Peptidic Constructs with Amino Acid Surrogates

Abstract

Peptidic constructs including at least one ring-constrained amino acid surrogate of formula I: where R1, R2, R3, R4, R5, R6a, R6b, R7, and y are as defined in the specification, and a plurality of amino acid residues.

1 . A compound comprising a plurality of amino acid residues and at least one group of the formula: 
       
         
           
           
               
               
           
         
         or a synthetically acceptable salt thereof, wherein: 
         R 1  is a group of a formula: 
       
       
         
           
           
               
               
           
         
         R 2  is H or alkyl; 
         R 4  is H, alkyl, (CH 2 ) m C(═O)OH, (CH 2 ) q OH, (CH 2 ) q OBn, (CH 2 ) q Oallyl, (CH 2 ) m C(═O)N(R 8 ) 2 , or (CH 2 ) m C(═O)N(R 8 )(CH 2 ) p N(R 8 ) 2 ; 
         R 5  is H or alkyl; 
         R 6a  is H, alkyl, (CH 2 ) m C(═O)OH, (CH 2 ) q OH, (CH 2 ) q OBn, (CH 2 ) q Oallyl, (CH 2 ) m C(═O)N(R 8 ) 2 , or (CH 2 ) m C(═O)N(R 8 )(CH 2 ) p N(R 8 ) 2 ; 
         R 6b  is H or alkyl; 
         provided that one of R 4  and R 6a  is H or alkyl and the other of R 4  and R 6a  is (CH 2 ) m C(═O)OH, (CH 2 ) q OH, (CH 2 ) q OBn, (CH 2 ) q Oallyl, (CH 2 ) m C(═O)N(R 8 ) 2 , or (CH 2 ) m C(═O)N(R 8 )(CH 2 ) p N(R 8 ) 2 ; 
         R 7  is H, C(═O)alkyl or C(═O)(CH 2 ) m (NR 8 ) 2 ; 
         each occurrence of R 8  is independently H, aryl, or alkyl; 
         R 12  is H or a nitrogen protecting group; 
         Za is H or comprises one or more amino acid residues if Zb is present, and if Zb is not present, Za comprises a plurality of amino acid residues; 
         Zb comprises a plurality of amino acid residues; 
         each occurrence of m is an independent integer having a value between 0 and 6; 
         each occurrence of q is an independent integer having a value between 1 and 6; 
         p is an integer having a value between 1 and 10; and 
         y is 0 or 1. 
       
     
     
         2 . The compound of  claim 1 , wherein y is 1. 
     
     
         3 . The compound of  claim 1 , wherein y is 0. 
     
     
         4 . The compound of  claim 1 , wherein Zb is not present and R 4  is (CH 2 ) m C(═O)OH, (CH 2 ) m C(═O)N(R 8 ) 2 , (CH 2 ) m C(═O)N(R 8 )R 11 , or (CH 2 ) m C(═O)OR 11 , and R 6a  is H or alkyl. 
     
     
         5 . The compound of  claim 1 , wherein Zb is not present and R 6a  is (CH 2 ) m C(═O)OH, (CH 2 ) m C(═O)N(R 8 ) 2 , (CH 2 ) m C(═O)N(R 8 )R 11 , or (CH 2 ) m C(═O)OR 11 , and R 4  is H or alkyl. 
     
     
         6 . The compound of  claim 1 , wherein R 1  is the group of the formula: 
       
         
           
           
               
               
           
         
       
       and R 12  is H or triphenylmethylene, tert-butyloxycarbonyl, toluenesulphonyl, formyl, nitro or benzyloxycarbonyl and m is, for R 1 , an integer having a value between 2 and 6. 
     
     
         7 . The compound of  claim 1 , wherein R 7  is H. 
     
     
         8 . The compound of  claim 1 , wherein the compound is cyclized by a bond between side chains of two of the plurality of amino acid residues. 
     
     
         9 . The compound of  claim 1  wherein the plurality of amino acid residues comprises an N-terminus capping group. 
     
     
         10 . The compound of  claim 9  wherein the N-terminus capping group is
 —(CH 2 ) m —NH(v 3 ), 
 —(CH 2 ) m —CH 3 , 
 —C(═O)—(CH 2 ) m —CH 3 , 
 —C(═O)—(CH 2 ) m —NH(v 3 ), 
 —C(═O)—(CH 2 ) m —C(═O)—OH, 
 —C(═O)—(CH 2 ) m —C(═O)—(v 4 ), 
 —(CH 2 ) m —C(═O)—OH, 
 —(CH 2 ) m —C(═O)—(v 4 ), 
 —C(═O)—(CH 2 ) m —O(v 3 ), 
 —(CH 2 ) m —O(v 3 ), 
 —C(═O)—(CH 2 ) m —S(v 3 ), or 
 —(CH 2 ) m —S(v 3 ), 
 
       wherein: 
       v 3  is H or a C 1  to O 17  linear or branched alkyl chain; 
       v 4  is a C 1  to O 17  linear or branched alkyl chain; and
 m is 0 to 17. 
 
     
     
         11 . A compound comprising a plurality of amino acid residues and a group of the formula: 
       
         
           
           
               
               
           
         
         or a synthetically acceptable salt thereof, wherein: 
         Za comprises a plurality of amino acid residues; 
         each occurrence of R 8  is independently H, aryl, or alkyl; and 
         R 13  is —OH or —N(R 8 ) 2 . 
       
     
     
         12 . The compound of  claim 11  wherein the plurality of amino acid residues comprises an N-terminus capping group. 
     
