Beta-peptido sugar-copolymer
There is provided a β-peptido sugar-copolymer having the structure of formula (I) as defined herein, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of the same. There is provided a process to make the β-peptido sugar-copolymer as defined herein. There are further provided medical applications of the β-peptido sugar-copolymer as defined herein. In a preferred embodiment, a block-like copolymer poly(amido-D-glucose)-block-poly-β-(L)-homolysine (PDGu-b-PBLK) synthesized via anionic ring-opening polymerization (ROP) demonstrates an antimicrobial efficacy, an enhanced selectivity towards different bacteria, biocompatibility vs. mammalian cells and spontaneous assembly.
1. A β-peptido sugar-copolymer having the following structure of formula (I):
wherein:
A is selected from any amino acid residue;
x and y are independently selected from 1 to 50;
R 1 and R 2 are independently selected from the group consisting of H, a substituted or unsubstituted C 1 -C 20 alkyl, a substituted or unsubstituted C 1 -C 20 alkoxy, a substituted or unsubstituted C 2 -C 20 alkenyl, a substituted or unsubstituted C 3 -C 20 alicyclic group; and
n is an integer selected from 0 to 4;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of the same.
2. The β-peptido sugar-copolymer of claim 1 , wherein A is selected from the group consisting of
—(CH 2 ) 4 —NH 2 and —(CH 2 ) 3 —NHC(NH)NH 2 .
3. The β-peptido sugar-copolymer of claim 1 , wherein A is —(CH 2 ) 4 —NH 2 .
4. The β-peptido sugar-copolymer of claim 1 , wherein the β-peptido sugar-copolymer has the following structure of formula (II):
wherein R′, R 2 , A, n, x and y are as defined in claim 1 ,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of the same.
5. The β-peptido sugar-copolymer of claim 1 , wherein the β-peptido sugar-copolymer has the following structure of formula (III):
wherein R′, R 2 , A, n, x and y are as defined in claim 1 ,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of the same.
6. The β-peptido sugar-copolymer of claim 1 , wherein x and y are independently selected from 1 to 20.
7. The β-peptido sugar-copolymer of claim 1 , wherein x and y are independently selected from 5 to 15.
8. The β-peptido sugar-copolymer of claim 1 , wherein the sum of x and y is 15.
9. The β-peptido sugar-copolymer of claim 1 , wherein x is about 5 and y is about 10.
10. The β-peptido sugar-copolymer of claim 1 , wherein R 1 is selected from a substituted or unsubstituted C 1 -C 20 alkyl.
11. The β-peptido sugar-copolymer of claim 1 , wherein the β-peptido moiety of the copolymer forms a left-handed helical structure.
12. The β-peptido sugar-copolymer of claim 1 , wherein the sugar moiety of the copolymer forms a secondary helical structure.
13. The β-peptido sugar-copolymer of claim 1 , wherein the β-peptido sugar-copolymer adopts a sequential double helix structure.
14. A pharmaceutical composition comprising the β-peptido sugar-copolymer of claim 1 .
15. A process for making the β-peptido sugar-copolymer of claim 1 , comprising a first step of reacting a cyclic sugar derived β-lactam monomer of Formula (IV)
with a β-lactam monomer of formula (V)
further comprising a compound of the following Formula (VI)
to give a β-peptido sugar-copolymer of formula (VII)
further comprising at least one second step of deprotecting the β-peptido sugar-copolymer of Formula (VII) to give the β-peptido sugar-copolymer of Formula (I),
wherein PG refers to a protecting group, A(PG) refers to an optionally protected amino acid residue and
A is selected from any amino acid residue;
x and y are independently selected from 1 to 50;
R 1 and R 2 are independently selected from the group consisting of H, a substituted or unsubstituted C 1 -C 20 alkyl, a substituted or unsubstituted C 1 -C 20 alkoxy, a substituted or unsubstituted C 2 -C 20 alkenyl, a substituted or unsubstituted C 3 -C 20 alicyclic group; and
n is an integer selected from 0 to 4.
16. The process of claim 15 , wherein PG in the cyclic sugar-derived block is —Bn and PG in the amino acid-derived block is —CBz.
17. The process of claim 15 , wherein all protecting groups of the β-peptido sugar-copolymer of Formula (VII) are cleaved in one step.
18. A method of treating skin and soft tissue infections comprising administering to a mammal a therapeutically effective amount of a β-peptido sugar-copolymer of claim 1 .
19. The method of claim 18 , wherein the therapeutically effective amount is 10 to 500 mg per day.
20. A method of treating skin and soft tissue infections comprising administering to a mammal a therapeutically effective amount of a pharmaceutical composition of claim 14 .