Heterogeneous foldamers containing α, β, and/or γ-amino acids

Patent metadata

Field	Value
Publication number	US-10322998-B2
Application number	US-94738210-A
Country	US
Kind code	B2
Filing date	Nov 16, 2010
Priority date	Aug 26, 2002
Publication date	Jun 18, 2019
Grant date	Jun 18, 2019

Abstract

Disclosed are isolated, unnatural polypeptides containing cyclically-constrained β-amino acid residues and cyclically-constrained γ-amino acid residues. The compounds are unnatural and because they contain rotationally constrained residues that are not amenable to enzymatic degradation, the compounds are useful to probe protein-protein and other large molecule interactions.

First claim

What is claimed is:

1. An isolated, unnatural polypeptide compound comprising six or more residues, wherein each residue is independently selected from the group consisting of α-amino acid residues, β-amino acid residues, and γ-amino acid residues;
wherein at least two of the residues are one each of a β-amino acid residue and a γ-amino acid residue, wherein one of the β-amino acid residue or the γ-amino acid residue is cyclically-constrained in a monocyclic or bicyclic C 4 to C 10 cycloalkyl ring;
wherein at least one of the residues is an α-amino acid residue, and the at least one α-amino acid residue is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, nor-valine, nor-leucine, ornithine, hydroxylated derivatives thereof and N-alkylated derivatives thereof; and
wherein the polypeptide comprises an N-terminus.

2. The compound of claim 1 , wherein the N-terminus comprises an N-terminal residue, the N-terminal residue is one of the six or more residues, and the N-terminal residue comprises a free amino group, a protonated amino group, or an amino group protected with an amino-terminus protecting group.

3. The compound of claim 2 , wherein the amino-terminus protecting group is selected from the group consisting of methyl, formyl, ethyl, acetyl, t-butyl, benzyl, trifluoroacetyl, t-butoxycarbonyl, benzoyl, 4-methylbenzyl, benzyloxymethyl, 4-nitrophenyl, benzyloxycarbonyl, 2-nitrobenzoyl, 2-nitrophenylsulphenyl, 4-toluenesulphonyl, pentafluorophenyl, diphenylmethyl, 2-chlorobenzyloxycarbonyl, 2,4,5-trichlorophenyl, 2-bromobenzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, triphenylmethyl, and 2,2,5,7,8-pentamethyl-chroman-6- sulphonyl.

4. The compound of claim 1 , wherein one or more of the at least one α-amino acid residue is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, nor-valine, nor-leucine, ornithine, hydroxylated derivatives thereof and N-alkylated derivatives thereof.

5. An isolated, unnatural polypeptide compound comprising six or more residues, wherein each residue is independently selected from the group consisting of α-amino acid residues, β-amino acid residues, and γ-amino acid residues;
wherein at least two of the residues are one each of a β-amino acid residue and a γ-amino acid residue, wherein one of the β-amino acid residue or the γ-amino acid residue is cyclically-constrained in a monocyclic or bicyclic C 4 to C 10 cycloalkyl ring; and
wherein at least one of the residues is an α-amino acid residue, and the at least one α-amino acid residue is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, nor-valine, nor-leucine, ornithine, hydroxylated derivatives thereof and N-alkylated derivatives thereof;
wherein one or more of the at least one α-amino acid residue is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, nor-valine, nor-leucine, ornithine, hydroxylated derivatives thereof and N-alkylated derivatives thereof.

6. An isolated, unnatural polypeptide compound selected from the group consisting of:

wherein:
each X and each Z is independently variable and is selected from the group consisting of α-amino acid residues, β-amino acid residues, and γ-amino acid residues, provided that at least one X or Z comprises an α-amino acid residue and at least another two of X or Z comprise two cyclically-constrained γ-amino acid residues;
the at least one α-amino acid residue is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, nor-valine, nor-leucine, ornithine, hydroxylated derivatives thereof, and N-alkylated derivatives thereof;
one or more of the at least one α-amino acid residue is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, nor-valine, nor-leucine, ornithine, hydroxylated derivatives thereof, and N-alkylated derivatives thereof;
each cyclically-constrained γ-amino acid residue is independently selected from the group consisting of:

