Glycosylated histone deacetylase inhibitors and methods of making and using the same
Provided herein are glycosylated compounds as histone deacetylase (HDACi) inhibitors or a diastereomer, solvate, or a pharmaceutically acceptable salt thereof. Also provided are pharmaceutical compositions and medicaments that include the compounds described herein as well as methods of treating inflammatory disease and cancer.
1 . A compound of Formula I:
wherein:
X is O or NCH 3 ;
R 1 is absent, H, COCH 3 , CH 3 , C 1-6 alkyl, C 1-6 alkanoate, C 2-6 carbamate, or C 5-6 aryl ester, optionally substituted with heteroatoms;
R 2 and R 3 are each independently H, OH or OR 4 ;
R 4 is C 1-6 alkyl, C 1-6 alkanoate, C 2-6 carbamate, or C 5-6 aryl ester, optionally substituted with heteroatoms;
Y is O;
A is substituted or unsubstituted aryl;
B is absent or 1,2,3-triazolyl;
C is C 2-8 alkyl, optionally substituted with one or more double bonds;
D is H, F, OH, OCOCH 3 , NH 2 , OR 5 , or NHR 5 ;
R 5 is C 1-6 alkanoate, C 2-6 carbamate, C 5-6 aryl ester optionally substituted with heteroatoms, or C 5-6 fused aryl ester optionally substituted with heteroatoms; and
ZBG is selected from
wherein Z is halo or heteroaryl;
or a diastereomer, solvate, or a pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 , wherein R 1 is H, COCH 3 , or CH 3 .
3 . The compound of claim 1 , wherein R 2 and R 3 are OH.
4 . The compound of claim 1 , wherein X is O.
5 . The compound of claim 1 , wherein D is OH or OCOCH 3 .
6 . The compound of claim 1 , wherein B is a 1,2,3-triazole.
7 . The compound of claim 1 , wherein C is five to six —CH 2 — groups.
8 . The compound of claim 1 , wherein ZBG is N-(2-amino-5-fluorophenyl)acylamide.
9 . The compound of claim 1 , wherein ZBG is N-(2-amino-5-(thiophen-2-yl)phenyl)-acylamide.
10 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a diastereomer, solvate, or a pharmaceutically acceptable salt thereof.
11 . A pharmaceutical composition comprising:
the compound of claim 1 or a pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable carrier, adjuvant or vehicle.
12 . A method of inhibiting histone deacetylases comprising:
contacting the histone deacetylase cells with the compound of claim 1 or a pharmaceutical composition thereof.
13 . A method of treating a histone deacetylase dysfunction-driven disease, disorder or condition in a subject in need thereof comprising:
administering to the subject a therapeutically effective amount of the compound of claim 1 or a pharmaceutical composition thereof.
14 . The method of claim 13 , wherein the histone deacetylase dysfunction-driven disease, disorder or condition is an inflammatory disease or cancer.
15 . A method of treating an inflammatory disease, disorder or condition in a subject in need thereof comprising:
administering to the subject a therapeutically effective amount of the compound of claim 1 or a pharmaceutical composition thereof.
16 . The method of claim 15 , wherein the inflammatory disease is selected from the group consisting of acute and chronic inflammatory disorders, sepsis, acute endotoxemia, encephalitis, Chronic Obstructive Pulmonary Disease (COPD), allergic inflammatory disorders, asthma, pulmonary fibrosis, arthritis, rheumatoid arthritis, osteoarthritis, inflammatory osteolysis, ulcerative colitis, psoriasis, vasculitis, autoimmune disorders, thyroiditis, Meliodosis, (mesenteric) Ischemia reperfusion, and Inflammatory Bowel Disease (IBD).
17 . A method of treating a cancer in a subject in need thereof comprising:
administering to the subject a therapeutically effective amount of the compound of claim 1 or a pharmaceutical composition thereof.
18 . The method of claim 17 , wherein the cancer is selected from the group consisting of squamous cell carcinoma, small-cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, squamous cell lung cancer, liver cancer, and breast cancer.
19 . The method of claim 17 , wherein the cancer is liver cancer.