Alkynes and methods of reacting alkynes with 1,3-dipole-functional compounds
View Patent ↗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.
1. An alkyne of the formula:
wherein:
each R 1 is independently selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, nitrate, nitrite, sulfate, and a C1-C10 organic group;
each R 2 is independently selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, nitrate, nitrite, sulfate, and a C1-C10 organic group;
X represents C═O, C═N—OR 3 , C═N—NR 3 R 4 , CHOR 3 , or CHNHR 3 ; and
each R 3 and R 4 independently represents hydrogen or an organic group.
2. The alkyne of claim 1 wherein R 3 comprises a covalently bound organic dye.
3. The alkyne of claim 1 wherein X represents C═N—OR 3 and R 3 represents an organic group having the formula —(CH 2 ) a C(O)Y, wherein:
a is 1-3;
Y represents OH or NHR 5 ; and
R 5 represents hydrogen or a biotinylation product of a primary amine-containing organic group.
4. The alkyne of claim 3 wherein the biotinylation product is the biotinylation product of a primary amine-containing group of the formula —(CH 2 CH 2 O) b (CH 2 ) c -L d -(CH 2 CH 2 O) e (CH 2 ) f NH 2 and/or —(CD 2 CD 2 O) b (CD 2 ) c -L d -(CD 2 CD 2 O) e (CD 2 ) f NH 2 , wherein b=0 to 100; c=0 to 100; d=0 to 100; e=0 to 100; f=0 to 100; and L is an optional cleavable linker.
5. The alkyne of claim 4 wherein the cleavable linker, if present, is a disulfide.
6. The alkyne of claim 1 wherein X represents CHOR 3 and R 3 is selected from the group consisting of an alkyl group, an aryl group, an alkaryl group, and an aralkyl group.
7. The alkyne of claim 6 wherein R 3 represents —C(O)Z, wherein:
Z represents an alkyl group, OR 6 , or NHR 7 ;
R 6 and R 7 are each independently selected from the group consisting of an alkyl group, an aryl group, an alkaryl group, and an aralkyl group.
8. An alkyne of the formula:
wherein:
each R 1 is independently selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, nitrate, nitrite, sulfate, and a C1-C10 organic group;
each R 2 is independently selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, nitrate, nitrite, sulfate, and a C1-C10 organic group;
X represents CHOR 3 ;
R 3 represents —C(O)Z, wherein:
Z represents an alkyl group, OR 6 , or NHR 7 ;
R 6 is selected from the group consisting of an alkyl group, an aryl group, an alkaryl group, and an aralkyl group; and
R 7 is a biotinylation product of a primary amine-containing organic group.
9. The alkyne of claim 8 wherein the biotinylation product is the biotinylation product of a primary amine-containing group of the formula —(CH 2 CH 2 O) b (CH 2 ) c -L d -(CH 2 CH 2 O) e (CH 2 ) f NH 2 and/or —(CD 2 CD 2 O) b (CD 2 ) c -L d -(CD 2 CD 2 O) e (CD 2 ) f NH 2 , wherein b=0 to 100; c=0 to 100; d=0 to 100; e=0 to 100; f=0 to 100; and L is an optional cleavable linker.
10. The alkyne of claim 9 wherein the cleavable linker, if present, is a disulfide.
11. An alkyne of the formula:
wherein:
each R 1 is independently selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, nitrate, nitrite, sulfate, and a C1-C10 organic group;
each R 2 is independently selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, nitrate, nitrite, sulfate, and a C1-C10 organic group;
X represents C═O, C═N—OR 3 , C═N—NR 3 R 4 , CHOR 3 , or CHNHR 3 ;
R 3 represents a polymeric or a copolymeric group; and
R 4 represents hydrogen or an organic group.
12. The alkyne of claim 11 wherein the copolymeric group comprises a hydrophilic segment and a hydrophobic segment.
13. The alkyne of claim 11 wherein the copolymeric group comprises a fragment of the formula —[CH 2 CH 2 O] n [C(O)(CH 2 ) 5 O] m —H, wherein n=0 to 100 and m=0 to 100.
14. An alkyne of the formula:
15. An alkyne of the formula:
16. An alkyne of the formula:
17. An alkyne of the formula:
wherein R 3 represents hydrogen or an organic group.
18. A composition comprising a blend of:
an alkyne according to claim 11 ; and
a polymer or a copolymer.
19. The composition of claim 18 wherein the composition forms a copolymer micelle.
20. A method for controlling the delivery of drugs, the method comprising:
combining at least one 1,3-dipole-functional drug with a copolymer micelle according to claim 19 comprising an alkyne; and
allowing the at least one 1,3-dipole-functional drug and the copolymer micelle comprising the alkyne to react under conditions effective to form a heterocyclic compound.
21. A method of preparing a heterocyclic compound, the method comprising:
combining at least one 1,3-dipole-functional compound with at least one alkyne according to claim 1 ; 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.
22. A substrate having on the surface thereof an alkyne according to claim 1 .
23. A method of immobilizing a biomolecule on a substrate, the method comprising:
providing a substrate according claim 22 ;
contacting the substrate with a 1,3-dipole-functional biomolecule under conditions effective to form a heterocyclic compound.
24. A method for immobilizing a cell, the method comprising:
providing a substrate according to claim 22 ;
contacting the substrate with a cell comprising a 1,3-dipole-functional biomolecule under conditions effective to form a heterocyclic compound.