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. β-polypeptides selected from the group consisting of copolymers having the structures:
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
at least one of R 3 or R 4 , combined with one of R 5 or R 6 , together with the carbon atoms to which they are attached define a cyclic moiety “A”,
wherein “A” 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
provided that at least two of R 3 , R 4 , R 5 , and R 6 are not simultaneously hydrogen, and in at least one subunit that does not contain a cyclic moiety “A” at least one of R 3 , R 4 , R 5 , and R 6 is selected from the group consisting of amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl.
2. The β-polypeptides of claim 1 , 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.
3. The β-polypeptides of claim 1 , wherein R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl.
4. The β-polypeptides of claim 1 , wherein R 5 and R 6 are each independently selected from the group consisting of substituted or unsubstituted C 1 -C 6 -alkyl.
5. The β-polypeptides of claim 1 , wherein R 5 and R 6 are each independently selected from the group consisting of substituted or unsubstituted C 1 -C 6 -alkyl; and
R 3 and R 4 are each independently selected from the group consisting of hydrogen, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl, provided that one of R 3 or R 4 is not hydrogen.
6. An antibiotic composition comprising, in combination:
an antibiotic-effective amount of at least one β-polypeptide selected from the group consisting of copolymers having the structures:
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
at least one of R 3 or R 4 , combined with one of R 5 or R 6 , together with the carbon atoms to which they are attached define a cyclic moiety “A”,
wherein “A” 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;
provided that at least two of R 3 , R 4 , R 5 , and R 6 are not simultaneously hydrogen, and in at least one subunit that does not contain a cyclic moiety “A” at least one of R 3 , R 4 , R 5 , and R 6 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 pharmaceutically acceptable carrier.
7. The antibiotic composition of claim 6 , 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.
8. The antibiotic composition of claim 6 , wherein R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl.
9. The antibiotic composition of claim 6 , wherein R 5 and R 6 are each independently selected from the group consisting of substituted or unsubstituted C 1 -C 6 -alkyl.
10. The antibiotic composition of claim 6 , wherein R 5 and R 6 are each independently selected from the group consisting of substituted or unsubstituted C 1 -C 6 -alkyl; and
R 3 and R 4 are each independently selected from the group consisting of hydrogen, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl.