Enterobactin conjugates and uses thereof

Patent metadata

Field	Value
Publication number	US-9902986-B2
Application number	US-201414516440-A
Country	US
Kind code	B2
Filing date	Oct 16, 2014
Priority date	Oct 16, 2013
Publication date	Feb 27, 2018
Grant date	Feb 27, 2018

Abstract

The present invention provides novel enterobactin-cargo conjugates, such as compounds of Formula (I), and salts thereof, where X is the cargo and may be an antibiotic, a fluorophore, or biotin. The present invention also provides complexes, compositions, kits, and methods that involve the compounds of Formula (I) and are useful in delivering a cargo to a bacterium, treating a bacterial infection, cystic fibrosis, and/or inflammatory bowel disease in a subject, preventing a bacterial infection, cystic fibrosis, and/or inflammatory bowel disease in a subject, inhibiting the growth of or killing a bacterium, or determining the concentration of a bacterium in a biological sample. In certain embodiments, the bacterium is a Gram-negative bacterium.

First claim

What is claimed is:

1. A compound of Formula (I):

or a salt thereof, wherein:
each instance of L is independently a bond or a divalent linker;
one instance of X is:
an antibiotic selected from the group consisting of β-lactam antibiotics, aminoglycoside antibiotics, ansamycin antibiotics, glycopeptide antibiotics, lincosamide antibiotics, lipopeptide antibiotics, macrolide antibiotics, nitrofuran antibiotics, oxazolidonone antibiotics, quinolone antibiotics, sulfonamide antibiotics, and tetracycline antibiotics; or
a fluorophore selected from the group consisting of coumarin 343, coumarin 1, coumarin 6, coumarin 30, coumarin 153, coumarin 314, coumarin 334, coumarin 545t, 6,8-difluoro-7-hydroxy-4-methylcoumarin, 7-amino-4-methyl-6-sulfocoumarin-3-acetic acid, 7-methoxycoumarin-4-acetic acid, 7-hydroxy-4-methylcoumarin, rhodamine, Oregon green, eosin, Texas red, dansyl, cyanine, indocarbocyanine, oxacarbocyanine, thiacarbocyanine, merocyanine, pyridyloxazole, nitrobenzoxadiazole, benzoxadiazole, cascade blue, Nile red, Nile blue, cresyl violet, oxazine 170, proflavin, acridine orange, acridine yellow, auramine, crystal violet, malachite green, porphin, phthalocyanine, and bilirubin;

all other instances of X are independently hydrogen, an antibiotic, a fluorophore, or a biotin moiety of the formula:

one instance of n is 1, 2, or 3; and
the other two instances of n are independently 0, 1, 2, or 3;
provided that the molecular weight of each instance of X is less than 1,000 Da.

2. The compound of claim 1 , wherein the compound is of the formula:

or a salt thereof.

3. The compound of claim 1 , wherein the compound is of the formula:

or a salt thereof.

4. The compound of claim 1 , or a salt thereof, wherein at least one instance of L is hydrolytically stable under physiological conditions.

5. The compound of claim 1 , or a salt thereof, wherein at least one instance of L is hydrolytically unstable under physiological conditions.

6. The compound of claim 1 , or a salt thereof, wherein:
each instance of L is independently a bond or a substituted or unsubstituted C 1-100 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —O—, —S—, —NR L —, —S(═O)—, —S(═O) 2 —, or substituted or unsubstituted heteroarylene; and
each instance of R L is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group.

7. The compound of claim 6 , or a salt thereof, wherein one carbon unit of at least one instance of L is replaced with unsubstituted heteroarylene of the formula:

8. A method of preparing a compound of claim 7 , or a salt thereof, the method comprising:
contacting a compound of Formula (A1):

or a salt thereof, with a compound of Formula (B1):
X-L B -C≡CH   (B1),

or a salt thereof, or contacting a compound of Formula (A2):

or a salt thereof, with a compound of Formula (B2):
X-L B -N 3    (B2),

or a salt thereof;
wherein:
each instance of L A is independently a bond or substituted or unsubstituted C 1-17 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —O—, —S—, —NR LA —, —S(═O)—, or —S(═O) 2 —;
each instance of R LA is independently hydrogen, unsubstituted C 1-6 alkyl, C 1-6 alkyl substituted with at least one halogen, or a nitrogen protecting group;
one instance of m is 1, 2, or 3;
two instances of m are independently 0, 1, 2, or 3;
each instance of L B is independently a bond or substituted or unsubstituted C 1-17 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —O—, —S—, —NR LB —, —S(═O)—, or —S(═O) 2 —; and
each instance of R LB is independently hydrogen, unsubstituted C 1-6 alkyl, C 1-6 alkyl substituted with at least one halogen, or a nitrogen protecting group.

9. The compound of claim 6 , or a salt thereof, wherein one carbon unit of each instance of L is replaced with unsubstituted heteroarylene of the formula:

10. The compound of claim 6 , or a salt thereof, wherein at least one instance of L is of the formula:

wherein:
L 1 and L 4 are independently —NR L C(═O)— or —C(═O)NR L —;
L 2 and L 3 are independently unsubstituted C 1-50 alkylene or C 1-50 alkylene substituted with at least one halogen, optionally wherein one to six carbon units of the C 1-50 alkylene are replaced with —O—;
L 5 is a bond, unsubstituted C 1-6 alkylene, or C 1-6 alkylene substituted with at least one halogen, optionally wherein one or two carbon units of the C 1-6 alkylene are replaced with —O—; and
L 6 is unsubstituted C 2-90 alkylene, or C 2-90 alkylene substituted with at least one halogen, optionally wherein one to eight carbon units of the C 2-90 alkylene are replaced with —O—.

11. The compound of claim 10 , wherein the compound is of the formula:

or a salt thereof.

12. The compound of claim 10 , wherein the compound is of the formula:

or a salt thereof.

13. The compound of claim 1 , or a salt thereof, wherein the molecular weight of at least one instance of X is less than 300 Da.

14. The compound of claim 1 , or a salt thereof, wherein the molecular weight of at least one instance of X is less than 600 Da.

15. The compound of claim 1 , or a salt thereof, wherein at least one instance of X is an antibiotic selected from the group consisting of β-lactam antibiotics, aminoglycoside antibiotics, ansamycin antibiotics, glycopeptide antibiotics, lincosamide antibiotics, lipopeptide antibiotics, macrolide antibiotics, nitrofuran antibiotics, oxazolidonone antibiotics, quinolone antibiotics, sulfonamide antibiotics, and tetracycline antibiotics.

16. The compound of claim 15 , or a salt thereof, wherein the antibiotic is effective against a Gram-negative bacterium.

17. The compound of claim 16 , or a salt thereof, wherein the Gram-negative bacterium is an Escherichia species, a Pseudomonas species, a Klebsiella species, a Salmonella species, or an Acinetobacter species.

18. The compound of claim 17 , or a salt thereof, wherein the Gram-negative bacterium is an Escherichia coli strain or a Pseudomonas aeruginosa strain.

19. The compound of claim 15 , or a salt thereof, wherein the antibiotic is a β-lactam

Assignees

• Massachusetts Inst Technology

Inventors

• Nolan Elizabeth Marie
• Zheng tengfei
• Chairatana Phoom

Classifications

• A61K31/496 Primary

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K47/549

  Sugars, nucleosides, nucleotides or nucleic acids · CPC title

• C07H7/04

  Carbocyclic radicals · CPC title

• C12Q1/06 Primary

  Quantitative determination · CPC title

• A61K47/545

  Heterocyclic compounds (A61K47/558 takes precedence) · CPC title