Redox-directed chelators targeting intracellular metal ions

Abstract

The present invention provides redox-activated chelators and methods for using the same to treat cancer. In one particular embodiment, the redox-activated chelator is of the formula: wherein each of m and n is an integer from 0 to 4; each of Ar 1 and Ar 2 is independently aryl or heteroaryl; each of R 1 , R 2 , R 5 and R 6 is independently hydrogen, alkyl, aryl, electron withdrawing group or an anion stabilizing group; each of R 3 and R 4 is independently alkyl, halide, or other electron withdrawing group or an anion stabilizing group.

What is claimed is: 
     
         1 . A method for treating a clinical condition associated with a metal ion dysregulation in a subject in need of such a treatment, said method comprising administering to the subject a therapeutically effective amount of a redox-activated pro-chelator, wherein said redox-activated pro-chelator is preferentially reduced within a cell having a metal ion dysregulation to produce a metal ion chelating moiety whereby chelation of metal ion by said metal ion chelating moiety within the cell with a metal dysregulation alleviates said clinical condition associated with the metal dysregulation. 
     
     
         2 . The method of  claim 1 , wherein said metal ion chelating moiety comprises a thiosemicarbazone moiety. 
     
     
         3 . The method of  claim 1 , wherein said redox-activated pro-chelator comprises a disulfide linkage that is configured to selectively be reduced within a cancer cell to produce a thiol compound that is configured to chelate iron ion within the cancer cell. 
     
     
         4 . The method of  claim 3 , wherein said redox-activated pro-chelator is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 each of m and n is an integer from 0 to 4; 
 each of Ar 1  and Ar 2  is independently aryl or heteroaryl; 
 each of R 1 , R 2 , R 5  and R 6  is independently hydrogen, alkyl, aryl, electron withdrawing group or an anion stabilizing group; 
 each of R 3  and R 4  is independently alkyl, halide, electron withdrawing group or an anion stabilizing group. 
 
     
     
         5 . The method of  claim 4 , wherein m and n are 0. 
     
     
         6 . The method of  claim 4 , wherein each of R 1  and R 2  is independently hydrogen, methyl or phenyl. 
     
     
         7 . The method of  claim 4 , wherein said redox-activated pro-chelator is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 m, n, R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are those defined in  claim 4 . 
 
     
     
         8 . A method for treating cancer in a subject, said method comprising administering to said subject in need of such a treatment a therapeutically effective amount of a redox-activated pro-chelator that is selectively reduced within a cancer cell, wherein said redox-activated pro-chelator is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 each of m and n is an integer from 0 to 4; 
 each of Ar 1  and Ar 2  is independently aryl or heteroaryl; 
 each of R 1 , R 2 , R 5  and R 6  is independently hydrogen, alkyl, aryl, electron withdrawing group or an anion stabilizing group; 
 each of R 3  and R 4  is independently alkyl, halide, electron withdrawing group or an anion stabilizing group. 
 
     
     
         9 . A method for treating a clinical condition associated with iron ion dysregulation in a cell, said method comprising administering to a patient in need of such a treatment a redox-activated pro-chelator that is selectively reduced within a cell with iron ion dysregulation, wherein said redox-activated pro-chelator is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 each of m and n is an integer from 0 to 4; 
 each of Ar 1  and Ar 2  is independently aryl or heteroaryl; 
 each of R 1 , R 2 , R 5  and R 6  is independently hydrogen, alkyl, aryl, electron withdrawing group or an anion stabilizing group; 
 each of R 3  and R 4  is independently alkyl, halide, electron withdrawing group or an anion stabilizing group. 
 
     
     
         10 . The method of  claim 9 , wherein said clinical condition comprises cancer, a neurodegenerative disorder, hemochromatosis, or thalassemia. 
     
     
         11 . The method of  claim 10 , wherein said clinical condition comprises breast cancer, lung cancer, prostate cancer, leukemia or ovarian cancer.