Aldehyde capture ligation technology for synthesis of amide bonds

Patent metadata

Field	Value
Publication number	US-9593142-B2
Application number	US-201414583586-A
Country	US
Kind code	B2
Filing date	Dec 26, 2014
Priority date	Dec 26, 2013
Publication date	Mar 14, 2017
Grant date	Mar 14, 2017

Abstract

The present invention relates to ligation agents and their use in making an amide ligation product. Methods of making the ligation agents are also disclosed.

First claim

What is claimed:

1. A method of forming an amide ligation product, said method comprising:
reacting a compound containing an amino group with a ligation agent, said ligation agent comprising a seleno ester group, under conditions effective to produce an amide ligation product;
wherein:
(i) the compound containing an amino group does not have an N-terminal cysteine, an N-terminal serine, or an N-terminal threonine; or
(ii) the method does not proceed through the formation of a pseudoproline intermediate.

2. The method of claim 1 , wherein the amide ligation product has the formula A-C(O)—N(R 9 )—B,
wherein
A and B are each independently selected from the group consisting of H, (R 1 ) 2 N(C(R 2 ) 2 ) n —, —NR 5 R 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —OH, C 1 -C 6 alkoxy, aryl, amino acids, peptides, proteins, carbohydrates, nucleic acids, cytotoxic small molecule drugs, dyes, and polymers;
each n is 1-3;
each R 1 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, amino acids, peptides, and protecting groups for the protection of an amine;
each R 2 is independently selected from the group consisting of H, —C(O)R 7 , —C(O)OR 8 , —C(O)NR 5 R 6 , NO 2 , —NR 5 R 6 , halogen, OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, C 1 -C 6 alkoxy, and amino acid side chains;
R 5 , R 6 , R 7 , and R 8 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and aryl; and
R 9 is selected from the group consisting of H, OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, C 1 -C 6 alkoxy, amino acids, peptides, proteins, carbohydrates, and nucleic acids.

3. The method of claim 1 , wherein the compound containing an amino group has the formula B—N(R 9 )H,
wherein
B is selected from the group consisting of H, (R 1 ) 2 N(C(R 2 ) 2 ) n —, —NR 5 R 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —OH, C 1 -C 6 alkoxy, aryl, amino acids, peptides, proteins, carbohydrates, nucleic acids, cytotoxic small molecule drugs, dyes, and polymers;
R 5 and R 6 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and aryl; and
R 9 is selected from the group consisting of H, OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, C 1 -C 6 alkoxy, amino acids, peptides, proteins, carbohydrates, and nucleic acids.

4. The method of claim 1 , wherein the compound containing an amino group is selected from the group consisting of amino acids, peptides, proteins, carbohydrates, and nucleic acids.

5. The method of claim 1 , wherein the ligation agent has the formula:

wherein
A is selected from the group consisting of H, (R 1 ) 2 N(C(R 2 ) 2 ) n —, —NR 5 R 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —OH, C 1 -C 6 alkoxy, aryl, amino acids, peptides, proteins, carbohydrates, nucleic acids, cytotoxic small molecule drugs, dyes, and polymers;
X is selected from the group consisting of

represents a point of attachment to —C(O)—Se—X—(CR 4 2 ) m C(O)R 3 ;

represents a point of attachment to (CR 4 2 ) m C(O)R 3 ;

represents a point of attachment to —Se—C(O)-A;
n is 1-3;
m is 0-3;
each R 1 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, amino acids, peptides, and protecting groups for the protection of an amine;
each R 2 is independently selected from the group consisting of H, —C(O)R 7 , —C(O)OR 8 , —C(O)NR 5 R 6 , NO 2 , —NR 5 R 6 , halogen, OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, C 1 -C 6 alkoxy, and amino acid side chains;
R 3 is selected from the group consisting of H, C 1 -C 6 alkyl, and aryl;
each R 4 is independently selected from the group consisting of H, —C(O)R 7 , —C(O)OR 8 , NO 2 , —NR 5 R 6 , halogen, OH, C 1 -C 6 alkyl, aryl, and C 1 -C 6 alkoxy; and
R 5 , R 6 , R 7 , and R 8 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and aryl;
with the proviso that m is 0-3 when A is (R 1 ) 2 N(C(R 2 ) 2 ) n — and X is

and
with the proviso that m is 0-2 when A is (R 1 ) 2 N(C(R 2 ) 2 ) n — and X is

6. The method of claim 5 , wherein A is (R 1 ) 2 N(C(R 2 ) 2 ) n —, a fluorescent dye, or a cytotoxic small molecule drug.

7. The method of claim 6 , wherein X is

8. The method of claim 7 , wherein the ligation agent is selected from the group consisting of:

wherein R 3 is an aryl or an alkyl;

wherein R 3 is an aryl or an alkyl.

9. The method of claim 6 , wherein X is

10. The method of claim 9 , wherein the ligation agent is selected from the group consisting of:

wherein R3 is an aryl or an alkyl.

11. The method of claim 1 , wherein the compound containing an amino group does not have an N-terminal cysteine, an N-terminal serine, or an N-terminal threonine.

12. The method of claim 1 , wherein the method does not proceed through the formation of a pseudoproline intermediate.

Assignees

• Arora Paramjit S
• Raj Monika
• Wu Huabin
• Univ New York

Inventors

• Arora Paramjit S
• Raj Monika
• Wu Huabin

Classifications

• C07K1/1075 Primary

  by covalent attachment of amino acids or peptide residues · CPC title

• C07C2603/10

  containing five-membered rings · CPC title

• C07C391/02 Primary

  having selenium atoms bound to carbon atoms of six-membered aromatic rings · CPC title

• C07K5/06034

  the side chain containing 2 to 4 carbon atoms · CPC title

• C07K5/1008

  the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala · CPC title