Alkynes and methods of reacting alkynes with 1,3-dipole-functional compounds

• US 9,932,297 B2
• Filed: 07/24/2017
• Issued: 04/03/2018
• Est. Priority Date: 11/21/2007
• Status: Active Grant

• Current Assignee: The University of Georgia Research Foundation, Inc.
• Original Assignee: The University of Georgia Research Foundation, Inc.
• Inventors: Boons, Geert-Jan, Guo, Jun, Ning, Xinghai, Wolfert, Margaretha
• Primary Examiner(s): Yoo, Sun Jae
• Application Number:
  US15/657,601
• Publication Number:
  US 20170320815A1
• Time in Patent Office: 253 Days
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: A61K 47/6921 the form being a particulate, a powder, an adsorbate, a bead or a sphere
• CPC Class Codes: A61K 49/0021 the fluorescent group being a small organic molecule
• CPC Class Codes: A61K 49/0043 Fluorescein, used in vivo
• CPC Class Codes: A61K 49/0052 Small organic molecules oligomers, polymers, dendrimers A61K49/0054
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: C07C 211/42 with six-membered aromatic rings being part of the condensed ring systems
• CPC Class Codes: C07C 251/44 with the carbon atom of at least one of the oxyimino groups being part of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 251/58 of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 2603/36 containing eight-membered rings
• CPC Class Codes: C07C 271/34 with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 35/37 with a hydroxy group on a condensed system having three rings
• CPC Class Codes: C07C 49/683 having unsaturation outside the aromatic rings
• CPC Class Codes: C07D 249/16 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 261/20 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 271/12 : condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 307/94 : spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
• CPC Class Codes: C07D 311/90 : with hydrocarbon radicals, substituted by amino radicals, directly attached in position 9
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: C07H 21/00 : Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C07K 14/00 : Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
• CPC Class Codes: C07K 2/00 : Peptides of undefined number of amino acids; Derivatives thereof
• CPC Class Codes: G01N 33/582 : with fluorescent label

Abstract

1,3-Dipole-functional compounds (e.g., azide functional compounds) can be reacted with certain alkynes in a cyclization reaction to form heterocyclic compounds. Useful alkynes (e.g., strained, cyclic alkynes) and methods of making such alkynes are also disclosed. The reaction of 1,3-dipole-functional compounds with alkynes can be used for a wide variety of applications including the immobilization of biomolecules on a substrate.

Claims

1. A compound of the formula:

2. The compound of claim 1 wherein R⁸ represents a biomolecule.

3. The compound of claim 2 wherein the biomolecule is selected from the group consisting of peptides, proteins, glycoproteins, nucleic acids, lipids, saccharides, oligosaccharides, polysaccharides, and combinations thereof.

7. A method of preparing the compound of claim 1, the method comprising:

combining at least one alkyne with at least one 1,3-dipole-functional compound, comprising a nitrile oxide-functional compound; and

allowing the at least one 1,3-dipole-functional compound and the at least one alkyne to react under conditions effective to form the heterocyclic compound;

wherein the alkyne is of the formula;

8. The method of claim 7 wherein conditions effective to form the heterocyclic compound comprise the substantial absence of added catalyst.

9. The method of claim 7 wherein the at least one 1,3-dipole-functional compound comprises a 1,3-dipole-functionalized biomolecule.

10. The method of claim 7 wherein the at least one 1,3-dipole-functional compound comprises a detectable label.

11. The method of claim 10 further comprising detecting the heterocyclic compound.

12. The method of claim 10 wherein the detectable label is an affinity label.

13. The method of claim 12 further comprising isolating the heterocyclic compound using affinity binding.

4. A compound of the formula:

5. The compound of claim 4 wherein the at least one R¹⁰ representing an organic group represents a biomolecule.

6. The compound of claim 5 wherein the biomolecule is selected from the group consisting of peptides, proteins, glycoproteins, nucleic acids, lipids, saccharides, oligosaccharides, polysaccharides, and combinations thereof.

14. A method of preparing the compound of claim 4, the method comprising:

combining at least one alkyne with at least one 1,3-dipole-functional compound comprising a nitrone-functional compound; and

allowing the at least one 1,3-dipole-functional compound and the at least one alkyne to react under conditions effective to form the heterocyclic compound;

wherein the alkyne is of the formula;

15. The method of claim 14 wherein conditions effective to form the heterocyclic compound comprise the substantial absence of added catalyst.

16. The method of claim 14 wherein the at least one 1,3-dipole-functional compound comprises a 1,3-dipole-functionalized biomolecule.

17. The method of claim 14 wherein the at least one 1,3-dipole-functional compound comprises a detectable label.

18. The method of claim 17 further comprising detecting the heterocyclic compound.

19. The method of claim 17 wherein the detectable label is an affinity label.

20. The method of claim 19 further comprising isolating the heterocyclic compound using affinity binding.