2 Methoxy antimycin a derivatives and methods of use
AssigneeFred Hutchinson Cancer Research Center
InventorsDavid Hockenbery, Julian Simon, Shie-Pon Tzung
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Abstract
Disclosed are 2-methoxy antimycin derivatives or analogs that modulate apoptosis by binding to the hydrophobic groove of a Bcl-2 family member protein (e.g., Bcl-2 or BCl-xL). The 2-methoxy antimycin derivatives or analogs are used in disclosed methods for treating apoptosis-associated diseases such as, for example, neoplastic disease (e.g., cancer) or other proliferative diseases associated with the over-expression of a Bcl-2 family member protein.
Claims40
A 2-methoxy derivative or analog of antimycin that modulates apoptosis by binding to a Bcl-2 family member protein and having the structural formula represented by Formula (II)
- wherein
- R1 is a hydrogen, a C1-C8 linear or branched alkane, a hydroxyl, a C1-C8 hydroxyalkane, an amino, a C1-C8 di- or tri-amine, a C1-C8 amide, a C1-C8 carboxylic acid, or a substituted alkyl group;
- R2 is a C1-C8 acyl group;
- R3 is a hydrogen, a C1-C8 linear or branched alkane, a hydroxyl, a C1-C8 hydroxyalkane, an amino, a C1-C8 di- or tri-amine, a C1-C8 amide, a C1-C8 carboxylic acid, or a substituted alkyl group;
- and
- R4 is a hydrogen, a C1-C8 linear or branched alkane, a hydroxyl, a C1-C8 hydroxyalkane, an amino, a C1-C8 di- or tri-amine, a C1-C8 amide, a C1-C8 carboxylic acid, or a substituted alkyl group,
- with the proviso that the 2-methoxy antimycin derivative is not 2-methoxy antimycin A3.
A method for treating an apoptosis-associated disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a 2-methoxy antimycin derivative or analog that modulates apoptosis by binding to a Bcl-2 family member protein and having the structural formula represented by Formula (I)
- wherein
- R1 is a hydrogen, a C1-C8 linear or branched alkane, a hydroxyl, a C1-C8 hydroxyalkane, an amino, a C1-C8 di- or tri-amine, a C1-C8 amide, a C1-C8 carboxylic acid, or a substituted alkyl group;
- R2 is a C1-C8 acyl group;
- R3 is a hydrogen, a C1-C8 linear or branched alkane, a hydroxyl, a C1-C8 hydroxyalkane, an amino, a C1-C8 di- or tri-amine, a C1-C8 amide, a C1-C8 carboxylic acid, or a substituted alkyl group;
- and
- R4 is a hydrogen, a C1-C8 linear or branched alkane, a hydroxyl, a C1-C8 hydroxyalkane, an amino, a C1-C8 di- or tri-amine, a C1-C8 amide, a C1-C8 carboxylic acid, or a substituted alkyl group.
Dependencies are inferred from the claim text.