Inhibitors of protein fucosylation and uses thereof
AssigneeSimon Fraser University
InventorsDavid J. VOCADLO, Robert BRITTON, Yang WANG, Venkata Narasimharao THOTA, Anthony FERS-LIDOU
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Abstract
The present invention relates to inhibitors of protein fucosylation. More specifically, the present invention relates to carbacyclic compounds of Formula (I) useful as inhibitors of protein fucosylation, or for treating a cancer, an autoimmune disease, an infectious disease, an inflammatory disease, or sickle cell disease.
Claims21
A method of inhibiting fucosylation of a protein, or fragment or derivative thereof, comprising contacting a eukaryotic cell or a mammal with a compound of Formula (I) or a salt thereof:
- wherein
- R1 is optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkenyl, or optionally substituted C1-C10 alkynyl;
- R2 is H or —C(═O)(C1-C6)alkyl;
- R3 is halo, OH, or O—C(═O)(C1-C6)alkyl;
- and
- R4 is H, —C(═O)(C1-C6)alkyl, or —P(═O)(OR5)(OR6), wherein R5 and R6 are each independently H, (C1-C6)alkyl, (CH2)2SC(═O)CH3, CH2OC(═O)OR7 or CH2OC(═O)R7 wherein R7 is C1-C8 alkyl, or wherein R5 and R6 are connected to form a ring,
- wherein fucosylation of the protein is reduced by at least 5% in the eukaryotic cell or mammal relative to the amount of fucosylation of the protein in the absence of administration of the compound.
A mammalian cell culture medium comprising an effective amount of a compound of Formula (I) or a salt thereof:
- wherein
- R1 is optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkenyl, or optionally substituted C1-C10 alkynyl;
- R2 is H or —C(═O)(C1-C6)alkyl;
- R3 is halo, OH, or O—C(═O)(C1-C6)alkyl;
- and
- R4 is H, —C(═O)(C1-C6)alkyl, or —P(═O)(OR5)(OR6), where R5 and R6 are each independently H, (C1-C6)alkyl, (CH2)2SC(═O)CH3, CH2OC(═O)OR7 or CH2OC(═O)R7 wherein R7 is C1-C8 alkyl, or where R5 and R6 are connected to form a ring.
A method of treating a cancer, an autoimmune disease, an infectious disease, an inflammatory disease, or sickle cell disease comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
- wherein
- R1 is optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkenyl, or optionally substituted C1-C10 alkynyl;
- R2 is H or —C(═O)(C1-C6)alkyl;
- R3 is halo, OH, or O—C(═O)(C1-C6)alkyl;
- and
- R4 is H, —C(═O)(C1-C6)alkyl, or —P(═O)(OR5)(OR6), wherein R5 and R6 are each independently H, (C1-C6)alkyl, (CH2)2SC(═O)CH3, CH2OC(═O)OR7 or CH2OC(═O)R7 wherein R7 is C1-C8 alkyl, or wherein R5 and R6 are connected to form a ring, to a mammal in need thereof.
(canceled)
A compound of Formula (II) or a pharmaceutically acceptable salt thereof:
- wherein
- R1 is optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkenyl, or optionally substituted C1-C10 alkynyl;
- R2 is H or —C(═O)(C1-C6)alkyl;
- R3 is halo, OH, or O—C(═O)(C1-C6)alkyl;
- and
- R4 is H, —C(═O)(C1-C6)alkyl, or —P(═O)(OR5)(OR6)], wherein R5 and R6 are each independently H, (C1-C6)alkyl, (CH2)2SC(═O)CH3, CH2OC(═O)OR7 or CH2OC(═O)R7 wherein R7 is C1-C8 alkyl, or wherein R5 and R6 are connected to form a ring,
- wherein when R1 is CH3, R2 is not H, R3 is not OH, and R4 is not H.
Dependencies are inferred from the claim text.