S-dimethylarsino-thiosuccinic acid S-dimethylarsino-2-thiobenzoic acid S-(dimethylarsino) glutathione as treatments for cancer

Abstract

Arsenic trioxide, an inorganic compound, is commercially available anti-cancer agent but it carries significant toxicity. Organic arsenicals, on the other hand, are much less toxic, to the extent that the methylation of inorganic arsenic in vivo into organic arsenicals has been considered a detoxification reaction. New organic arsenic derivatives have been synthesized, including S-dimethylarsino-glutathione, S-dimethylarsino-thiosuccinic acid and S-dimethylarsino-thiobenzoic acid, and established its potent in vitro cytotoxic activity against numerous human tumor cell lines, both of solid and hematological origin, as well as against malignant blood cells from patients with leukemia. Results form a basis for the development of S-dimethylarsino-glutathione, S-dimethylarsino-thiosuccinic acid, S-dimethylarsino-thiobenzoic acid, and other organic arsenicals as an anti-cancer therapy, combining high efficacy with very low, if any, toxicity.

1 . A compound having anti-cancer activity comprising:  
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently alkyls with 1-10 carbon atoms;  
         X is S or Se;  
         R 3  is —H, —COOH, —CH 2 —COOH, —CH 2 —CH 2 —COOH, —CH(CH 3 )—COOH, —CH(CH 2 —CH 3 )—COOH, or —CH 2 —CH 2 —CH 2 —COOH;  
         n is 0 or 1;  
         R 4  is —OH, —H, —CH 3 , or a Glutamine substituent;  
         R 3 , R 4 , C 1  and C 2  all independently comprise part of an aromatic ring or substituted aromatic ring; and  
         R5 is a —OH, or Glycine substituent;  
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         2 . The compound of  claim 1 , wherein said compound has the formula:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         3 . The compound of  claim 1 , wherein said compound has the formula:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         4 . The compound of  claim 1 , wherein said compound has the formula:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         5 . A pharmaceutical composition having anti-cancer activity comprising a pharmaceutical carrier and an organic arsenical compound having the formula:  
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently alkyls with 1-10 carbon atoms;  
         X is S or Se;  
         R 3  is —H, —COOH, —CH 2 —COOH, —CH 2 —CH 2 —COOH, —CH(CH 3 )—COOH, —CH(CH 2    
         —CH 3 )—COOH, or —CH 2 —CH 2 —CH 2 —COOH;  
         n is 0 or 1;  
         R 4  is —OH, —H, —CH 3 , or a Glutamine substituent;  
         R 3 , R 4 , C 1  and C 2  all independently comprise part of an aromatic ring or substituted aromatic ring; and  
         R 5  is a —OH, or Glycine substituent;  
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         6 . A method of treating a patient with cancer comprising of administering a composition comprising a therapeutically effective amount of a compound having  
       
         
           
           
               
               
           
         
         the formula:  
         wherein R 1  and R 2  are independently alkyls with 1-10 carbon atoms;  
         X is S or Se;  
         R 3  is —H, —COOH, —CH 2 —COOH, —CH 2 —CH 2 —COOH, —CH(CH 3 )—COOH, —CH(CH 2 —CH 3 )—COOH, or —CH 2 —CH 2 —CH 2 —COOH;  
         n is 0 or 1;  
         R 4  is —OH, —H, —CH 3 , or a Glutamine substituent;  
         R 3 , R 4 , C 1  and C 2  all independently comprise part of an aromatic ring or substituted aromatic ring; and  
         R 5  is a —OH, or a Glycine substituent;  
         or a pharmaceutically acceptable salt thereof to said patient.  
       
     
     
         7 . The method of  claim 6 , wherein said compound has the formula:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         8 . The method of  claim 6 , wherein said compound has the formula:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         9 . The method of  claim 6 , wherein said compound has the formula:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         10 . The method of  claim 6 , wherein said cancer comprises a solid tumor.  
     
     
         11 . The method of  claim 10 , wherein said cancer is brain, lung, liver, spleen, kidney, lymph node, small intestine, pancreas, blood cells, bone, colon, stomach, breast, endometrium, prostate, testicle, ovary, central nervous system, skin, head and neck, esophagus, or bone marrow cancer.  
     
     
         12 . The method of  claim 6 , wherein said cancer is a hematological cancer.  
     
     
         13 . The method of  claim 12 , wherein said cancer is leukemia, lymphoma, multiple myeloma, myelodysplasia, myeloproliferative disease, or refractory anemia.  
     
     
         14 . The method of  claim 13 , wherein said cancer is acute promyelocytic leukemia.  
     
     
         15 . The method of  claim 6 , wherein said pharmaceutically effective amount is 0.1-1000 mg/kg.  
     
     
         16 . The method of  claim 15 , wherein said pharmaceutically effective amount is 1-500 mg/kg.  
     
     
         17 . The method of  claim 16 , wherein said pharmaceutically effective amount is 10-100 mg/kg.  
     
     
         18 . The method of  claim 6 , wherein said compound is administered daily.  
     
     
         19 . The method of  claim 6 , wherein said compound is administered by injection.  
     
     
         20 . The method of  claim 6 , wherein an additional agent is administered to said patient.  
     
     
         21 . The method of  claim 20 , wherein said additional agent is all-trans-retinoic acid, 9-cis retinoic acid, Am-80 or ascorbic acid.