Fucosyltransferase specific inhibition using fucose mimetics
View Patent ↗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.
1. A fucose mimetic compound having Structure A
and/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 the group consisting of 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 fat acid with saturated and 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 X′ is C, S, S═O, SO 2 , O, or N.
2. The fucose mimetic compound according to claim 1 having Structure B
wherein the five member cycle is substituted with up to four R 3 substituents; wherein each R 3 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, amino, thiol, sulfide, keto, formyl, carboxyl, azide, ester, amide, and anhydride thereof; X′ is C, S, S═O, SO 2 , O, or N; and wherein X′ can be present in any position of the five member cycle.
3. The fucose mimetic compound according to claim 1 having Structure C
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.
4. The fucose mimetic compound according to claim 1 having Structure D
wherein the dotted line is an aliphatic or heteroaliphatic ring substituted with up to twelve R 5 substituents; n is an integer selected from the group consisting of 2, 3, 4, 5, and 6; X′ is C, S, S═O, SO 2 , O, or N; wherein each R 5 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, amino, thiol, sulfide, keto, formyl, carboxyl, azide, ester, amide, and anhydride; and wherein X′ can be present in any position of the aliphatic or heteraliphatic ring.
5. A fucose mimetic compound having Structure E
and/or a therapeutically effective salt thereof, wherein:
X and Y each independently are 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, 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, (D/L)-cysteine, a mono-, di-, tri-thiol containing molecule, a fat acid with saturated and unsaturated alkyl chains, a natural ceramide, a sulphonamide, and a myristoyl-Gly-Cys molecule, or R can form an ester with the adjacent oxygen atom.
6. A composition comprising the fucose mimetic compound and/or a multivalent system containing the fucose mimetic compound according to claim 1 .
7. The composition according to claim 6 comprising a therapeutically effective amount of
and a pharmaceutically acceptable carrier.
8. The composition according to claim 6 comprising a therapeutically effective amount of
and a pharmaceutically acceptable carrier.
9. A composition comprising the fucose mimetic compound and/or a multivalent system containing the fucose mimetic compound according to claim 5 , wherein the compound is compound 9
and a pharmaceutically acceptable carrier.
10. A composition comprising the fucose mimetic compound and/or a multivalent system containing the fucose mimetic compound according to claim 5 , wherein the compound is compound 10
and a pharmaceutically acceptable carrier.
11. A composition comprising the fucose mimetic compound and/or a multivalent system containing the fucose mimetic compound according to claim 5 , wherein the compound is
and a pharmaceutically acceptable carrier.
12. The fucose mimetic compound of claim 5 , wherein R is independently selected from hydrogen, (D/L)-cysteine, a fat acid with saturated and unsaturated alkyl chains, a natural ceramide, and a sulphonamide, or R can form an ester with the adjacent oxygen atom.