Novel nucleoside analogs and use thereof in therapeutic treatment

Abstract

The present disclosure is directed to novel nucleoside analog compounds and methods for treating diseases characterized by high expression levels of adenosine kinase (ADK).

1 . A 6-ETI analog having the following chemical structure: 
       
         
           
           
               
               
           
         
         wherein: 
         A 1 , A 2 , A 3 , A 4 , A 5  are independently a carbon atom or a heteroatom, wherein the heteroatom is B, O, N, or S; 
         Y is alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, alkoxy, aryloxy, heteroalkoxy, or heteroaryloxy; 
         R 1  and R 2  are independently hydrogen, halo, amino, N 3 , alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, alkylthio, arylthio, heteroalkylthio, or heteroarylthio; 
         X 1  and X 2  are independently hydrogen, hydroxyl, alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, alkylthio, arylthio, heteroalkylthio, heteroarylthio, arylsufonyl, araalkylsulfonyl, acyloxy, or aralkyloxy; and 
         X 3  is phosphate, hydroxyl, alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, aryloxy, heteroalkoxy, heteroaryloxy, alkylthio, arylthio, heteroalkylthio, heteroarylthio, arylsufonyl, araalkylsulfonyl, acyloxy, or aralkyloxy, 
         or X 1  and X 2  are taken together to form a heterocyclic moiety, wherein the heterocyclic moiety is optionally substituted with alkyl, 
         or X 2  and X 3  are taken together to form a cyclic monophosphate, or a heterocyclic moiety containing a heteroatom selected from the group consisting of B, N and S, 
         with the proviso that when X 1  is hydroxyl, X 2  is hydroxyl, then X 3  is not hydroxyl, phosphate, or acyloxy. 
       
     
     
         2 . The 6-ETI analog of  claim 1 , wherein:
 A 1  is O;   A 2 , A 3 , A 4  and A 5  are independently N;   Y is alkyl;   R 1  and R 2  are independently H,   X 1  and X 2  are independently acyloxy, or X 1  and X 2  are taken together to form a heterocyclic moiety, wherein the heterocyclic moiety is optionally substituted with alkyl; and   X 3  is hydroxyl, acyloxy, or aralkyloxy.   
     
     
         3 . The 6-ETI analog of  claim 2  having a chemical structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The 6-ETI analog of  claim 1 , wherein:
 A 1  is O;   A 2 , A 3 , A 4  and A 5  are independently N;   Y is alkyl;   R 1  and R 2  are independently H,   X 1  and X 2  are independently hydroxyl; and   X 3  is aralkyloxy.   
     
     
         5 . The 6-ETI analog of  claim 4  having the following chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The 6-ETI analog of  claim 1 , wherein
 A 1  is O;   A 2 , A 3 , A 4  and A 5  are independently N;   Y is alkyl;   R 1  and R 2  are independently H,   X 1  is OH; and   X 2  and X 3  are taken together to form a cyclic monophosphate.   
     
     
         7 . The 6-ETI analog of  claim 6  having the following chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
         8 . A 6-ETI analog having the following chemical structure: 
       
         
           
           
               
               
           
         
         wherein R is Cl, NH 2 , Br or N 3 . 
       
     
     
         9 . A method of treating a subject suffering from a condition associated with a high level expression of Adenosine Kinase (ADK), comprising administering to said subject an effective amount of a compound as a single agent or in combination with other regiments, wherein the compound is a 6-ETI or a 6-ETI analog. 
     
     
         10 . The method of  claim 9 , wherein the condition is a cancer. 
     
     
         11 . The method of  claim 10 , wherein the cancer is selected from a cancer of plasma cell origin or adenocarcinoma. 
     
     
         12 . The method of  claim 11 , wherein the cancer of plasma cell origin is selected from the group consisting of primary effusion lymphoma (PEL), multiple myeloma (MM) and plasmablastic lymphoma (PBL). 
     
     
         13 . The method of  claim 11 , wherein the adenocarcinoma is selected from the group consisting of pulmonary adenocarcinoma, adenocarcinoma of the colon, and pancreatic adenocarcinoma. 
     
     
         14 . The method of  claim 9 , wherein the condition is a disease associated with Kaposi's Sarcoma Herpes Virus (KSHV). 
     
     
         15 . The method of  claim 14 , wherein the disease is selected from the group consisting of Kaposi's Sarcoma (KS), multicentric Castleman's Disease (MCD), and primary effusion lymphoma (PEL). 
     
     
         16 . The method of  claim 9 , further comprising identifying the subject as having a high level expression of Adenosine Kinase (ADK) prior to the administration of the compound. 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . A method according to  claim 9 , wherein the compound is activated by an adenosine kinase (ADK). 
     
     
         21 . A method according to  claim 9 , wherein the compound has the following chemical structure: 
       
         
           
           
               
               
           
         
         wherein: 
         A 1 , A 2 , A 3 , A 4 , A 5  are independently a carbon atom or a heteroatom, wherein the heteroatom is B, O, N, or S; 
         Y is alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, alkoxy, aryloxy, heteroalkoxy, or heteroaryloxy; 
         R 1  and R 2  are independently hydrogen, halo, amino, N 3 , alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, alkylthio, arylthio, heteroalkylthio, or heteroarylthio; and 
         X 1 , X 2 , X 3  are independently hydrogen, hydroxyl, phosphate, alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, alkylthio, arylthio, heteroalkylthio, heteroarylthio, arylsufonyl, araalkylsulfonyl, acyloxy, or aralkyloxy, 
         or X 1  and X 2  are taken together to form a heterocyclic moiety, wherein the heterocyclic moiety is optionally substituted with alkyl, 
         or X 2  and X 3  are taken together to form a cyclic monophosphate, or a heterocyclic moiety containing a heteroatom selected from the group consisting of B, N and S. 
       
