Poly-β-peptides from functionalized β-lactam monomers and antibacterial compositions containing same

Patent metadata

Field	Value
Publication number	US-10323121-B2
Application number	US-201715595557-A
Country	US
Kind code	B2
Filing date	May 15, 2017
Priority date	Aug 26, 2005
Publication date	Jun 18, 2019
Grant date	Jun 18, 2019

Abstract

Disclosed is a method of making β-polypeptides. The method includes polymerizing β-lactam-containing monomers in the presence of a base initiator and a co-initiator which is not a metal-containing molecule to yield the product β-polypeptides. Specifically disclosed are methods wherein the base initiator is potassium t-butoxide, lithium bis(trimethylsilyl)amide (LiN(TMS) 2 ), potassium bis(trimethyl-silyl)amide, and sodium ethoxide, and the reaction is carried out in a solvent such as chloroform, dichloromethane, dimethylsulfoxide, or tetrahydrofuran.

First claim

What is claimed is:

1. A β-polypeptide comprising internal subunits having a structure selected from the group consisting of:

wherein:
R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alkylaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl;
A together with the carbon atoms to which it is attached is selected from the group consisting of substituted or unsubstituted C 5 -C 12 cycloalkyl, C 5 -C 12 cycloalkenyl, and five- to twelve-membered heterocyclic;
the β-polypeptide has a molecular weight (M n ) of from 3,300 Da to 20,000 Da; and
the β-polypeptide comprises heterochiral internal subunits.

2. The β-polypeptide of claim 1 , wherein the β-polypeptide has a molecular weight (M n ) of from 4,950 Da to 20,000 Da.

3. The β-polypeptide of claim 1 , wherein the β-polypeptide comprises a terminal subunit having a structure of:

wherein R is selected from the group consisting of linear, branched, or cyclic alkyl, alkenyl, alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted arylalkyl.

4. The β-polypeptide of claim 3 , wherein R in the terminal subunit is:

wherein R 7 is selected from the group consisting of tert-butyl, chloromethyl, aldehyde, an ester, a thioester, an amine, and an imide.

5. The β-polypeptide of claim 3 , wherein R in the terminal subunit is selected from the group consisting of:

6. The β-polypeptide of claim 3 , wherein the β-polypeptide comprises a second terminal subunit selected from the group consisting of:

wherein R 3 , R 4 , R 5 , R 6 , and A are as previously defined.

7. The β-polypeptide of claim 6 , wherein at least one of R 3 , R 4 , R 5 , and R 6 in the second terminal subunit is selected from the group consisting of amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl.

8. The β-polypeptide of claim 1 , wherein at least one of the internal subunits has a structure of:

wherein A is as previously defined.

9. The β-polypeptide of claim 8 , wherein A is selected from the group consisting of substituted or unsubstituted cyclohexane, cyclooctane, cyclooctene, and dodecane.

10. A β-polypeptide comprising internal subunits having a structure selected from the group consisting of:

wherein:
R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alkylaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl;
A together with the carbon atoms to which it is attached is selected from the group consisting of substituted or unsubstituted C 5 -C 12 cycloalkyl, C 5 -C 12 cycloalkenyl, and five- to twelve-membered heterocyclic;
the β-polypeptide has a molecular weight (M n ) of from 4,950 Da to 20,000 Da; and
at least one of the internal subunits has a structure of:

wherein at least one of R 3 , R 4 , R 5 , and R 6 in the at least one of the internal subunits is selected from the group consisting of amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl.

11. The β-polypeptide of claim 10 , wherein the β-polypeptide comprises heterochiral internal subunits.

12. A β-polypeptide comprising internal subunits having a structure selected from the group consisting of:

wherein:
R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alkylaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl;
A together with the carbon atoms to which it is attached is selected from the group consisting of substituted or unsubstituted C 5 -C 12 cycloalkyl, C 5 -C 12 cycloalkenyl, and five- to twelve-membered heterocyclic; and
the β-polypeptide comprises heterochiral internal subunits.

13. The β-polypeptide of claim 12 , wherein the β-polypeptide has a molecular weight (M n ) of from 1,180 Da to 20,000 Da.

14. The β-polypeptide of claim 12 , wherein the β-polypeptide has a molecular weight (M n ) of from 7,300 Da to 20,000 Da.

15. The β-polypeptide of claim 12 , wherein the β-polypeptide comprises a terminal subunit having a structure of:

wherein R is selected from the group consisting of linear, branched, or cyclic alkyl, alkenyl, alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted arylalkyl.

16. The β-polypeptide of claim 15 , wherein the β-polypeptide has a molecular weight (M n ) of from 3,300 Da to 20,000 Da.

17. The β-polypeptide of claim 15 , wherein R in the terminal subunit is:

wherein R 7 is selected from the group consisting of tert-butyl, chloromethyl, aldehyde, an ester, a thioester, an amine, and an imide.

18. The β-polypeptide of claim 15 , wherein R in the terminal subunit is selected from the group consisting of:

19. The β-polypeptide of claim 15 , wherein the β-polypeptide comprises a second terminal subunit selected from the group consisting of:

wherein R 3 , R 4 , R 5 , R 6 , and A are as previously defined.

20. The β-polypeptide of claim 19 , wherein at least one of R 3 , R 4 , R 5 , and R 6 in the second terminal subunit is selected from the group consisting of amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl.

21. The β-polypeptide of claim 12 , wherein the β-polypeptide comprises a terminal subunit selected from the group consisting of:

wherein R 3 , R 4 , R 5 , R 6 , and A are as previously defined.

22. The β-polypeptide of claim 21 , wherein at least one of R 3 , R 4 , R 5 , and R 6 in the terminal subunit is selected from the group consisting of amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl.

23. The β-polypeptide of claim 12 , wherein at least one of the internal subunits has a structure of:

Assignees

• Wisconsin Alumni Res Found

Inventors

• Stahl Shannon S
• Gellman Samuel H
• Lee Sarah E
• Ilker Mehmet F
• Weisblum Bernard
• Kissounko Denis

Classifications

• C08G69/22 Primary

  Beta-lactams · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• C07D205/08

  with one oxygen atom directly attached in position 2, e.g. beta-lactams · CPC title

• C07K1/02

  in solution {(C07K1/003, C07K1/006 take precedence)} · CPC title