Vitamin E derivatives bearing a carboxylic group have recently gained great attention because of their antitumoral properties. Garcinoic acid (trans-13'-carboxy-delta-tocotrienol) is a vitamin E analog extracted from Garcinia Kola seeds in which the carboxylic group is at the end of the aliphatic side chain and reported to be a racemate based on the optical rotation measurements. However, CD determination of a sample of the acid analyzed by us gave a positive peak at 208 nm, indicating that it is not a racemate. To assess the enantiomeric composition of garcinoic acid, it was thus transformed to alpha-tocopherol and analyzed by chiral HPLC on column OD-H. On the basis of the elution order of alpha-tocopherol stereoisomers, the garcinoic acid sample resulted to be enantiopure with R configuration at carbon 2 of the chroman ring. Moreover, in a preliminary test, the acid and some of its derivatives showed a marked antiproliferative effect on glioma C6 cancer cells.
[Show abstract][Hide abstract] ABSTRACT: Although the metabolism of vitamin E has been extensively studied in cell culture, animals, and humans, biochemical analyses of intermediate metabolites are scarce. We here describe the synthesis and proapoptotic properties of long-chain metabolites of α- and δ-tocopherol. Several long-chain vitamin E metabolites, namely 13'-hydroxy- and 13'-carboxychromanols, were synthesized from garcinoic acid, a δ-tocotrienol derivative extracted from the African bitter nut Garcinia kola. Both α- and δ-13'-carboxychromanol induced cell death in HepG2 cells at EC(50) of 13.5 and 6.5 μM, respectively. Apoptosis was quantified by annexin V/7-AAD staining and flow cytometry analysis. By immunoblot analyses, we observed activation of both caspase-3 and caspase-9 as well as PARP-1 cleavage. Parameters of mitochondrial dysfunction including reduced mitochondrial membrane potential and increased intracellular and intramitochondrial reactive oxygen species formation were observed after metabolite treatment. Last, long-chain hydroxychromanols were readily metabolized to the corresponding carboxychromanols in HepG2 cells. Taken together, these results indicate that long-chain metabolites may be responsible for antiproliferative properties of vitamin E vitamers.
Free Radical Biology and Medicine 11/2010; 49(8):1315-22. DOI:10.1016/j.freeradbiomed.2010.07.024 · 5.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vitamin E is an essential nutrient of still increasing economic importance. Vitamin E derivatives include many nonracemic chiral compounds whose chirooptical characterization is scarcely described in the literature. We report the CD spectra of delta-tocopherol and its unsaturated analog delta-tocotrienol. TDDFT calculations demonstrate that the weak CD of delta-tocopherol is determined by the helicity of dihydropyrane ring. In addition, the moderate CD of delta-tocotrienol is due to the exciton interaction between the aromatic ring and the closest alkene group. Direct exciton-coupled CD calculations on structures generated by two different conformational sampling approaches reveal that, although such exciton coupling is expected to be weak, it is sufficient to explain the spectral differences between tocopherol and tocotrienol.
[Show abstract][Hide abstract] ABSTRACT: A small library of vitamin E analogues, with a free acid group linked to the chroman core through an amide, ether or ester bond, was synthesized and evaluated for their anticancer potency on C6 murine glioma cells. Several compounds showed antitumor activity better than temozolomide, the mostly commonly used drug in the treatment of gliomas.
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