Inhibitors of polysialic acid de-N-acetylase and methods for using the same
AssigneeChildern's Hospital & Research Center at Oakland
InventorsGregory R. Moe, Brent T. Hagen
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Abstract
The invention relates to inhibitors of polysialic (PSA) de-N-acetylase, methods of their production and use. The methods involve use of a PSA de-N-acetylase inhibitor for modifying the growth of cells, such as inhibiting the growth of cancer cells. The compositions include an inhibitor of a PSA de-N-acetylase, such as N-substituted derivatives of the amino sugars hexosamine and neuraminic acid, as well as conjugates and aggregates. Also provided are pharmaceutical compositions that include a PSA de-N-acetylase inhibitor of the invention. Kits containing one or more inhibitor compositions of the invention, as well as methods of preparing the compositions also are provided.
Claims15
A method of inhibiting growth of a cancerous cell in a subject, said method comprising:
- administering to the subject a pharmaceutical composition comprising an effective amount of an inhibitor of a polysialic acid (PSA) de-N-acetylase in a pharmaceutically acceptable vehicle, wherein the inhibitor is a monomer of an N-substituted derivative of a hexosamine compound of formula (I):
- or the pharmaceutically acceptable salts, solvate, prodrug, anomers, tautomers and stereoisomers forms thereof;
- wherein R2 is a radical selected from the group consisting of —C(O)CH2F, —C(O)CH2Cl, —C(O)CH2Br, —C(O)CH2I, and —C(O)CH═CH2;
- each R1, R3, R4 and R6 is independently hydrogen or a substituted or unsubstituted moiety selected from the group consisting of heteroatom, cycloalkyl, heteroaryl, alkenyl, acetyl, sulfonyl, lipid, nucleic acid, peptide and polypeptide,
- with the proviso that said inhibitor of PSA de-N-acetylase is other than N-acryl glucosamine;
- an unacetylated or tetra-O-acetylated N-haloacetyl mannosamine;
- an unacetylated or tetra-O-acetylated N-haloacetyl galactosamine;
- and an unacetylated or tetra-O-acetylated N-haloacetyl glucosamine;
- and
- wherein said administering facilitates reduction in viability of cancerous cells exposed to said inhibitor.
A pharmaceutical composition comprising an effective amount of inhibitor of a polysialic acid (PSA) de-N-acetylase in a pharmaceutically acceptable vehicle, wherein said inhibitor is a monomer of an N-substituted derivative of a hexosamine compound of formula (I):
- or the pharmaceutically acceptable salts, and prodrug forms thereof, anomers, tautomers and stereoisomers thereof;
- wherein R2 is a radical selected from the group consisting of —C(O)CH2F, —C(O)CH2Cl, —C(O)CH2Br, —C(O)CH2I, and —C(O)CH═CH2;
- and
- each R1, R3, R4 and R6 is independently hydrogen or a substituted or unsubstituted moiety selected from the group consisting of heteroatom, cycloalkyl, heteroaryl, alkenyl, acetyl, sulfonyl, lipid, nucleic acid, peptide and polypeptide,
- with the proviso that said inhibitor of PSA de-N-acetylase is other than N-acryl glucosamine;
- an unacetylated or tetra-O-acetylated N-haloacetyl mannosamine;
- an unacetylated or tetra-O-acetylated N-haloacetyl galactosamine;
- and an unacetylated or tetra-O-acetylated N-haloacetyl glucosamine.
Dependencies are inferred from the claim text.