title: Optimization of tocotrienols as antiproliferative and antimigratory leads.
abstract: The vitamin E family members γ- and δ-tocotrienols (2 and 3, respectively) are known natural products with documented anticancer activities. Redox-silent structural modifications, such as esterification, etherification and carbamoylation, of 2 and 3 significantly enhanced their anticancer activities. However, hit-to-lead optimization of tocotrienols and their analogs was yet to be reported at the outset of the project described herein. Subjecting the chroman ring of 2 and 3 to the electrophilic substitution reactions, namely, Mannich and Lederer-Manasse procedures, afforded 42 new products. These included the 3,4-dihydro-1,3-oxazines 3-29 and 35-44, Mannich bases 30-31, and the hydroxymethyl analogs 32-34. Of these, the δ-tocotrienol analogs 8, 11, 18, 24, 25, 27, and 40 inhibited the proliferation of the highly metastatic +SA mammary epithelial cancer cell line, with IC(50) values in the nanomolar (nM) range. In NCI's 60 human tumor cell line panel, 8, 17, 38, and 40 showed antiproliferative activity, with nM GI(50) values. The δ-tocotrienol analogs 10 and 38 inhibited the migration of the highly metastatic human breast cancer cell line MDA-MB-231 with IC(50) values of 1.3 and 1.5 μM, respectively, in the wound-healing assay. A dose of 0.5 mg/day for 14 days of one of the active analogs, 30, significantly slowed the growth of +SA mammary tumors in the syngeneic BALB/c mouse model, compared to the vehicle- and the parent γ-tocotrienol-treated control groups. Electrophilic substitution reactions promoted tocotrienols to lead level and can enable their future use to control metastatic breast malignancies.
authors.affiliation: Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA.
authors.forename: Fathy A
authors.initials: FA
authors.lastname: Behery
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Akl
authors.forename: Suryatheja
authors.initials: S
authors.lastname: Ananthula
authors.forename: Parash
authors.initials: P
authors.lastname: Parajuli
authors.forename: Paul W
authors.initials: PW
authors.lastname: Sylvester
authors.forename: Khalid A
authors.initials: KA
authors.lastname: El Sayed
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D010938:Plant Oils / Q000737:chemistry; D024508:Tocotrienols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D010938:Plant Oils; D024508:Tocotrienols