Poly-β-peptides from functionalized β-lactam monomers and antibacterial compositions containing same
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.
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:
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.
24. The β-polypeptide of claim 12 , wherein at least one of the internal subunits has a structure of:
wherein A is as previously defined.
25. The β-polypeptide of claim 24 , wherein A is selected from the group consisting of substituted or unsubstituted cyclohexane, cyclooctane, cyclooctene, and dodecane.