Natural products as molecular targeted agents for breast cancer

• Main Author: Mora Vivas, Flor Dolveni
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2005
• Subjects: Pharmaceutical sciences; Pharmaceuticals
• ISBN: 9780542328053; 0542328054

Two main targets: peroxisome proliferator-activated receptor γ (PPARγ) and the hypoxia-inducible factor-1 (HIF-1) are used in this research to accomplish the specific research goals, as a part of a program targeted at the discovery of new anticancer agents from plants and marine organisms. Therefore, this research is divided into two major sections. In the first section, crude extracts, chromatographic fractions and pure compounds, from plants and marine organisms were examined, in a human breast carcinoma MCF-7 cell-based reporter assay for PPARγ activation. Further bioassay-guided isolation of the active extracts afforded the active lead compounds physalin B, physalin F, and psammaplin A. Activation of PPARγ in the reporter assay correlates the efficacy of these compounds as inducers of apoptosis in MCF-7 cells. At the same time, a novel yet inactive compound epi-physalin G was isolated. The epoxide ring in the molecule of physalin F appears to impart significant bioactivity, while the introduction of an extra double bond to the A ring as in epi-physalin G, reduces the activity dramatically. In the second section, an ongoing study of the potent HIF-1-inhibitory extract of Saururus cernuus was expanded to include other structurally related compounds. The isolation of three new sesquineolignans - 4-O-methyl-4''-O-demethylsaucerneol, 4''- O-methylsaucerneol C1, and 4''-O-methylsaucerneol C, - as well as the two known sesquineolignans - saucerneol and 4- O-methylsaucerneol, was performed. In addition, three dineolignans - manassantin A, manassantin A1, and manassantin A2 - were also purified. The absolute configurations of their propanoid side chains were determined from spectroscopic analysis of the intact natural products and semisynthetic modified Mosher ester derivatives. A structure-activity relationship study to determine the inhibition of the activation of HIF-1 by these compounds was performed using a cell-based reporter assay in the human breast cancer T47D cells. Appendix section I presents the results of the evaluation of approximately 4,000 terrestrial plant extracts, for their potential use in the control of agriculturally important pathogenic fungi. After preliminary screening using a direct bioautographic assay (Colletotrichum fragariae), the active extracts of the genus Picramnia were selected for further bioassay-guided isolation, affording the active compound chrysophanol.