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Vitamin E analogues as inducers of apoptosis: structure-function relation.

Birringer M, EyTina JH, Salvatore BA, Neuzil J - Br. J. Cancer (2003)

Bottom Line: Recent results show that alpha-tocopheryl succinate (alpha-TOS) is a proapoptotic agent with antineoplastic activity.Both Trolox and its succinylated derivative were inactive. alpha-tocotrienol (alpha-T3 H) failed to induce apoptosis, while gamma-T3 H was apoptogenic, and more so when succinylated.It is hoped that these observations will lead to the synthesis of analogues with even higher apoptogenic and, consequently, antineoplastic efficacy.

View Article: PubMed Central - PubMed

Affiliation: German Institute of Human Nutrition, Potsdam-Rehbrücke, Germany.

ABSTRACT
Recent results show that alpha-tocopheryl succinate (alpha-TOS) is a proapoptotic agent with antineoplastic activity. As modifications of the vitamin E (VE) molecule may affect its apoptogenic activity, we tested a number of newly synthesised VE analogues using malignant cell lines. Analogues of alpha-TOS with lower number of methyl substitutions on the aromatic ring were less active than alpha-TOS. Replacement of the succinyl group with a maleyl group greatly enhanced the activity, while it was lower for the glutaryl esters. Methylation of the free succinyl carboxyl group on alpha-TOS and delta-TOS completely prevented the apoptogenic activity of the parent compounds. Both Trolox and its succinylated derivative were inactive. alpha-tocotrienol (alpha-T3 H) failed to induce apoptosis, while gamma-T3 H was apoptogenic, and more so when succinylated. Shortening the aliphatic side chain of gamma-T3 by one isoprenyl unit increased its activity. Neither phytyl nor oleyl succinate caused apoptosis. These findings show that modifications of different functional moieties of the VE molecule can enhance apoptogenic activity. It is hoped that these observations will lead to the synthesis of analogues with even higher apoptogenic and, consequently, antineoplastic efficacy.

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Analogues of VE used in this study. The items shown in bold indicate newly synthesised compounds.
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fig2: Analogues of VE used in this study. The items shown in bold indicate newly synthesised compounds.

Mentions: Functional domains in the molecule of VE. Vitamin E analogues (represented here by α-TOH and α-TOS) comprise three distinct domains, each responsible for a separate ‘function’ of the agent. Domain I, the functional domain, decides whether the compound is redox-active or redox-inactive. Domains II, the signalling domain, is responsible for effects of the analogues such as deregulation of the protein kinase C/protein phosphatase 2A pathway. Domain III, the hydrophobic domain, is responsible for docking of VE analogues in biological membranes and lipoproteins.


Vitamin E analogues as inducers of apoptosis: structure-function relation.

Birringer M, EyTina JH, Salvatore BA, Neuzil J - Br. J. Cancer (2003)

Analogues of VE used in this study. The items shown in bold indicate newly synthesised compounds.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2741106&req=5

fig2: Analogues of VE used in this study. The items shown in bold indicate newly synthesised compounds.
Mentions: Functional domains in the molecule of VE. Vitamin E analogues (represented here by α-TOH and α-TOS) comprise three distinct domains, each responsible for a separate ‘function’ of the agent. Domain I, the functional domain, decides whether the compound is redox-active or redox-inactive. Domains II, the signalling domain, is responsible for effects of the analogues such as deregulation of the protein kinase C/protein phosphatase 2A pathway. Domain III, the hydrophobic domain, is responsible for docking of VE analogues in biological membranes and lipoproteins.

Bottom Line: Recent results show that alpha-tocopheryl succinate (alpha-TOS) is a proapoptotic agent with antineoplastic activity.Both Trolox and its succinylated derivative were inactive. alpha-tocotrienol (alpha-T3 H) failed to induce apoptosis, while gamma-T3 H was apoptogenic, and more so when succinylated.It is hoped that these observations will lead to the synthesis of analogues with even higher apoptogenic and, consequently, antineoplastic efficacy.

View Article: PubMed Central - PubMed

Affiliation: German Institute of Human Nutrition, Potsdam-Rehbrücke, Germany.

ABSTRACT
Recent results show that alpha-tocopheryl succinate (alpha-TOS) is a proapoptotic agent with antineoplastic activity. As modifications of the vitamin E (VE) molecule may affect its apoptogenic activity, we tested a number of newly synthesised VE analogues using malignant cell lines. Analogues of alpha-TOS with lower number of methyl substitutions on the aromatic ring were less active than alpha-TOS. Replacement of the succinyl group with a maleyl group greatly enhanced the activity, while it was lower for the glutaryl esters. Methylation of the free succinyl carboxyl group on alpha-TOS and delta-TOS completely prevented the apoptogenic activity of the parent compounds. Both Trolox and its succinylated derivative were inactive. alpha-tocotrienol (alpha-T3 H) failed to induce apoptosis, while gamma-T3 H was apoptogenic, and more so when succinylated. Shortening the aliphatic side chain of gamma-T3 by one isoprenyl unit increased its activity. Neither phytyl nor oleyl succinate caused apoptosis. These findings show that modifications of different functional moieties of the VE molecule can enhance apoptogenic activity. It is hoped that these observations will lead to the synthesis of analogues with even higher apoptogenic and, consequently, antineoplastic efficacy.

Show MeSH