Colchicine neoglycosides and methods for their synthesis and use

Abstract

Colchicine neoglycosides, method for their synthesis and methods for their use are disclosed. The invention provides analogs of colchicine glycosylated to include a sugar moiety on a colchicine scaffold that is generally unglycosylated in nature. The colchicine neoglycosides disclosed herein are shown to have cytotoxic effects equivalent to at least the known cytotoxins paclitaxel and doxorubicin. Further, the neoglycosides disclosed according to the invention have physiologic effects not previously recognized in the alkaloid family that includes colchicine but recognized in other cytotoxic drug families such as the taxanes which act by stabilizing tubulin formation.

1 . A colchicine neoglycoside having the structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         2 . The colchicine neoglycoside of  claim 1 , wherein R is: 
       
         
           
           
               
               
           
         
       
     
     
         3 . A methoxyamine-appended colchicine according to the structure: 
       
         
           
           
               
               
           
         
       
     
     
         4 . A method of synthesizing a colchicine neoglycoside according to the reaction: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . The method of  claim 4 , wherein the reaction is carried out at 40° C. in the presence of 3:1 dimethylformamide/acetic acid. 
     
     
         6 . The method of  claim 4 , wherein an intermediate in the synthesis is a methoxyamine-appended colchicine according to the structure: 
       
         
           
           
               
               
           
         
       
     
     
         7 . A method of treating cancer, arthritis, Mediterranean fever, amyloidosis, scleroderma, irritable bowel syndrome or gout comprising administering to a patient in need thereof a therapeutically effective amount of the colchicine neoglycoside according to  claim 1 . 
     
     
         8 . The method of  claim 7  wherein the colchicine neoglycoside is administered in combination with other therapeutically effective drugs. 
     
     
         9 . The method of  claim 7 , wherein the other therapeutically effective drugs are selected from the group consisting of an alkaloid, an anthraclycline, a taxane and combinations thereof. 
     
     
         10 . The method of  claim 7 , wherein the colchicine neoglycoside has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The method of  claim 9 , wherein the alkaloid is colchicine. 
     
     
         12 . The method of  claim 9 , wherein the anthracycline is doxorubicin. 
     
     
         13 . The method of  claim 9 , wherein the taxane is paclitaxel.