Method of modulating ribonucleotide reductase

Abstract

A method of modulating ribonucleotide reductase activity in a neoplastic cell includes administering to the cell an amount of a triazole or an oxadiazole ribonucleotide reductase modulator (RRmod), the amount being effective to inhibit neoplastic cell growth.

1 - 42 . (canceled) 
     
     
         43 : A pharmaceutical composition comprising a ribonucleotide reductase allosteric modulator (RRmod), the RRmod inhibiting cell growth when administered to a neoplastic cell, wherein the RRmod including an oxadiazole having the following formula (II): 
       
         
           
           
               
               
           
         
         wherein Y is an oxadiazole; 
         A and Z are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 24  alkyl, C 2 -C 24  alkenyl, C 2 -C 24  alkynyl, C 3 -C 20  aryl, heteroaryl, cycloalkyl, heterocyclyl, heterocycloalkenyl containing from 5-6 ring atoms, C 6 -C 24  alkaryl, C 6 -C 24  aralkyl, halo, —Si(C 1 -C 3  alkyl) 3 , hydroxyl, sulfhydryl, C 1 -C 24  alkoxy, C 2 -C 24  alkenyloxy, C 2 -C 24  alkynyloxy, C 5 -C 20  aryloxy, acyl, acyloxy, C 2 -C 24  alkoxycarbonyl, C 6 -C 20  aryloxycarbonyl, C 2 -C 24  alkylcarbonato, C 6 -C 20  arylcarbonato, carboxy, carboxylato, carbamoyl, C 1 -C 24  alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C 1 -C 24  alkyl amino, C 5 -C 20  aryl amino, C 2 -C 24  alkylamido, C 6 -C 20  arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C 1 -C 24  alkylsulfanyl, arylsulfanyl, C 1 -C 24  alkylsulfinyl, C 5 -C 20  arylsulfinyl, C 1 -C 24  alkylsulfonyl, C 5 -C 20  arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkylethers, phosphates, phosphate esters, piperidine, pyridine, pyrazine, pyrimidine, pyridazine, groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH; and pharmaceutically acceptable salts thereof. 
       
     
     
         44 : The composition of  claim 43 , wherein Y is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         45 : The composition of  claim 43 , wherein the RRmod is an oxadiazole having the following formula (III): 
       
         
           
           
               
               
           
         
         wherein X 1  is CH 2 , COH, C═O, CH 2 C═O, or CH 2 CH(NH 2 ); 
         n 1  is 0 or 1; 
         R 19  and R 20  are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 24  alkyl, C 2 -C 24  alkenyl, C 2 -C 24  alkynyl, C 3 -C 20  aryl, heteroaryl, cycloalkyl, heterocyclyl, heterocycloalkenyl containing from 5-6 ring atoms, C 6 -C 24  alkaryl, C 6 -C 24  aralkyl, halo, —Si(C 1 -C 3  alkyl) 3 , hydroxyl, sulfhydryl, C 1 -C 24  alkoxy, C 2 -C 24  alkenyloxy, C 2 -C 24  alkynyloxy, C 5 -C 20  aryloxy, acyl, acyloxy, C 2 -C 24  alkoxycarbonyl, C 6 -C 20  aryloxycarbonyl, C 2 -C 24  alkylcarbonato, C 6 -C 20  arylcarbonato, carboxy, carboxylato, carbamoyl, C 1 -C 24  alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C 1 -C 24  alkyl amino, C 5 -C 20  aryl amino, C 2 -C 24  alkylamido, C 6 -C 20  arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C 1 -C 24  alkylsulfanyl, arylsulfanyl, C 1 -C 24  alkylsulfinyl, C 5 -C 20  arylsulfinyl, C 1 -C 24  alkylsulfonyl, C 5 -C 20  arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkylethers, phosphates, phosphate esters, pyridine, groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH; and pharmaceutically acceptable salts thereof. 
       
     
     
         46 : The composition of  claim 43 , wherein the RRmod is an oxadiazole having the following formula (IV): 
       
         
           
           
               
               
           
         
         wherein R 21  is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
     
     
         47 : The composition of  claim 43 , wherein the RRmod is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof. 
     
