscopic methods combined with spectral correlation with the known compound melcanthin A. Tentative configurational and conformational assignments were made by considering proton nuclear magnetic resonance coupling data and the dihedral angels from stereo models (Karplus correlation). For structure-biological activity correlation studies (antineoplastic activity, cytotoxicity, and phosphofructokinase deactivation), acetate, isobutyrate, hexanoate, and palmitate ester derivatives were prepared of four melampolide-type sesquiterpene lactones from Melampodium: melampodin B (86), melcanthin B (99), melampodin A (100), and cinerenin (101). The cinnamate of cinerenin was prepared, but attempts to prepare methacrylates of this series of melampolides by several methods failed. Twenty-two melampolide-type sesquiterpene lactones and their ester derivatives were tested for inhibition of the enzyme phosphofructokinase (PFK) and the apparent K(,i) values were determined. All compounds showed considerable PFK inhibition. Within each series of ester derivatives, PFK inhibition was observed to increase with increasing chain length of the ester moiety, rising to maximum inhibition for hexanoate esters. Comparison of these and other structural variations with cytotoxicity and limited antineoplastic activity data (obtained under the auspices of the National Cancer Institute) indicated possible correlations between cytotoxicity of these compounds is due to PFK deactivation. No correlation between antineoplastic activity and PFK inhibition was observed.

Pages

217

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