Polypeptides, peptides, and proteins functionalized by alkylation of thioether groups via ring-opening reactions

Patent metadata

Field	Value
Publication number	US-10351591-B2
Application number	US-201615559981-A
Country	US
Kind code	B2
Filing date	Mar 21, 2016
Priority date	Mar 20, 2015
Publication date	Jul 16, 2019
Grant date	Jul 16, 2019

Abstract

Some embodiments of the invention involve methods for introduction of various functional groups onto polypeptides, peptides and proteins by alkylation of thioether (a.k.a. sulfide) groups by ring opening reactions, creating new compositions of matter that may be useful for medical therapeutic or diagnostic applications. The thioether groups may either be present in the polypeptides, or may be added to polypeptides by chemical modification, such as by alkylation of thiol (sulfhydryl) groups.

First claim

What is claimed is:

1. A compound of Formula I:

wherein, independently for each occurrence,
R 1 is H or alkyl;
R 2 is alkyl;
R 3 is H or substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, azido, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, halo, substituted or unsubstituted allyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted phosphonate, substituted or unsubstituted carbamate, or substituted or unsubstituted amido;
m is 1-200, inclusive;
n is 1-4, inclusive;
A 1 is H, an amine protecting group, a natural or unnatural alpha amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
A 2 is OH, —O-(a carboxylate protecting group), a natural or unnatural alpha amino acid, a peptide, an oligopeptide, a polypeptide, or a protein; and
X is a monovalent anion.

2. The compound of claim 1 , wherein R 3 is substituted alkyloxy.

3. The compound of claim 2 , wherein R 3 is heterocycloalkyloxy, phosphonate-substituted alkyloxy, acyloxyalkyloxy, aminoalkyloxy, aminoalkylamidoalkyloxy, or alkyloxycarbonylalkyloxy.

4. The compound of claim 1 , wherein R 3 is -L-halo, -L-azide, -L-NHR 1 , -L-NR 1 -TFA, -L-NR 1 —C(O)—O-alkyl, -L-NR 1 —C(O)—CH 2 —NR 1 -TFA, -L-O—CH 2 —CH═CH 2 , -L-O—CH 2 CCH, -L-O-alkyl, -L-O—C(O)-alkyl, -L-P(O)(O-alkyl) 2 , -L-P(O)(OH) 2 , -L-O—C(O)—C(halo)(alkyl) 2 , -L-CH 2 —P(O)(O-alkyl) 2 , -L-CH 2 —P(O)(OH) 2 , -L-O—CH 2 CH—(C(O)NR 1 -alkyl)(NR 1 -TFA), -L-O—CH 2 CH—(C(O)OR 1 )(NR 1 -TFA), -L-OCH 2 —C(O)—OR 1 , -L-CH—(CO 2 -alkyl) 2 , -L-CH—(CO 2 H) 2 , -L-SO 2 (O-alkyl), -L-SO 2 (O-aryl), -L-SO 3 H,

L
is a bond or —(OCH 2 CH 2 ) x —, and x is 1-10.

5. The compound of claim 1 , wherein A 1 or A 2 is methionine, or A 1 or A 2 is a peptide comprising a methionine residue, an oligopeptide comprising a methionine residue, a polypeptide comprising a methionine residue, or a protein comprising a methionine residue.

6. The compound of claim 1 , wherein A 1 or A 2 is cysteine, or A 1 or A 2 is a peptide comprising a cysteine residue, an oligopeptide comprising a cysteine residue, a polypeptide comprising a cysteine residue, or a protein comprising a cysteine residue.

7. A peptide, an oligopeptide, a polypeptide, or a protein, wherein the peptide, oligopeptide, polypeptide, or protein comprises substructure I

wherein,
R 1 is H or alkyl;
R 2 is alkyl;
R 3 is H or substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, azido, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, halo, substituted or unsubstituted allyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted phosphonate, substituted or unsubstituted carbamate, or substituted or unsubstituted amido;
n is 1-4, inclusive; and
X is a monovalent anion.

8. The peptide, oligopeptide, polypeptide, or protein of claim 7 , wherein the peptide, oligopeptide, polypeptide, or protein comprises a plurality of substructures I.

9. The peptide, oligopeptide, polypeptide, or protein of claim 7 , wherein R 3 is substituted alkyloxy.

10. The peptide, oligopeptide, polypeptide, or protein of claim 9 , wherein R 3 is heterocycloalkyloxy, phosphonate-substituted alkyloxy, acyloxyalkyloxy, aminoalkyloxy, aminoalkylamidoalkyloxy, or alkyloxycarbonylalkyloxy.

