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OH CH3

Figure 28.15 • a-Tocopheryl succinate.

peroxide damage in these cells by electrophilic peroxyni-trites or other mutagens, y-tocopherol is also needed that, in addition to forming the orthoquinone, acts in vivo as a trap for these membrane-soluble electrophilic mutagens forming stable adducts through the nucleophilic C5, which is blocked in a-tocopherol (Fig. 28.13). It has been suggested that because a-tocopherol supplementation suppresses y-toco-pherol levels, a combination of the two tocopherols in the ratios found in the diet may be more useful than a-toco-pherol, alone.99

The well-documented antioxidant property of the toco-pherols led to their examination for anticancer activity without any consistent success;43,100 although some studies have shown a reduction in prostate cancer in smokers.44 It is interesting that the ethers (RO-), esters (RCOO-), and amides (RCONH-) at C6 of the chromanol ring (a-toco-pheryl succinate ester is the prototype, Fig. 28.15) have shown to be potent antineoplastic agents. The antineoplas-tic potency of the tocopherol analogs is not related to their antioxidant property, which was proven by synthesizing a series of "redox-silent" analogs and testing them against various neoplastic cell lines. The detailed molecular biology studies revealed that these are mainly mitocans (mito-chondrially targeted anticancer drugs) that selectively destabilize the mitochondria in malignant cells and suppressed cancer in preclinical models. Although they are fully recognized as potent anticancer agents, detailed clinical studies for their therapeutic application are yet to be completed.101

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