γ-AApeptides with potent and broad-spectrum antimicrobial activity

Patent metadata

Field	Value
Publication number	US-10144764-B2
Application number	US-201615292162-A
Country	US
Kind code	B2
Filing date	Oct 13, 2016
Priority date	Jan 23, 2012
Publication date	Dec 4, 2018
Grant date	Dec 4, 2018

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 method of making a γ-AApeptide, the method comprising:
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:

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 method of claim 1 , wherein the solid support is a Rink amide resin or a Knorr resin.

3. The method 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 method of claim 1 , wherein the repeating step is preformed to couple between 5 and 50 γ-AApeptide building blocks.

5. The method of claim 1 , wherein the step of reacting an Fmoc protected amino aldehyde with glycine benzyl ester further comprises sodium cyanoborohydride.

6. The method 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 method of claim 1 , wherein hydrogenation to form γ-AApeptide building blocks comprises a palladium on carbon catalyst and molecular hydrogen.

8. The method of claim 1 , wherein attaching a first γ-AApeptide building block to a solid support further comprises N,N′-Diisopropylcarbodiimide and oxohydroxybenzotriazole.

9. The method 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 method 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 method 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 method 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 method of claim 1 , wherein the γ-AApeptide is a cyclic γ-AApeptide.

14. The method of claim 1 , further comprising: purifying the γ-AApeptide by high performance liquid chromatography.

15. The method of claim 10 , further comprising: lyophizing the γ-AApeptide.

16. The method of claim 1 , further comprising: lyophizing the γ-AApeptide.

17. The method of claim 1 , wherein the substituted or unsubstituted alkanoic acid is ethanoic acid or 4-methyl pentanoic acid.

18. The method 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 method of claim 1 , wherein the substituted or unsubstituted aryl is a substituted or unsubstituted hydrocinnamic acid.

20. The method 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

• A61K47/543

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

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K7/64

  Cyclic peptides containing only normal peptide links · CPC title

• A61K38/12

  Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)} · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title