11. The peptide, oligopeptide, polypeptide, or protein of claim 7 , wherein R 3 is -L-halo, -L-azide, -L-NHR 1 , -L-NR 1 -TFA,-L-NR 1 —C(O)—O-alkyl -L-NR 1 —C(O)—CH 2 —NR 1 -TFA, -L-O—CH 2 —CH═CH 2 , -L-O—CH 2 CCH, -L-O-alkyl, -L-O—C(O)-alkyl, -L-P(O)(O-alkyl) 2 , -L-P(O)(OH) 2 , -L-O—C(O)—C(halo)(alkyl) 2 , -L-CH 2 —P(O)(O-alkyl) 2 , -L-CH 2 —P(O)(OH) 2 , -L-O—CH 2 CH—(C(O)NR 1 -alkyl)(NR 1 -TFA), -L-O—CH 2 CH—(C(O)OR 1 )(NR 1 -TFA) , -L-OCH 2 —C(O)—OR 1 , -L-CH—(CO 2 -alkyl) 2 , -L-CH—(CO 2 H) 2 , -L-SO 2 (O-alkyl), -L-SO 2 (O-aryl), -L-SO 3 H,

L is a bond or —(OCH 2 CH 2 ) x —, and x is 1-10.

12. The peptide, oligopeptide, polypeptide, or protein of claim 7 , wherein R 3 is —(OCH 2 CH 2 ) 3 —OCH 3 .

13. The peptide, oligopeptide, polypeptide, or protein of claim 7 , wherein R 3 is

14. A process for chemically modifying a peptide, oligopeptide, polypeptide, or protein by alkylation of one or more thioether groups, comprising the steps of:
contacting a compound of formula II with an aqueous or polar organic solvent

wherein, independently for each occurrence,
R 1 is H or alkyl;
R 2 is alkyl;
m is 1-200, inclusive;
n is 1-4, inclusive;
A 1 is H, an amine protecting group, a natural or unnatural alpha amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
A 2 is OH, —O-(a carboxylate protecting group), a natural or unnatural alpha amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;

adding a compound of formula III

wherein, independently for each occurrence,
R 3 is H or substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, azido, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, halo, substituted or unsubstituted allyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted phosphonate, substituted or unsubstituted carbamate, or substituted or unsubstituted amido; and

reacting the compound of formula II with the compound of formula III, thereby creating a compound of formula I

15. The process of claim 14 , wherein R 3 is substituted alkyloxy.

16. The process of claim 15 , wherein R 3 is heterocycloalkyloxy, phosphonate-substituted alkyloxy, acyloxyalkyloxy, aminoalkyloxy, aminoalkylamidoalkyloxy, or alkyloxycarbonylalkyloxy.

17. The process of claim 14 , wherein R 3 is -L-halo, -L-azide, -L-NHR 1 , -L-NR 1 TFA, -L-NR 1 —C(O)—O-alkyl, -L-NR 1 —C(O)—CH 2 —NR 1 -TFA, -L-O—CH 2 —CH═CH 2 , -L-O—CH 2 CCH, -L-O-alkyl, -L-O—C(O)-alkyl, -L-P(O)(O-alkyl) 2 , -L-P(O)(OH) 2 , -L-O—C(O)—C(halo)(alkyl) 2 , -L-CH 2 —P(O)(O-alkyl) 2 , -L-CH 2 —P(O)(OH) 2 , -L-O—CH 2 CH—(C(O)NR 1 -alkyl)(NR 1 -TFA), -L-O—CH 2 CH—(C(O)OR 1 )(NR 1 -TFA), -L-OCH 2 —C(O)—OR 1 , -L-CH—(CO 2 -alkyl) 2 , -L-CH—(CO 2 H) 2 , -L-SO 2 (O-alkyl), -L-SO 2 (O-aryl), -L-SO 3 H,

L is a bond or —(OCH 2 CH 2 ) x —, and x is 1-10.

18. The process of claim 14 , wherein A 1 or A 2 is methionine, or A 1 or A 2 is a peptide comprising a methionine residue, an oligopeptide comprising a methionine

Assignees

• Univ California

Inventors

• Deming Timothy J
• Gharakhanian Eric G

Classifications

• C08G69/10

  Alpha-amino-carboxylic acids {(polysuccinimides C08G73/1092)} · CPC title

• C07K1/006 Primary

  of peptides containing derivatised side chain amino acids · CPC title

• G01N33/68

  involving proteins, peptides or amino acids {(involving lipoproteins G01N33/92)} · CPC title

• C08G69/48

  Polymers modified by chemical after-treatment · CPC title

• C07K7/06

  having 5 to 11 amino acids · CPC title