Peptide nucleic acids having 2,6-diaminopurine nucleobases

Abstract

A novel class of compounds, known as peptide nucleic acids, bind complementary DNA and RNA strands more strongly than a corresponding DNA strand, and exhibit increased sequence specificity and binding affinity. The peptide nucleic acids of the invention comprise ligands selected from a group consisting of naturally-occurring nucleobases and non-naturally-occurring nucleobases attached to a polyamide backbone. Some PNAs of the invention also contain C 1 -C 8 alkylamine side chains.

What is claimed is:  
     
         1 . A peptide nucleic acid having formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 each L is independently selected from a group consisting of naturally-occurring nucleobases and non-naturally-occurring nucleobases, at least one of said L being a 2,6-diaminopurine nucleobase;  
 each R 7′  is independently hydrogen or C 1 -C 8  alkylamine;  
 R h  is OH, NH 2  or NHLysNH 2 ;  
 R i  is H, COCH 3  or t-butoxycarbonyl; and  
 n is an integer from 1 to 30.  
 
     
     
         2 . The peptide nucleic acid of  claim 1  wherein said R 7′  is C 3 -C 6  alkylamine.  
     
     
         3 . The peptide nucleic acid of  claim 2  wherein said R 7′  is C 4 -C 5  alkylamine.  
     
     
         4 . The peptide nucleic acid of  claim 3  wherein said R 7′  is butylamine.  
     
     
         5 . The peptide nucleic acid of  claim 1  wherein at least one of said R 7′  is C 1 -C 8  alkylamine.  
     
     
         6 . The peptide nucleic acid of  claim 5  wherein at least one of said R 7′  is C 3 -C 6  alkylamine.  
     
     
         7 . The peptide nucleic acid of  claim 6  wherein at least one of said R 7′  is C 4 -C 5  alkylamine.  
     
     
         8 . The peptide nucleic acid of  claim 7  wherein at least one of said R 7′  is butylamine.  
     
     
         9 . The peptide nucleic acid of  claim 7  wherein substantially all of said R 7′  is butylamine.  
     
     
         10 . The peptide nucleic acid of  claim 1  wherein the carbon atom to which the substituent R 7′  is attached is stereochemically enriched.  
     
     
         11 . The peptide nucleic acid of  claim 10  wherein said stereochemical enrichment is of the R configuration.  
     
     
         12 . The peptide nucleic acid of  claim 1  wherein said R 7′  are butylamine; and the carbon atoms to which said R 7′  groups are attached have R configuration.  
     
     
         13 . The peptide nucleic acid for  claim 1  wherein said peptide nucleic acid is derived from an amino acid.  
     
     
         14 . The peptide nucleic acid for  claim 13  wherein said peptide nucleic acid is derived from D-lysine.  
     
     
         15 . A compound having formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 L is a 2,6-diaminopurine nucleobase;  
 R 7′  is hydrogen or C 1 -C 8  alkylamine;  
 E is COOH or an activated or protected derivative thereof; and  
 Z is NH 2  or NHPg, where Pg is an amino-protecting group.  
 
     
     
         16 . The compound of  claim 15  wherein said R 7′  is C 3 -C 6  alkylamine.  
     
     
         17 . The compound of  claim 16  wherein said R 7′  is C 4 -C 5  alkylamine.  
     
     
         18 . The compound of  claim 17  wherein said R 7′  is butylamine.  
     
     
         19 . The compound of  claim 15  wherein the carbon atom to which the substituent R 7′  is attached is stereochemically enriched.  
     
     
         20 . The compound of  claim 19  wherein said stereochemical enrichment is of the R configuration.  
     
     
         21 . The compound of  claim 15  wherein said compound is derived from an amino acid.  
     
     
         22 . The compound of  claim 21  wherein said compound is derived from D-lysine.  
     
     
         23 . The compound of  claim 15  wherein said Pg is t-butoxycarbonyl.  
     
     
         24 . A pharmaceutical composition comprising a peptide nucleic acid according to  claim 1  and at least one pharmaceutically effective carrier, binder, thickener, diluent, buffer, preservative, or surface active agent.