Nt Nt

Source: From Yu, W. et al. Nutr Cancer. 1999; 33:26-32. With permission.

succinyl moiety that makes a-TOS proapoptotic. To understand the importance of the individual domains in the activity of VE analogs, we synthesized compounds in which the various domains were modified or completely removed, and tested the resulting analogs for their efficacy to cause apoptosis in malignant cell types.25

The individual analogs studied are shown in Figure 6.2 and their effects on cancer cells are listed in Table 6.4. Compounds derived from a-TOH with a lower number of methyl substituents in the signaling domain showed no proapoptotic activity. Esterification of the hydroxyl group with dicarboxylic fatty acids of various lengths revealed that a-tocopheryl maleate and a-tocopheryl fumarate were the most efficient. Presence of an uncharged fatty acid moiety in the functional domain, as suggested by a-tocopheryl acetate, resulted in no apoptotic activity, and methylation of the free carboxylate of the ester group, as shown in case of a-TOS or 8-TOS methyl ester completely abrogated the apoptogenic activity.25 Removal of the hydrophobic domain also wiped out the activity, as exemplified by a-Trolox succinate.

An interesting modification to the hydrophobic domain is an exchange of the fully saturated phytyl change by the chain with three double bonds. While a-T3H does not cause apoptosis,25 y- and 8-T3H are apoptogenic.25 26 Reasons for the activity of y- and 8-T3H are not known, although the polyunsaturated hydrophobic

OOC CH2CH,CO(

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