     
         48 : The composition of  claim 43 , wherein the RRmod is an oxadiazole having the following formula (V): 
       
         
           
           
               
               
           
         
         wherein Y is an oxadiazole; 
         R 4  to R 13  are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 24  alkyl, C 2 -C 24  alkenyl, C 2 -C 24  alkynyl, C 3 -C 20  aryl, heteroaryl, cycloalkyl, heterocyclyl, heterocycloalkenyl containing from 5-6 ring atoms, C 6 -C 24  alkaryl, C 6 -C 24  aralkyl, halo, —Si(C 1 -C 3  alkyl) 3 , hydroxyl, sulfhydryl, C 1 -C 24  alkoxy, C 2 -C 24  alkenyloxy, C 2 -C 24  alkynyloxy, C 5 -C 20  aryloxy, acyl, acyloxy, C 2 -C 24  alkoxycarbonyl, C 6 -C 20  aryloxycarbonyl, C 2 -C 24  alkylcarbonato, C 6 -C 20  arylcarbonato, carboxy, carboxylato, carbamoyl, C 1 -C 24  alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C 1 -C 24  alkyl amino, C 5 -C 20  aryl amino, C 2 -C 24  alkylamido, C 6 -C 20  arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C 1 -C 24  alkylsulfanyl, arylsulfanyl, C 1 -C 24  alkylsulfinyl, C 5 -C 20  arylsulfinyl, C 1 -C 24  alkylsulfonyl, C 5 -C 20  arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkylethers, phosphates, phosphate esters, pyridine, groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH; and pharmaceutically acceptable salts thereof, wherein adjacent R groups can be linked to form a cyclic or polycyclic ring, wherein the ring is a substituted or unsubstituted aryl, heteroaryl, cycloalkyl or heterocyclyl. 
       
     
     
         49 : The composition of  claim 43 , wherein the RRmod is an oxadiazole having the following formula (VI): 
       
         
           
           
               
               
           
         
         wherein Y is an oxadiazole; 
         R 14  is H, OH or a halogen; and 
         R 15  to R 18  are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 24  alkyl, C 2 -C 24  alkenyl, C 2 -C 24  alkynyl, C 3 -C 20  aryl, heteroaryl, cycloalkyl, heterocyclyl, heterocycloalkenyl containing from 5-6 ring atoms, C 6 -C 24  alkaryl, C 6 -C 24  aralkyl, halo, —Si(C 1 -C 3  alkyl) 3 , hydroxyl, sulfhydryl, C 1 -C 24  alkoxy, C 2 -C 24  alkenyloxy, C 2 -C 24  alkynyloxy, C 5 -C 20  aryloxy, acyl, acyloxy, C 2 -C 24  alkoxycarbonyl, C 6 -C 20  aryloxycarbonyl, C 2 -C 24  alkylcarbonato, C 6 -C 20  arylcarbonato, carboxy, carboxylato, carbamoyl, C 1 -C 24  alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C 1 -C 24  alkyl amino, C 5 -C 20  aryl amino, C 2 -C 24  alkylamido, C 6 -C 20  arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C 1 -C 24  alkylsulfanyl, arylsulfanyl, C 1 -C 24  alkylsulfinyl, C 5 -C 20  arylsulfinyl, C 1 -C 24  alkylsulfonyl, C 5 -C 20  arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkylethers, phosphates, phosphate esters, pyridine, groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH; and pharmaceutically acceptable salts thereof, wherein R 15  and R 16  or R 17  and R 18  can be linked to form a cyclic or polycyclic ring, wherein the ring is a substituted or unsubstituted aryl, heteroaryl, cycloalkyl or heterocyclyl. 
       
     
     
         50 : The composition of  claim 43 , the neoplastic cell comprising a cancer cell. 
     
     
         51 : The composition of  claim 50 , the cancer cell comprising a pancreatic, breast, lung, colon or glyoblastoma cancer cell. 
     
     
         52 : The composition of  claim 43 , further comprising another therapeutic agent in conjunction with the RRmod. 
     
     
         53 : The composition of  claim 52 , the other therapeutic agent comprising at least one of a chemotherapeutic agent, an antimetabolite, a DNA damaging agent, a ribonucleotide reductase inhibiting agent, an antitumorgenic agent, an antimitotic agent, an antiviral agent, an antineoplastic agent, an immunotherapeutic agent, and a radiotherapeutic agent.