Thiol-X click foldamers for polymer affinity and catalysis libraries

Patent metadata

Field	Value
Publication number	US-10017510-B2
Application number	US-201515116978-A
Country	US
Kind code	B2
Filing date	Feb 6, 2015
Priority date	Feb 6, 2014
Publication date	Jul 10, 2018
Grant date	Jul 10, 2018

Abstract

Click thiol-X monomers and polymers containing such monomers are disclosed. The clickable sequence controllable monomers include an optionally protected thiol moiety; an optionally protected Michael acceptor moiety; a primary functional side chain and one ore more secondary functional side chains. A clickable sequence controllable monomer, can have the structure:

wherein independently Y and Z are atoms having a valence electrons of 3 or more; n is a integer from 0-10; m is a integer from 0-10; x is a integer from 0-10; PFS is a functional group SFSi; SFS2; and SFS3 are independently a combination of hydrogen, hydroxyl, aromatic, amine, carboxyl, and carbonyls, optionally substituted to form hydrophilic, hydrophobic, amphiphilic, or charged (positive or negative or both) side chains; T is an optionally protected thiol; and TCA is an optionally protected thiol-click acceptor. Methods of using such polymers are also disclosed.

First claim

We claim:

1. A thiol-X clickable monomer having the formula:

wherein Y and Z are each independently carbon or nitrogen;
n is an integer from 0-10;
m is an integer from 0-10;
x is an integer from 0-10;
PFS has the formula:

NB is a nucleobase;
T is a thiol having the formula:

p is an integer from 0 to 4; and
TCA is a thiol-click acceptor.

2. The thiol-X clickable monomer according to claim 1 , wherein the thiol-X clickable monomer has the formula:

3. The thiol-X clickable monomer according to claim 2 , wherein the monomer is a 6-atom unit that includes the carbon atom to which the thiol moiety of the TCA thiol-click acceptor is bonded thereto.

4. The thiol-X clickable monomer according to claim 2 , wherein Y is carbon and Z is nitrogen.

5. The thiol-X clickable monomer according to claim 2 , wherein the thiol-click acceptor comprises a vinyl, vinyl ether, allyl ether, norbornene, vinyl sulfone, epoxy, acrylate, isocyanate, alkyne, methacrylate, maleimide, halide or alkyl extensions thereof.

6. The thiol-X clickable monomer according to claim 5 , wherein the vinyl moiety has the formula:
—CR 5 ═CR 6 R 7 ,

wherein R 5 , R 6 , and R 7 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, substituted heterocyclo, alkyl, substituted alkyl, acyl, —C(O)R, —C(O)OR, or —C(O)NR a R b , substituted or unsubstituted aryl or a heterocyclic ring; R is hydrocarbyl, substituted hydrocarbyl or heterocyclo, R a and R b are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.

7. The thiol-X clickable monomer according to claim 1 , wherein the index n is 0 and the index p is 1.

8. The thiol-X clickable monomer according to claim 1 , wherein the thiol-click acceptor is chosen from:

where X is a halide and R is a hydrogen or alkyl chain.

9. The thiol-X clickable monomer according to claim 1 , wherein nucleobase has the formula:

10. A click nucleic acid polymer having the formula:

wherein NB is a nucleobase, and the index n is from 4 to about 500.

11. The polymer according to claim 10 , wherein the nucleobase is chosen from 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosyl-queosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methyl-cytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, methoxyamino-methyl-2-thiouracil, beta-D-mannosylqueosine, 5′-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid, pseudo-uracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid, 5-methyl-2-thiouracil, 3-(3-amino-3-N2-carboxypropyl)uracil, and 2,6-diaminopurine.

12. The polymer according to claim 10 , wherein the nucleobase has the formula:

13. The polymer according to claim 10 , wherein n is from 18 to 30.

14. A composition, comprising a thiol-X clickable monomer having the formula:

wherein Y and Z are each independently carbon or nitrogen;
n is an integer from 0-10;
m is an integer from 0-10;
x is an integer from 0-10;
PFS has the formula:

NB is a nucleobase;
T is a thiol having the formula:

p is an integer from 0 to 4; and
TCA is a thiol-click acceptor.

15. The composition according to claim 14 , wherein the thiol-X clickable monomer has the formula:

16. The composition according to claim 15 , wherein the monomer is a 6-atom unit that includes the carbon atom to which the thiol moiety of the TCA thiol-click acceptor is bonded thereto.

17. The composition according to claim 15 , wherein Y is carbon and Z is nitrogen.

18. The composition according to claim 14 , further comprising a pharmaceutically acceptable carrier.

19. The composition according to claim 14 , wherein the nucleobase is chosen from 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosyl-queosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methyl-cytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, methoxyamino-methyl-2-thiouracil, beta-D-mannosylqueosine, 5′-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid, pseudo-uracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid, 5-methyl-2-thiouracil, 3-(3-amino-3-N2-carboxypropyl)uracil, and 2,6-diaminopurine.

20. The composition according to claim 14 , wherein the nucleobase has the formula:

Assignees

• Univ Colorado Regents

Inventors

• Bowman Christopher N
• Kloxin Christopher J
• Xi Weixian
• Gong Tao
• Pattanayak Sankha

Classifications

• C07D239/47

  One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine · CPC title

• C12N15/1048

  SELEX · CPC title

• C12Q1/68

  involving nucleic acids · CPC title

• C12Q1/6876

  Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes · CPC title

• C07D239/54

  as doubly bound oxygen atoms or as unsubstituted hydroxy radicals · CPC title