Gamma-AApeptides with potent and broad-spectrum antimicrobial activity

Patent metadata

Field	Value
Publication number	US-10308686-B2
Application number	US-201816205500-A
Country	US
Kind code	B2
Filing date	Nov 30, 2018
Priority date	Jan 23, 2012
Publication date	Jun 4, 2019
Grant date	Jun 4, 2019

Abstract

The present invention is directed to a novel class of antimicrobial agents called γ-AApeptides. The current invention provides various categories of γ-AApeptides, for example, linear γ-AApeptides, cyclic γ-AApeptides, and lipidated γ-AApeptides. γ-AApeptides of the current invention are designed to exert antimicrobial activity while being stable and non-toxic. γ-AApeptides also do not appear to lead to the development of microbial resistance in treated microorganisms. Thus, the disclosed γ-AApeptides can be used for the treatment of various medical conditions associated with pathogenic microorganisms.

First claim

We claim:

1. A γ-AApeptide prepared by a process comprising the steps of:
reacting an Fmoc protected amino aldehyde comprising:

wherein R 1 is a straight or branched chain C 1 to C 10 alkyl group, —CH 2 —CH 2 —S—CH 3 ; a —(CH 2 ) 1-5 -aryl group, or an —(CH 2 ) 1-5 -heteroaryl group, and wherein the alkyl group, the aryl group or the heteroaryl group can be substituted or unsubstituted,

with glycine benzyl ester comprising:

to form a secondary amine comprising:

reacting

with a substituted or unsubstituted aryl, substituted or unsubstituted 5-membered heterocyclic ring of which one to four member(s) may be heteroatoms, γ-Boc-amino butyric acid, di-Boc-guanidinopropionic acid, mono-allyl succinate or substituted or unsubstituted alkanoic acid followed by hydrogenation to form γ-AApeptide building blocks comprising:

wherein R 2 is substituted or unsubstituted aryl, substituted or unsubstituted 5-membered heterocyclic ring of which one to four member(s) may be heteroatoms, amino-propyl, allyl-propyl, or substituted or unsubstituted alkyl;
attaching a first γ-AApeptide building block to a solid support;
coupling the first γ-AApeptide building block with a second γ-AApeptide building block;
repeating the coupling step to form the γ-AApeptide attached to the solid support; and
cleaving the γ-AApeptide attached to the solid support from the solid support to form the γ-AApeptide.

2. The γ-AApeptide prepared by the process of claim 1 , wherein the solid support is a Rink amide resin or a Knorr resin.

3. The γ-AApeptide prepared by the process of claim 1 , wherein R 1 is a methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, s-butyl or t-butyl group.

4. The γ-AApeptide prepared by the process of claim 1 , wherein the repeating step is performed to couple between 5 and 50 γ-AApeptide building blocks.

5. The γ-AApeptide prepared by the process of claim 1 , wherein the step of reacting an Fmoc protected amino aldehyde with glycine benzyl ester further comprises sodium cyanoborohydride.

6. The γ-AApeptide prepared by the process of claim 1 , wherein the step of reacting

with the substituted or unsubstituted aryl, substituted or unsubstituted 5-membered heterocyclic ring of which one to four member(s) may be heteroatoms, γ-Boc-amino butyric acid, di-Boc-guanidinopropionic acid, mono-allyl succinate or substituted or unsubstituted alkanoic acid further comprises diisopropylcarbodiimide, 3-4-dihydro-3-hydroxy-4-oxo-1-2-3-benzotriazine, and dimethylformamide.

7. The γ-AApeptide prepared by the process of claim 1 , wherein hydrogenation to form γ-AApeptide building blocks comprises a palladium on carbon catalyst and molecular hydrogen.

8. The γ-AApeptide prepared by the process of claim 1 , wherein attaching a first γ-AApeptide building block to a solid support further comprises N,N′-Diisopropylearbodiimide and oxohydroxybenzotriazole.

9. The γ-AApeptide prepared by the process of claim 1 , wherein coupling the first γ-AApeptide building block with a second γ-AApeptide building block further comprises N,N′-Diisopropylcarbodiimide and oxohydroxybenzotriazole.

10. The γ-AApeptide prepared by the process of claim 1 , wherein coupling the first γ-AApeptide building block with a second γ-AApeptide building block further comprises benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate.

11. The γ-AApeptide prepared by the process of claim 1 , wherein coupling the first γ-AApeptide building block with a second γ-AApeptide building block further comprises 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and hydroxybenzotriazole.

12. The γ-AApeptide prepared by the process of claim 1 , wherein cleaving the γ-AApeptide attached to the solid support from the solid support to form the γ-AApeptide further comprises trifluoroacetic acid, methylene chloride, and triisopropylsilane.

13. The γ-AApeptide prepared by the process of claim 1 , wherein the γ-AApeptide is a cyclic γ-AApeptide.

14. The γ-AApeptide prepared by the process of claim 1 , the process further comprising the step of purifying the γ-AApeptide by high performance liquid chromatography.

15. The γ-AApeptide prepared by the process of claim 11 , the process further comprising lyophizing the γ-AApeptide.

16. The γ-AApeptide prepared by the process of claim 1 , the process further comprising: lyophizing the γ-AApeptide.

17. The γ-AApeptide prepared by the process of claim 1 , wherein the substituted or unsubstituted alkanoic acid is ethanoic acid or 4-methyl pentanoic acid.

18. The γ-AApeptide prepared by the process of claim 1 , wherein the substituted or unsubstituted 5-membered heterocyclic ring is selected from furanyl, thienyl, pyrrolyl, N-alkyl pyrrolyl, or imidazole.

19. The γ-AApeptide prepared by the process of claim 1 , wherein the substituted or unsubstituted aryl is a substituted or unsubstituted hydrocinnamic acid.

20. The γ-AApeptide prepared by the process of claim 19 , wherein the substituted or unsubstituted hydrocinnamic acid is α-cyano-4-hydroxy-cinnamic acid.

Assignees

• Cai Jianfeng
• Niu Youhong
• Wu Haifan
• Padhee Shruti
• Univ South Florida

Inventors

• Cai Jianfeng
• Niu Youhong
• Wu Haifan
• Padhee Shruti

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• A61K49/0056

  Peptides, proteins, polyamino acids · CPC title

• A61K47/543

  Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine · CPC title

• C07K7/56 Primary

  the cyclisation not occurring through 2,4-diamino-butanoic acid · CPC title

• C07K7/06

  having 5 to 11 amino acids · CPC title