Compositions And Methods Pertaining To PNA Synthons And Oligomers Comprising A Universal Base

Abstract

This invention is related to compositions and methods pertaining to PNA synthons, PNA oligomers and/or PNA/DNA Chimeras comprising a universal base.

1 . A method comprising:
 a) alkylating a substituted or unsubstituted 3-aminopyrazole-4-carbonitrile compound with a halo acetate compound of the formula:   
     
       
         
         
             
             
         
       
       
         wherein,
 each W is independently hydrogen, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group; 
 R 1  is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group; 
 Hal is Cl, Br or I; and 
 each X 1  is O or S. 
 
       
     
   
   
       2 . The method of  claim 1 , wherein each W is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or sec-butyl. 
   
   
       3 . The method of  claim 1 , wherein R 1  is methyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, allyl, trimethylsilyl, tert-butyldimethylsilyl or phenyl. 
   
   
       4 . The method of  claim 1 , wherein each X 1  is O. 
   
   
       5 . The method of  claim 1 , wherein one of the products of the reaction is a substituted or unsubstituted heterocyclic compound of the formula: 
     
       
         
         
             
             
         
       
       wherein,
 each W is independently hydrogen, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group; 
 R 2  is hydrogen or an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group; and 
 each X 1  is O or S. 
 
     
   
   
       6 . A method comprising:
 a) reacting a substituted or unsubstituted heterocyclic compound of the formula:   
     
       
         
         
             
             
         
       
       
         with a substituted or unsubstituted compound of the formula: 
       
     
     
       
         
         
             
             
         
       
       
         or a substituted or unsubstituted compound of the formula: 
       
     
     
       
         
         
             
             
         
       
       
         wherein the reaction produces a substituted or unsubstituted heterocyclic compound of the formula: 
       
     
     
       
         
         
             
             
         
       
       
         
           wherein,
 each W is independently hydrogen, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group; 
 W′ is hydrogen or NH 2 ; 
 R 1  is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group; 
 H—Ac is an acidic group capable of protonating the diamine; and 
 each X 1  is independently O or S. 
 
         
       
     
   
   
       7 . The method of  claim 6 , wherein the solvent for the reaction is compound IVb, methanol, ethanol, n-propanol, isopropanol or t-butanol, N,N-dimethylformamide (DMF) or dimethylsulphoxide (DMSO). 
   
   
       8 . The method of  claim 6 , wherein the reaction is allowed to reflux. 
   
   
       9 . The method of  claim 6 , further comprising:
 b) protecting the exocyclic amine of the substituted or unsubstituted heterocyclic compound V with a amine protecting group to thereby produce a compound of the formula:   
     
       
         
         
             
             
         
       
       
         wherein,
 each W is independently hydrogen, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group; 
 Pg 1  is an amine protecting group; 
 R 1  is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group; and 
 each X 1  is O or S. 
 
       
     
   
   
       10 . The method of  claim 9 , wherein the amine protecting group is Fmoc, Bhoc, Z, t-boc or Cyoc. 
   
   
       11 . The method of  claim 6 , further comprising:
 b) converting the ester group of compound V to a carboxylic acid group to thereby produce a substituted or unsubstituted heterocyclic compound of the formula:   
     
       
         
         
             
             
         
       
       
         wherein,
 each W is independently hydrogen, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group; and 
 each X 1  is O or S. 
 
       
     
   
   
       12 . The method of  claim 9 , further comprising:
 c) converting the ester group of compound VI to a carboxylic acid group to thereby produce a substituted or unsubstituted heterocyclic compound of the formula:   
     
       
         
         
             
             
         
       
       
         wherein,
 each W is independently hydrogen, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group; 
 Pg 1  is an amine protecting group; and 
 each X 1  is O or S. 
 
       
     
   
   
       13 . The method of  claim 12 , wherein Pg 1  is Fmoc, Bhoc, Z, t-boc or Cyoc. 
   
   
       14 . A method comprising:
 a) reacting the carbonyl or thiocarbonyl carbon of the activated carboxylic acid group, thiocarboxylic acid group or active ester group of a substituted or unsubstituted heterocyclic compound of the formula:   
     
       
         
         
             
             
         
       
       
         with the secondary nitrogen of a substituted or unsubstituted N-(2-aminoethyl)glycine moiety,
 wherein,
 each W is independently hydrogen, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group; 
 Pg 1  is an amine protecting group; 
 R 2  is —SH, —OH or an active ester leaving group; and 
 X 1  is O or S. 
 
