Fucosyltransferase specific inhibition using fucose mimetics

Patent metadata

Field	Value
Publication number	US-12486298-B2
Application number	US-202218075625-A
Country	US
Kind code	B2
Filing date	Dec 6, 2022
Priority date	Dec 29, 2020
Publication date	Dec 2, 2025
Grant date	Dec 2, 2025

Abstract

Provided are compositions and methods for specific fucosyltransferase inhibition for treatment of a variety of diseases. The compositions of the invention comprise a glycomimetic of L-Fucose that selectively inhibits the generation of sialyl Lewis X by FTVI and FTVII but has no effect on the generation of Lewis X by FTIX.

First claim

We claim:

1 . A method for treating a subject who suffers from a disease or condition that can be treated and/or prevented by a modification of fucosylated cell surface glycoconjugates, wherein the method comprises administering to a subject in need of such treatment a therapeutically effective amount of a composition comprising a compound that inhibits a fucosyltransferase, wherein the inhibition of the fucosyltransferase induces a modification of fucosylated cell surface glycoconjugates in the subject, wherein the compound has Structure A, Structure C or Structure E;
wherein Structure A is as follows:

or a therapeutically effective salt thereof:
wherein the dotted line is an aliphatic, an aromatic, a heteroaliphatic, or a heteroaromatic ring and is substituted with at least one R 1 , wherein the ring can be substituted with any number of R 1 substituents up to the maximum number permitted by the structure of the ring, and n is an integer selected from 2, 3, 4, 5, 6, 7 and 8;
wherein at each occurrence R is hydrogen or a group selected from hydroxyl, alkoxy, amino, thiol, sulfoxide, sulfone, sulfonamide, sulphate, sulfonate, keto, formyl, carboxylic, azido, (mono-, di, tri-) phosphate, (mono-, di-, tri-) phosphonate, ester, amide, and anhydride wherein said group further comprises a protecting group, wherein the protecting group can form an ester with the adjacent oxygen atom or is independently selected from (D/L)-cysteine, a mono-di-, tri-thiol containing molecule, a fatty acid molecule with saturated or unsaturated alkyl chains, a natural ceramide, a sulphonamide, and a myristoyl-Gly-Cys molecule;
wherein at each occurrence R 1 is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-aryl, a substituted or unsubstituted polycyclic group, amino, thiol, sulfide, keto, formyl, carboxyl, azide, phosphyl, ester, amide, and anhydride, wherein the substituents are selected from keto, amino, phosphate, halogen, hydroxyl, nitro, alkyl, alkenyl, aryl, formyl, and acetyl;
wherein X and Y are independently CH 2 , S, S═O, SO 2 , O, or NH;
R 2 is CH 2 R″, CH 2 OR″, CH 2 N(R″) 2 , or CH 2 SR″; R″ is selected from the group consisting of hydrogen, hydroxyl, amino, thiol, sulfide, keto, formyl, carboxyl, azide, (mono-, di-, tri-) phosphate, (mono-, di-, tri-) phosphonate, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and
wherein X′ is C, S, S═O, SO 2 , O, or N;
wherein Structure C is as follows:

or a therapeutically effective salt thereof:
wherein at each occurrence R is hydrogen or a group selected from hydroxyl, alkoxy, amino, thiol, sulfoxide, sulfone, sulfonamide, sulphate, sulfonate, keto, formyl, carboxylic, azido, (mono-, di, tri-) phosphate, (mono-, di-, tri-) phosphonate, ester, amide, and anhydride wherein said group further comprises a protecting group, wherein the protecting group can form an ester with the adjacent oxygen atom or is independently selected from (D/L)-cysteine, a mono-di-, tri-thiol containing molecule, a fatty acid molecule with saturated or unsaturated alkyl chains, a natural ceramide, a sulphonamide, and a myristoyl-Gly-Cys molecule;
wherein X and Y are independently CH 2 , S, S═O, SO 2 , O, or NH;
R 2 is CH 2 R″, CH 2 OR″, CH 2 N (R″) 2 , or CH 2 SR″; R″ is selected from the group consisting of hydrogen, hydroxyl, amino, thiol, sulfide, keto, formyl, carboxyl, azide, (mono-, di-, tri-) phosphate, (mono-, di-, tri-) phosphonate, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and wherein X′ is C, S, S═O, SO 2 , O, or N;
wherein the six member cycle is substituted with up to four R 4 substituents wherein each R 4 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-aryl, amino, thiol, sulfide, keto, formyl, carboxyl, azide, ester, amide, and anhydride, wherein the substituents are selected from keto, amino, phosphate, halogen, hydroxyl, nitro, alkyl, alkenyl, aryl, formyl, and acetyl; and
X′ is C, S, S═O, SO 2 , O, or N; and wherein X′ can be present in any position of the six member cycle;
and wherein Structure E is as follows:

or a therapeutically effective salt thereof, wherein:
X and Y are each independently selected from CH 2 , S, S═O, SO 2 , O, or NH;
R 2 is selected from CH 2 R″, CH 2 OR″, CH 2 N (R″) 2 , or CH 2 SR″; R″ is selected from hydrogen, hydroxyl, amino, thiol, sulfide, keto, formyl, carboxyl, (mono-, di-, tri-) phosphate, (mono-. di-, tri-) phosphonate group, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
R 6 is selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted polycyclic group, amino, thiol, sulfide, keto, formyl, carboxyl, azide, phosphyl, ester, amide, and anhydride; wherein the substituents are selected from halogen, hydroxyl, alkoxy, nitro, alkyl, alkenyl, aryl, formyl, and acetyl;
R 7 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted polycyclic group, amino, thiol, sulfide, keto, formyl, carboxyl, azide, phosphyl, ester, amide, and anhydride; wherein the substituents are selected from halogen, hydroxyl, alkoxy, nitro, alkyl, alkenyl, aryl, formyl, acetyl; and
R is independently selected from hydrogen, ester, (D/L)-cysteine, a mono-di-, tri-thiol containing molecule, a fatty acid molecule with saturated and unsaturated alkyl chains, a natural ceramide, a sulphonamide, or a myristoyl-Gly-Cys molecule or R can form an ester with the adjacent oxygen atom; wherein the disease is an acute inflammatory disease, a chronic inflammatory disease, diabetes, cystic fibrosis, or a cancer.

2 . The method according to claim 1 , wherein the compound inhibits a fucosyltransferase VI or fucosyltransferase VII.

3 . The method according to claim 1 , wherein the acute inflammatory disease is a reperfusion injury, a septic shock, a bacterial infection, a viral infection, or a parasitic infection.

4 . The method according to claim 1 , wherein the chronic inflammatory disease is asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, or juvenile idiopathic arthritis.

5 . The method according to claim 1 , wherein the disease is cancer and the method further comprises administering the composition directly into a tumor, a tissue surrounding the tumor and/or a blood vessel supplying the tumor.

6 . The method according to claim 1 , wherein the compound has Structure A.

7 . The method according to claim 1 , wherein the compound has Structure C.

Assignees

• The Florida International Univ Board Of Trustees
• Univ Of Florence

Inventors

• Sackstein Robert
• Richichi Barbara
• Martin Kyle

Classifications

• A61K47/6921

  the form being a particulate, a powder, an adsorbate, a bead or a sphere · CPC title

• A61K47/64

  Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65) · CPC title

• A61K31/7048

  having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin} · CPC title

• A61K47/6923

  the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb · CPC title

• C07H9/00 Primary

  Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical · CPC title