Vitamin E (VE) analogues, epitomized by a-tocopheryl succinate (a-TOS), are proapoptotic agents with selective antineoplastic activity. The molecule of a-TOS comprises several structurally and functionally distinct moieties that can be modified in order to yield analogues with higher activity. In order to find analogues with higher apoptogenic efficacy, we prepared novel compounds where the ester bond was replaced by an amide bond. All of these analogues were significantly more proapoptotic than their ester counterparts, with a-tocopheryl maleyl amide being the most effective. Importantly, methylation of the free carboxylic group completely obliterated apoptogenic activity of the compounds. Similarly as shown for the ester analogues, the amides induced apoptosis by mitochondrial destabilization. Superiority of amides over the ester analogues may be due to their higher partitioning into the lipid phase, as suggested by the log p-values that were lower for the amides than the corresponding esters. In conclusion, we present evidence that modification of the ester bond of agents such as a-TOS can be used as a basis for generating novel analogues with higher efficacy of killing malignant cells, an activity that suggests anticancer effect of the agents. ' 2005 Wiley-Liss, Inc.