الفهرس 
IntroductionOnly 14 pages are availabe for public view
 |  | from | 32 |  |  |
| | | from | 32 | | |
Abstract
Tocotrienol and curcuphenol are two phenolic natural products. They have unique health-related biological activities. However little is reported about the impact of the structural modifications on the anticancer activities of these compounds. Esterification and electrophilic substitution (Mannich and Lederer-Manasse) reactions are simple one-pot reactions, and were used in the project described herein to modify tocotrienols and curcuphenol. The growth and migration inhibitory activities of the prepared analogs were evaluated, as well as water-solubility, and chemical and metabolic stability.Certain tocotrienol esters have shown improved water solubility (1000-fold), enhanced aqueous and metabolic stability, and increased antiproliferative and antimigratory activities. An acid with an optimum length of four carbons, a terminal ionizable group, and an α, β-unsaturated system was found to be the ester chain conferring best activity. Tocotrienol electrophilic substitution products have shown improved in-vitro antiproliferative and antimigratory activities in addition to in-vivo tumor growth inhibition activity, marking success in overcoming most barriers impeding the future clinical use for the control of metastatic breast cancer. Tocotrienol oxazines showed selective proliferation inhibition of blood and colon malignant cell lines of the National Cancer Institute panel. The oxazine analogs of δ-tocotrienol showed lower IC50 values than the analogs of the γ-isomer. Extending the length of the N3’’ substituent (up to eight carbons) proved to enhance the activity. In addition, a terminal OH group at N3’’ substituent was preferred over COOH, NH, or NO2 for the activity. Curcuphenol electrophilic substitution products have shown up to 9- and 12-fold increases in their antiproliferative and antimigratory activities, respectively. 1,3-oxazine ring with an N3’-substituent possessing a terminal group containing an electronegative atom (N or O) located at an optimum distance of 4-6 bonds away from N3’ are optimum for the activity. Mannich bases and hydroxymethyl analogs were inactive. Various approaches were pursued to identify the target(s) of tocotrienols. Tocotrienol analogs tagged with a fluorescent dye were created for use in protein binding assays. In addition, a tocotrienol ester inhibited the phosphorylation of the receptor complex protein Met in a competitive mode of action. This competitive inhibitor can be the basis for the rational design of tocotrienol analogs having greater potency as Met inhibitors. In conclusion, a number of analogs of tocotrienols and curcuphenols were designed following ligand-based approaches and then synthesized. In addition, steps toward tocotrienol target identification were taken. Tocotrienols and curcuphenol analogs are potential candidates as antiproliferative and antimigratory agents in the treatment of cancer.