Mitochondrially delivered anti-cancer compounds

Abstract

This invention relates to anti-cancer compounds and to methods for treating or preventing cancer. In one aspect the invention concerns mitochondrially delivered pro-oxidant anti-cancer compounds that generate reactive oxygen species and induce apoptosis of cancerous cells. The delivery moiety can be a lipophilic cation and the pro-oxidant moiety can be a pro-oxidant vitamin E analogue, such as α-tocopheryl succinate, α-tocopheryl maleate, α-tocopheryl maleyl amide, or 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)-chroman-6-yloxyacetic acid (α-tocopheryloxyacetic acid).

The invention claimed is: 
     
       1. A compound for inducing death of a cancerous cell, said compound comprising: a pro-oxidant moiety for (i) generating reactive oxygen species within mitochondria of the cancerous cell, (ii) inducing apoptosis of the cancerous cell, and (iii) interacting with mitochondrial complex II of the cancerous cell, wherein the pro-oxidant moiety comprises a vitamin E analogue comprising a functional domain at position C6 of a substituted chromanol ring that is capable of interacting with a Qp ubiquinone binding site of mitochondrial complex II, a domain that includes the substituted chromanol ring, and a hydrophobic domain comprising an at least seven-carbon long aliphatic chain; and a delivery moiety for delivering the pro-oxidant moiety to the mitochondria of the cancerous cell and for correctly positioning the functional domain for interaction with the Qp ubiquinone binding site, wherein the delivery moiety comprises a delocalized lipophilic triphenylphosphonium cation and said vitamin E analogue is selected from the group consisting of α-tocopheryl succinate, α-tocopheryl maleate, α-tocopheryl maleyl amide, and 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)-chroman-6-yloxyacetic acid (α-tocopheryloxyacetic acid)  
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       triphenylphosphonium tagged 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)-chroman-6-yloxyacetic acid (triphenylphosphonium tagged α-tocopheryloxyacetic acid), and a derivative of any of the foregoing;
 wherein said derivative has a functional domain substituted at position C6 of the chromanol ring of the compound that comprises a functional domain group selected from the group consisting of an ether, ester, amide, dissociated carboxylic acid, and hydrophilic head group comprising a dissociated acid, a charged ammonium group, or both; 
 and a physiologically acceptable salt of any of the foregoing. 
 
     
     
       2. The compound of  claim 1 , wherein the vitamin E analogue is α-tocopheryl succinate (α-TOS). 
     
     
       3. A pharmaceutical or veterinary composition comprising the compound of  claim 1 , or a physiologically acceptable salt thereof, and a physiologically acceptable carrier. 
     
     
       4. A method of inducing the death of a cancerous cell, said method comprising the step of administering to said cancerous cell or a subject having said cancerous cell a therapeutically effective amount of the compound according to  claim 1 . 
     
     
       5. The compound of  claim 1 , wherein the functional domain is selected from the group consisting of an ether, ester and amide substituted at position C6 of the chromanol ring. 
     
     
       6. The compound of  claim 1 , wherein the aliphatic chain comprises an 11 carbon long aliphatic chain. 
     
     
       7. The pharmaceutical or veterinary composition of  claim 3 , wherein the pro-oxidant moiety is a vitamin E analogue selected from the group consisting of α-tocopheryl succinate, α-tocopheryl maleate and α-tocopheryl maleyl amide, and the carrier is a transdermally applicable cream. 
     
     
       8. The pharmaceutical or veterinary composition of  claim 3 , wherein the pro-oxidant moiety is α-tocopheryloxyacetic acid and the carrier is suited for oral administration. 
     
     
       9. The compound of claim 1, wherein the compound is MitoVE 7 S or a physiologically acceptable salt thereof. 
     
     
       10. The compound of claim 1, wherein the compound is MitoVE 9 S or a physiologically acceptable salt thereof. 
     
     
       11. The compound of claim 1, wherein the compound is MitoVE 11 S or a physiologically acceptable salt thereof. 
     
     
       12. The compound of claim 1, wherein the compound is MitoVE 11 AE or a physiologically acceptable salt thereof. 
     
     
       13. The compound of claim 1, wherein the compound is TPP-α-TOS or a physiologically acceptable salt thereof. 
     
     
       14. A pharmaceutical or veterinary composition comprising the compound of claim 1, or a physiologically acceptable salt thereof, and a physiologically acceptable carrier. 
     
     
       15. The pharmaceutical or veterinary composition of claim 14, wherein the carrier is a cream. 
     
     
       16. The pharmaceutical or veterinary composition of claim 14, wherein the carrier is suited for oral administration. 
     
     
       17. A method of inducing death of a cancerous cell, said method comprising the step of administering to said cancerous cell or a subject having said cancerous cell a therapeutically effective amount of the compound according to claim 1, or a physiologically acceptable salt thereof. 
     
     
       18. The method of claim 17, wherein said method is used to treat cancer in the subject. 
     
     
       19. The compound of claim 1, wherein the compound is triphenylphosphonium tagged 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)-chroman-6-yloxyacetic acid (triphenylphosphonium tagged α-tocopheryloxyacetic acid) or a physiologically acceptable salt thereof. 
     
     
       20. The compound of claim 1, wherein the derivative is a maleate derivative of MitoVE 11 S or a physiologically acceptable salt thereof. 
     
     
       21. The compound of claim 1, wherein the derivative is a maleyl amide derivative of MitoVE 11 S or a physiologically acceptable salt thereof. 
     
     
       22. The compound of claim 1, wherein the derivative is a maleate derivative of TPP-α-TOS or a physiologically acceptable salt thereof. 
     
     
       23. The compound of claim 1, wherein the derivative is a maleyl amide derivative of TPP-α-TOS or a physiologically acceptable salt thereof. 
     
     
       24. A compound of Formula (I), or a physiologically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       wherein R 1  comprises a hydrophilic head group comprising a dissociated acid, an ammonium group, or both, and is linked to the chromanol ring through an ester bond, an amide bond, or an ether bond. 
     
     
       25. A compound of Formula (I), or a physiologically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       wherein R 1  comprises a carboxylate or ammonium group, and is linked to the chromanol ring through an ester bond, an amide bond, or an ether bond.