 
       
     
   
   
       15 . The method of  claim 14 , wherein the substituted or unsubstituted N-(2-aminoethyl)glycine moiety has the formula: 
     
       
         
         
             
             
         
       
       wherein,
 Pg 2  is an amine protecting group; 
 each Y 1  is independently hydrogen, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group; 
 Y 2  is hydrogen or a protected or unprotected amino acid side chain; 
 R 3  is —OH, —SH, —SR 1  or —OR 1 , wherein R 1  is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group; and 
 each X 1  is O or S. 
 
     
   
   
       16 . The method of  claim 15 , wherein R 1  is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, allyl, trimethylsilyl, tert-butyldimethylsilyl or phenyl. 
   
   
       17 . The method of  claim 14 , wherein the substituted or unsubstituted N-(2-aminoethyl)glycine moiety is a PNA subunit of a PNA oligomer or PNA/DNA Chimera. 
   
   
       18 . The method of  claim 14 , wherein, Pg 1  is Fmoc, Bhoc, Z, t-boc or Cyoc. 
   
   
       19 . The method of  claim 15 , wherein Pg 1  is Fmoc, Bhoc, Z, t-boc or Cyoc and wherein Pg 2  is different from Pg 1  and Pg 2  is independently Fmoc, Bhoc, Z, t-boc, Cyoc or trityl. 
   
   
       20 . The method of  claim 14 , wherein the active ester leaving group is a group of the formula: 
     
       
         
         
             
             
         
       
     
     wherein X 1  is O or S. 
   
   
       21 . A substituted or unsubstituted heterocyclic compound of the formula: 
     
       
         
         
             
             
         
       
       wherein,
 each W is independently hydrogen, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group; 
 R 1  is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group, provided however that R 1  is not ethyl; and 
 each X 1  is O or S. 
 
     
   
   
       22 . The compound of  claim 21 , wherein R 1  is methyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, allyl, trimethylsilyl, t-butyldimethylsilyl or phenyl. 
   
   
       23 . The compound of  claim 21 , wherein each X 1  is O. 
   
   
       24 . A substituted or unsubstituted heterocyclic compound of the formula: 
     
       
         
         
             
             
         
       
       wherein,
 Pg 3  is hydrogen or an amine-protecting group; 
 each W is independently hydrogen, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group; 
 X 1  is O or S; and 
 R 3  is —OH, —SH, —SR 1  or —OR 1 , wherein R 1  is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group. 
 
     
   
   
       25 . The compound of  claim 24 , wherein Pg 3  is Fmoc, Bhoc, Z, t-boc or Cyoc. 
   
   
       26 . The compound of  claim 24 , wherein R 1  is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, allyl, trimethylsilyl, t-butyldimethylsilyl or phenyl. 
   
   
       27 . The compound of  claim 24 , wherein X 1  is O. 
   
   
       28 . The compound of  claim 24 , having the formula: 
     
       
         
         
             
             
         
       
       wherein the compound is optionally substituted. 
     
   
   
       29 . A PNA synthon of the formula: 
     
       
         
         
             
             
         
       
       wherein,
 Pg 1  is an amine protecting group; 
 Pg 2  is an amine protecting group; 
 each W is independently hydrogen, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group; 
 each Y 1  is independently hydrogen, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group; 
 Y 2  is hydrogen or a protected or unprotected amino acid side chain; 
 R 3  is —OH, —SH, SR 1  or —OR 1 , wherein R 1  is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, a heteroalkynyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group; and 
 each X 1  is O or S. 
 
     
   
   
       30 . The PNA synthon of  claim 29 , wherein,
 Pg 1  is Fmoc, Bhoc, Z, t-boc or Cyoc; and   Pg 2  is an amine-protecting group different from Pg 1  selected from the group consisting of Fmoc, Bhoc, X, t-boc, Cyoc and trityl.   
   
   
       31 . The PNA synthon of  claim 29 , wherein the PNA synthon has the formula: