Compositions and methods for modulating apoptosis in cells over-expressing Bcl-2 family member proteins
The present invention provides agents and compositions for modulating the apoptotic state of a cell. The agents comprise derivatives of antimycins which bind to an anti-apoptotic Bcl-2 family member protein. Further, the agents preferentially induce apoptosis in cells that over-express anti-apoptotic Bcl-2 family member proteins and typically exhibit reduced binding affinity for cytochrome B. Pharmaceutical uses of the agents and compositions include treating apoptosis-associated disease, such as neoplasia and drug resistance, are also disclosed.
1. An apoptotic composition that induces apoptosis by binding to a Bcl-2 family member protein and preferentially inducing apoptosis in a cell that over-expresses the Bcl-2 family member protein, the composition having the following formula II,
having an absolute configuration of [2R, 3R, 4S, 7S, 8R], and wherein
R 1 is hydrogen, a C 1 –C 8 linear or branched alkane, hydroxyl, a C 1 –C 8 hydroxyalkane, amino, a C 1 –C 8 di- or tri-amine, a C 1 –C 8 amide, a C 1 –C 8 carboxylic acid, or a substituted alkyl group;
R 2 is hydrogen, a C 1 –C 8 linear or branched alkane, hydroxyl, a C 1 –C 8 hydroxyalkane, amino, a C 1 –C 8 di- or tri-amine, a C 1 –C 8 amide, a C 1 –C 8 carboxylic acid, or a substituted alkyl group;
R 3 is hydrogen, a C 1 –C 8 linear or branched alkane, hydroxyl, a C 1 –C 8 hydroxyalkane, amino, a C 1 –C 8 di- or tri-amine, a C 1 –C 8 amide, a C 1 –C 8 carboxylic acid, or a substituted alkyl group;
R 4 is hydrogen, a C 1 –C 8 linear or branched alkane, a C 1 –C 8 hydroxyalkane, or a substituted alkyl group;
R 5 is hydrogen, a C 1 –C 8 linear or branched alkane, hydroxyl, a C 1 –C 8 hydroxyalkane, amino, a C 3 –C 8 di- or tri-alkylamine, a C 1 –C 8 carboxylic acid, a C 2 –C 8 amide, or a substituted alkyl group; and
R 6 is hydrogen, a C 1 –C 8 linear or branched alkane, hydroxyl, a C 1 –C 8 hydroxyalkane, amino, a C 1 –C 8 di- or tri-amine, a C 1 –C 8 amide, a C 1 –C 8 carboxylic acid, or a substituted alkyl group.
2. The composition of claim 1 , further comprising a pharmaceutically acceptable carrier.
3. The composition of claim 1 for use in treating cancer in a subject in need thereof.
4. A method for treating a subject having cancer comprising administering to the subject a therapeutically effective amount of a composition, wherein the composition comprises an antimycin of the following formula, and having an absolute configuration of [2R, 3R, 4S, 7S, 8R]:
wherein R 1 is hydrogen, a C 1 –C 8 linear or branched alkane, hydroxyl, a C 1 –C 8 hydroxyalkane, amino, a C 1 –C 8 di- or tri-amine, a C 1 –C 8 amide, a C 1 –C 8 carboxylic acid, or a substituted alkyl group;
R 2 is hydrogen, a C 1 –C 8 linear or branched alkane, hydroxyl, a C 1 –C 8 hydroxyalkane, amino, a C 1 –C 8 di- or tri-amine, a C 1 –C 8 amide, a C 1 –C 8 carboxylic acid, or a substituted alkyl group;
R 3 is hydrogen, a C 1 –C 8 linear or branched alkane, hydroxyl, a C 1 –C 8 hydroxyalkane, amino, a C 1 –C 8 di- or tri-amine, a C 1 –C 8 amide, a C 1 –C 8 carboxylic acid, or a substituted alkyl group;
R 4 is hydrogen a C 1 –C 8 linear or branched alkane, hydroxyl, a C 1 –C 8 hydroxyalkane or a substituted alkyl group;
R 5 is hydrogen, a C 1 –C 8 linear or branched alkane, hydroxyl, a C 1 –C 8 hydroxyalkane, amino, a C 1 –C 8 di- or tri-alkylamine, a C 1 –C 8 amide, a C 1 –C 8 carboxylic acid, or a substituted alkyl group; and
R 6 is hydrogen, a C 1 –C 8 linear or branched alkane, hydroxyl, a C 1 –C 8 hydroxyalkane, amino, a C 1 –C 8 di- or tri-amine, a C 1 –C 8 amide, a C 1 –C 8 carboxylic acid, or a substituted alkyl group.
5. The method of claim 4 , wherein the antimycin derivative is 2-methoxy ether antimycin A or A 3 .
6. The method of claim 4 , wherein the subject is human.
7. The method of claim 4 , further comprising administering a pharmaceutical carrier.
8. The method of claim 4 , wherein the administration is intravenous, subcutaneous, intramuscular, intradermal, transdermal, intrathecal, intracerebral, intraperitoneal, epidural or oral.