     
         13 . The compound of  claim 12  wherein the N-terminus capping group is
 —(CH 2 ) m —NH(v 3 ), 
 —(CH 2 ) m —CH 3 , 
 —C(═O)—(CH 2 ) m —CH 3 , 
 —C(═O)—(CH 2 ) m —NH(v 3 ), 
 —C(═O)—(CH 2 ) m —C(═O)—OH, 
 —C(═O)—(CH 2 ) m —C(═O)—(v 4 ), 
 —(CH 2 ) m —C(═O)—OH, 
 —(CH 2 ) m —C(═O)—(v 4 ), 
 —C(═O)—(CH 2 ) m —O(v 3 ), 
 —(CH 2 ) m —O(v 3 ), 
 —C(═O)—(CH 2 ) m —S(v 3 ), or 
 —(CH 2 ) m —S(v 3 ), 
 
       wherein: 
       v 3  is H or a C 1  to O 17  linear or branched alkyl chain; 
       v 4  is a C 1  to O 17  linear or branched alkyl chain; and 
       m is 0 to 17. 
     
     
         14 . The compound of  claim 11 , wherein the compound is cyclized by a bond between side chains of two of the plurality of amino acid residues. 
     
     
         15 . A compound comprising a plurality of amino acid residues and a group of the formula: 
       
         
           
           
               
               
           
         
         or a synthetically acceptable salt thereof, wherein: 
         R 1  is alkyl-OR 8 , alkyl-C(═O)OR 8 , C(═O)OR 8 , alkyl-S—R 8 , alkyl-C(═O)N(R 8 ) 2 , or a group of a formula: 
       
       
         
           
           
               
               
           
         
         R 2  is H or alkyl; 
         R 4  is H, alkyl, (CH 2 ) m C(═O)OH, (CH 2 ) m C(═O)N(H)R 11 , (CH 2 ) m C(═O)OR 11 , (CH 2 ) q OH, (CH 2 ) q OBn, (CH 2 ) q Oallyl, (CH 2 ) m C(═O)N(R 8 ) 2 , or (CH 2 ) m C(═O)N(R 8 )(CH 2 ) p N(R 8 ) 2 ; 
         R 5  is H or alkyl; 
         R 6a  is H, alkyl, (CH 2 ) m C(═O)OH, (CH 2 ) m C(═O)N(H)R 11 , (CH 2 ) m C(═O)OR 11 , (CH 2 ) q OH, (CH 2 ) q OBn, (CH 2 ) q Oallyl, (CH 2 ) m C(═O)N(R 8 ) 2 , or (CH 2 ) m C(═O)N(R 8 )(CH 2 ) p N(R 8 ) 2 ; 
         R 6b  is H or alkyl; 
         provided that one of R 4  and R 6a  is H or alkyl and the other of R 4  and R 6a  is (CH 2 ) m C(═O)OH, (CH 2 ) m C(═O)N(H)R 11 , (CH 2 ) m C(═O)OR 11 , (CH 2 ) q OH, (CH 2 ) q OBn, (CH 2 ) q Oallyl, (CH 2 ) m C(═O)N(R 8 ) 2 , or (CH 2 ) m C(═O)N(R 8 )(CH 2 ) p N(R 8 ) 2 ; 
         R 7  is H, C(═O)alkyl, C(═O)(CH 2 ) m N(R 8 ) 2 , alkyl, aralkyl, or aryl; 
         each occurrence of R 8  is independently H, aryl, or alkyl; 
         R 9  is tert-butyl, allyl, or a group of a formula: 
       
       
         
           
           
               
               
           
         
         R 11  is a peptide solid support; 
         R 12  is H or a nitrogen protecting group; 
         Za comprises a plurality of amino acid residues; 
         each occurrence of m is an independent integer having a value between 0 and 6; 
         each occurrence of q is an independent integer having a value between 1 and 6; 
         p is an integer having a value between 1 and 10; and 
         y is 0 or 1. 
       
     
     
         16 . The compound of  claim 15 , wherein y is 1. 
     
     
         17 . The compound of  claim 15 , wherein y is 0. 
     
     
         18 . The compound of  claim 15 , wherein R 4  is (CH 2 ) m C(═O)OH, (CH 2 ) m C(═O)N(R 8 ) 2 , (CH 2 ) m C(═O)N(H)R 11 , or (CH 2 ) m C(═O)OR 11 , and R 6a  is H or alkyl. 
     
     
         19 . The compound of  claim 15  wherein the plurality of amino acid residues comprises an N-terminus capping group selected from the group consisting of:
 —(CH 2 ) m —NH(v 3 ), 
 —(CH 2 ) m —CH 3 , 
 —C(═O)—(CH 2 ) m —CH 3 , 
 —C(═O)—(CH 2 ) m —NH(v 3 ), 
 —C(═O)—(CH 2 ) m —C(═O)—OH, 
 —C(═O)—(CH 2 ) m —C(═O)—(v 4 ), 
 —(CH 2 ) m —C(═O)—OH, 
 —(CH 2 ) m —C(═O)—(v 4 ), 
 —C(═O)—(CH 2 ) m —O(v 3 ), 
 —(CH 2 ) m —O(v 3 ), 
 —C(═O)—(CH 2 ) m —S(v 3 ), or 
 —(CH 2 ) m —S(v 3 ), 
 
       wherein: 
       v 3  is H or a C 1  to O 17  linear or branched alkyl chain; 
       v 4  is a C 1  to O 17  linear or branched alkyl chain; and 
       m is 0 to 17. 
     
     
         20 . The compound of  claim 15 , wherein the compound is cyclized by a bond between side chains of two of the plurality of amino acid residues.