     
     
         22 . The method of  claim 21 , wherein:
 A 1  is O;   A 2 , A 3 , A 4  and A 5  are independently N;   Y is alkyl;   R 1  is H, Cl, NH 2 , Br or N 3 ,   R 2  is H, and   X 1 , X 2  and X 3  are independently hydroxyl, phosphate, acyloxy, or aralkyloxy,   or X 1  and X 2  are taken together to form a heterocyclic moiety, wherein the heterocyclic moiety is optionally substituted with alkyl,   or X 2  and X 3  are taken together to form cyclic monophosphate.   
     
     
         23 . The method of  claim 21 , wherein:
 A 1 , A 2 , A 3 , A 4 , A 5  are independently a carbon atom or a heteroatom, wherein the heteroatom is B, O, N, or S;   Y is alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, alkoxy, aryloxy, heteroalkoxy, or heteroaryloxy;   R 1  and R 2  are independently hydrogen, halo, amino, N 3 , alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, alkylthio, arylthio, heteroalkylthio, or heteroarylthio;   X 1  and X 2  are independently hydrogen, hydroxyl, alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, alkylthio, arylthio, heteroalkylthio, heteroarylthio, arylsufonyl, araalkylsulfonyl, acyloxy, or aralkyloxy; and   X 3  is phosphate, hydroxyl, alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, aryloxy, heteroalkoxy, heteroaryloxy, alkylthio, arylthio, heteroalkylthio, heteroarylthio, arylsufonyl, araalkylsulfonyl, acyloxy, or aralkyloxy;   or X 1  and X 2  are taken together to form a heterocyclic moiety, wherein the heterocyclic moiety is optionally substituted with alkyl,   or X 2  and X 3  are taken together to form a cyclic monophosphate, or a heterocyclic moiety containing a heteroatom selected from the group consisting of B, N and S,   with the proviso that when X 1  is hydroxyl, X 2  is hydroxyl, then X 3  is not hydroxyl, phosphate, or acyloxy.   
     
     
         24 . The method of  claim 23 , wherein:
 A 1  is O;   A 2 , A 3 , A 4  and A 5  are independently N;   Y is alkyl;   R 1  and R 2  are independently H,   X 1  and X 2  are independently acyloxy, or X 1  and X 2  are taken together to form a heterocyclic moiety, wherein the heterocyclic moiety is optionally substituted with alkyl; and   X 3  is hydroxyl, acyloxy, or aralkyloxy.   
     
     
         25 . The method of  claim 23 , wherein:
 A 1  is O;   A 2 , A 3 , A 4  and A 5  are independently N;   Y is alkyl;   R 1  and R 2  are independently H,   X 1  and X 2  are independently hydroxyl; and   X 3  is aralkyloxy.   
     
     
         26 . The method of  claim 23 , wherein
 A 1  is O;   A 2 , A 3 , A 4  and A 5  are independently N;   Y is alkyl;   R 1  and R 2  are independently H,   X 1  is OH; and   X 2  and X 3  are taken together to form a cyclic monophosphate.   
     
     
         27 . The method of  claim 22 , wherein the compound has a chemical structure selected from the following group: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein R is Cl, NH 2 , Br or N 3 ; and 
       
       
         
           
           
               
               
           
         
       
     
     
         28 . A method of determining whether a cancer is sensitive to treatment with a nucleoside analog compound wherein the nucleoside compound is 6-ETI or a 6-ETI analog, comprising:
 (a) detecting the expression level of adenosine kinase (ADK) in said cancer; and   (b) comparing the detected expression level of ADK in step (a) with a control expression level of ADK, wherein a higher ADK expression level relative to the control expression level indicates responsiveness to treatment with a nucleoside analog compound.   
     
     
         29 . The method of  claim 28 , wherein the ADK expression level is determined at the protein level or the RNA level. 
     
     
         30 . The method of  claim 29 , wherein the ADK expression level is determined by a technique selected from the group consisting of immunoblotting, immunohistochemistry, Reverse transcription polymerase chain reaction (RT-PCR), and RNA Sequencing (RNA-Seq). 
     
     
         31 . A method of identifying the effectiveness of a nucleoside analog compound in treating cancer characterized by high expression levels of ADK, comprising:
 (a) providing a 6-ETI-resistant cell line and a 6-ETI- sensitive cell line, wherein 6-ETI-resistant cell line comprises a mutated or deleted ADK gene and the 6-ETI-sensitive cell line comprises a wild type ADK gene;   (b) contacting the 6-ETI-resistant and 6-ETI-sensitive cell lines with a candidate nucleoside analog compound;   (c) assessing viability of the 6-ETI-resistant and sensitive cell lines; and   (d) identifying the candidate nucleoside analog compound as effective in treating cancer characterized by high expression levels of ADK if the candidate nucleoside analog compound decreases the viability of the 6-ETI-sensitive cell line but does not decrease the viability of the 6-ETI-resistant cell line.