R, together with the carbons to which it is attached, and further together with the β-position carbon in the γ-amino acid backbone where appropriate, independently defines a substituted or unsubstituted, monocyclic or bicyclic C 4 to C 10 cycloalkyl or cycloalkenyl moiety, provided that, in at least one of the cyclically-constrained γ-amino acid residues, R, together with the carbons to which it is attached, and further together with the β-position carbon in the γ-amino acid backbone where appropriate, defines a substituted or unsubstituted, monocyclic or bicyclic C 4 to C 10 cycloalkyl moiety;
each “Y” is independently variable and is a single bond or a reverse-turn moiety;
“A” is independently selected from the group consisting of hydrogen and an amino-terminus protecting group, and “A′” is selected from the group consisting of hydroxyl and a carboxy-terminus protecting group; and
each “a,” “c,” and “d” is an independently variable positive integer; and
“a”+“c”>3; and

salts thereof.

7. The compound of claim 6 , wherein at least one R, together with the carbons to which it is attached and together with a β-position carbon in the γ-amino acid backbone when the β-position carbon is present, independently defines a substituted C 5 to C 6 cycloalkyl or cycloalkenyl moiety; and
substituents on the cycloalkyl or cycloalkenyl moieties are independently selected from the group consisting of linear, branched, or cyclic C 1 -C 6 -alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C 1 -C 6 -alkyl, mono- or bicyclic heteroaryl-C 1 -C 6 -alkyl, —(CH 2 ) n+1 —OR 2 , —(CH 2 ) n+1 —SR 2 , —(CH 2 ) n+1 —S(═O)—CH 2 —R 2 , —(CH 2 ) n+1 —S(═O) 2 —CH 2 —R 2 , —(CH 2 ) n+1 —NR 2 R 2 , —(CH 2 ) n+1 —NHC(═O)R 2 , —(CH 2 ) n+1 —NHS(═O) 2 —CH 2 —R 2 , —(CH 2 ) n+1 —O—(CH 2 ) m —R 1 , —(CH 2 ) n+1 —S—(CH 2 ) m —R 1 , —(CH 2 ) n+1 —S(═O) 2 —(CH 2 ) m —R 1 2 , —(CH 2 ) n+1 —S(═O) 2 —(CH 2 ) m —R 1 , —(CH 2 ) n+1 —NH—(CH 2 ) m —R 1 , —(CH 2 ) n+1 —N—{(CH 2 ) m —R 1 } 2 , —(CH 2 ) n+1 —NHC(═O)—(CH 2 ) n+1 —R 1 , —(CH 2 ) n+1 —NHS(═O) 2 —(CH 2 ) m —R 1 , —(CH 2 ) n —OR, —(CH 2 ) n —SR 2 , —(CH 2 ) n —S(═O)—CH 2 —R 2 , —(CH 2 ) n —S(═O) 2 —CH 2 —R 2 , —(CH 2 ) n —NR 2 R 2 , —(CH 2 ) n —NHC(═O)R 2 , —(CH 2 ) n —NHS(═O) 2 —CH 2 —R 2 , —(CH 2 ) n —O—(CH 2 ) m —R 1 , —(CH 2 ) n —S—(CH 2 ) m —R 1 , —(CH 2 ) n —S(═O)—(CH 2 ) m —R 1 , —(CH 2 ) n —S(═O) 2 —(CH 2 ) m —R 1 , —(CH 2 ) n NH—(CH 2 )

Assignees

• Gellman Samuel H
• Hayen Ahlke
• Schmitt Margaret A
• Ngassa Felix N
• Wisconsin Alumni Res Found

Inventors

• Gellman Samuel H
• Hayen Ahlke
• Schmitt Margaret A
• Ngassa Felix N

Classifications

• C07D207/16

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D211/60

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07C2601/14

  The ring being saturated · CPC title

• C07C2601/08

  the ring being saturated · CPC title

• C07D207/48 Primary

  Sulfur atoms · CPC title