Ribonucleotide reductase inhibitors and methods of use

Abstract

Provided herein are novel compounds that inhibit ribonucleotide reductase (RR) by binding to RRM2 and interfering with the activity of the RRM1/RRM2 holoenzyme, as well as methods of synthesizing these novel compounds. The compounds may be used to inhibit RR activity and to treat various conditions associated with RRM2 expression, such as for example certain cancer types, mitochondrial diseases, or degenerative diseases.

What is claimed is: 
     
         1 . A method of synthesizing a compound having the structure: 
       
         
           
           
               
               
           
         
         comprising the steps: 
         (a) converting veratrole to 1-(3,4-dimethoxyphenyl)-2-phenylethanone; 
         (b) converting 1-(3,4-dimethoxyphenyl)-2-phenylethanone to 4-(3,4-dimethoxyphenyl)-5-phenylthiazol-2-amine; 
         (c) converting 4-(3,4-dimethoxyphenyl)-5-phenylthiazol-2-amine to N-(4-(3,4-dimethoxyphenyl)-5-phenylthiazol-2-yl)-3,4-dimethoxybenzamide; and 
         (d) converting N-(4-(3,4-dimethoxyphenyl)-5-phenylthiazol-2-yl)-3,4-dimethoxybenzamide to 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The method of  claim 1 , wherein synthesis occurs via the following pathway: 
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein,
 R is substituted or unsubstituted aryl, 
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  are independently hydrogen, substituted or unsubstituted aryl, or a substituted or unsubstituted alkyl; and 
 R 8 , R 9 , R 10  and R 11  are independently a hydroxyl protecting group, wherein R 8  and R 9  are optionally joined together to form a substituted or unsubstituted heterocycloalkyl and R 10  and R 11  are optionally joined together to form a substituted or unsubstituted heterocycloalkyl. 
 
       
     
     
         4 . The compound of  claim 3 , wherein
 R is unsubstituted aryl,   R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  are independently hydrogen, unsubstituted aryl, or unsubstituted alkyl.   
     
     
         5 . The compound of  claim 3 , wherein R 8  and R 9  are optionally joined together to form an acetal protecting group and R 10  and R 11  are optionally joined together to form an acetal protecting group. 
     
     
         6 . The compound of  claim 5 , wherein said acetal is a diphenyl methylene acetal. 
     
     
         7 . The compound of  claim 3  having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 7 , wherein R 8 , R 9 , R 10  and R 11  are independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl or a substituted silyl. 
     
     
         9 . The compound of  claim 7 , wherein R 8 , R 9 , R 10  and R 11  are independently an activated ethylene protecting group, a benzyl ether protecting group, a silicon-based carbonate protecting group, or a cyclic acetal protecting group. 
     
     
         10 . The compound of  claim 8 , wherein:
 R 8 , R 9 , R 10  and R 11  are independently methyl benzyl, p-methoxybenzyl, allyl, trityl, p-methoxyphenyl, tetrahydropyranyl, methoxymethyl, 1-ethoxyethyl, 2-methoxy-2-propy, 2,2,2-trichloroethoxymethyl, 2-methoxyethoxymethyl, 2-trimethylsilylethoxymethyl, methylthiomethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, triphenylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,   
       
         
           
           
               
               
           
         
       
       wherein
 n is 0 or 1; 
 R 12  is hydrogen, —OH, —OR 16  or substituted or unsubstituted alkyl, wherein R 16  is substituted or unsubstituted alkyl; and 
 R 13 , R 14  and R 15  are substituted or unsubstituted alkyl. 
 
     
     
         11 . A composition comprising the compound of  claim 3  and toluene, dimethylformamide or dichloromethane. 
     
     
         12 . A composition comprising the compound of  claim 3  and a hydroxyl deprotecting agent. 
     
     
         13 . The composition of  claim 12 , wherein said hydroxyl deprotecting agent is boron tribromide, an aryl methyl ether, tetrabutylammonium fluoride, hydrogen/Pd/C, Zn/acid or ammonia. 
     
     
         14 . A method of synthesizing a compound having the structure: 
       
         
           
           
               
               
           
         
         said method comprising contacting a hydroxyl deprotecting agent with a compound having the formula: 
       
       
         
           
           
               
               
           
         
         wherein,
 R is substituted or unsubstituted aryl, 
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  are independently hydrogen, substituted or unsubstituted aryl, or a substituted or unsubstituted alkyl; and 
 R 8 , R 9 , R 10  and R 11  are independently hydroxyl protecting groups wherein R 8  and R 9  are optionally joined together to form a substituted or unsubstituted heterocycloalkyl and R 10  and R 11  are optionally joined together to form a substituted or unsubstituted heterocycloalkyl. 
 
       
     
     
         15 . The method of  claim 14 , wherein said hydroxyl deprotecting agent is boron tribromide, an aryl methyl ether, tetrabutylammonium fluoride, hydrogen/Pd/C, Zn/acid or ammonia.