Poly-beta-peptides from functionalized beta-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 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl; and
wherein 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;
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; and
a terminal subunit selected from the group consisting of:
wherein R 3 , R 4 , R 5 , and R 6 in the terminal subunit are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl and A in the terminal subunit is as previously defined.
2. The β-polypeptide of claim 1 , 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.
3. The β-polypeptide of claim 1 , wherein at least one of 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.
4. The β-polypeptide of claim 1 , wherein each internal subunit has a structure of:
wherein at least one of R 3 , R 4 , R 5 , and R 6 in each internal 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.
5. 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 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl; and
wherein 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;
a terminal subunit selected from the group consisting of:
wherein R 3 , R 4 , R 5 , R 6 , and A are as previously defined; and
a second 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.
6. The β-polypeptide of claim 5 , wherein the second terminal subunit is:
wherein R 7 is tert-butyl or chloromethyl.
7. 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 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl; and
wherein 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;
wherein at least one internal subunit has a structure of:
wherein A is as previously defined; and
a terminal subunit selected from the group consisting of:
wherein R 3 , R 4 , R 5 , R 6 , and A are as previously defined.
8. The β-polypeptide of claim 7 , wherein A is selected from the group consisting of substituted or unsubstituted cyclohexane, cyclooctane, cyclooctene, and dodecane.
9. An antibiotic composition comprising, in combination:
an antibiotic-effective amount of at least one β-polypeptide or salt thereof, the at least one β-polypeptide or salt thereof 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 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl; and
wherein 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
a terminal subunit selected from the group consisting of:
wherein R 3 , R 4 , R 5 , R 6 , and A are as previously defined; and
a pharmaceutically acceptable carrier.
10. The antibiotic composition of claim 9 , 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.
11. The antibiotic composition of claim 9 , wherein at least one of 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.
12. The antibiotic composition of claim 9 , wherein the β-polypeptide comprises a second 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.
13. The antibiotic composition of claim 12 , wherein the second terminal subunit is:
wherein R 7 is tert-butyl or chloromethyl.
14. The antibiotic composition of claim 9 , wherein each internal subunit of the β-polypeptide has a structure of:
wherein at least one of R 3 , R 4 , R 5 , and R 6 in each internal 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.
15. The antibiotic composition of claim 9 , wherein at least one internal subunit in the β-polypeptide has a structure of:
wherein A is as previously defined.
16. The antibiotic composition of claim 15 , wherein A is selected from the group consisting of substituted or unsubstituted cyclohexane, cyclooctane, cyclooctene, and dodecane.
17. 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 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl; and
wherein 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
a terminal subunit selected from the group consisting of:
wherein R 3 , R 4 , R 5 , R 6 , and A are as previously defined,
wherein the β-polypeptide has a molecular weight (M n ) of from 1,180 Da to 20,000 Da.
18. The β-polypeptide of claim 17 , wherein the β-polypeptide has a molecular weight (M n ) of from 3,300 Da to 20,000 Da.
19. The β-polypeptide of claim 17 , wherein the β-polypeptide has a molecular weight (M n ) of from 4,950 Da to 20,000 Da.
20. The β-polypeptide of claim 17 , wherein the β-polypeptide has a molecular weight (M n ) of from 7,300 Da to 20,000 Da.
21. 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 2 -C 6 -alkyl, aryl, C 2 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl; and
wherein 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
a terminal subunit selected from the group consisting of:
wherein R 3 , R 4 , R 5 , R 6 , and A are as previously defined.