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US-12617813-B2 - Glycosylated histone deacetylase inhibitors and methods of making and using the same

US12617813B2US 12617813 B2US12617813 B2US 12617813B2US-12617813-B2

Abstract

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.

Inventors

  • Adegboyega Oyelere
  • Subhasish Tapadar
  • Bocheng Wu

Assignees

  • GEORGIA TECH RESEARCH CORPORATION

Dates

Publication Date
20260505
Application Date
20211228

Claims (19)

  1. 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. 2 . The compound of claim 1 , wherein R 1 is H, COCH 3 , or CH 3 .
  3. 3 . The compound of claim 1 , wherein R 2 and R 3 are OH.
  4. 4 . The compound of claim 1 , wherein X is O.
  5. 5 . The compound of claim 1 , wherein D is OH or OCOCH 3 .
  6. 6 . The compound of claim 1 , wherein B is a 1,2,3-triazole.
  7. 7 . The compound of claim 1 , wherein C is five to six —CH 2 — groups.
  8. 8 . The compound of claim 1 , wherein ZBG is N-(2-amino-5-fluorophenyl)acylamide.
  9. 9 . The compound of claim 1 , wherein ZBG is N-(2-amino-5-(thiophen-2-yl)phenyl)-acylamide.
  10. 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. 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. 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. 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. 14 . The method of claim 13 , wherein the histone deacetylase dysfunction-driven disease, disorder or condition is an inflammatory disease or cancer.
  15. 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. 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. 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. 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. 19 . The method of claim 17 , wherein the cancer is liver cancer.

Description

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with government support under NIH RO1 CA131217 awarded by the National Institutes of Health. The government has certain rights in the invention. TECHNICAL FIELD OF THE INVENTION Aspects of the invention are generally directed to small molecule inhibitors of the histone deacetylase (HDACi) and methods of making and using thereof. BACKGROUND OF THE INVENTION Histone deacetylases (HDACs) and histone acetyl transferase (HAT) are functionally opposing epigenetic regulators which control the acetylation states on histones and several non-histone proteins. HDACs, as part of multiprotein complexes, facilitate the removal of acetyl groups from the ε-amino groups of specific lysine residues of nucleosomal core histones and other proteins (Gryder, B.; Sodji, Q. H.; Oyelere, A. K. Targeted Cancer Therapy: Giving Histone Deacetylase Inhibitors All They Need to Succeed. Future Med. Chem. 4, 505-524 (2012)). Eighteen HDAC isoforms have been identified to date in human cells. These HDACs are grouped into four classes based on their homology to three Saccharomyces cerevisiae HDACs (RPD3, HDA1, and SIR2). Class I HDACs (HDACs 1, 2, 3 and 8); Class II HDACs (HDACs 4, 5, 6, 7, 9 and 10) and Class IV (HDAC 11) are zinc-dependent protein deacetylases. The Class III of HDACs consist of the sirtuins (SIRT 1-7), which are homologically distinct from the other HDACs and are NAD+-dependent deactylases (Yoshida, M.; Kudo, N.; Kosono, S.; Ito, A. Chemical and structural biology of protein lysine deacetylases. Proc. Jpn. Acad., Ser. B 93, 297-321 (2017)). Dysfunction in the activities of HDACs have been linked to several diseases including cancers, inflammation disorders, tissue fibrosis, cognitive disorders, cardiovascular diseases, neurological diseases and parasitic protozoan's diseases such as malaria, Chagas, trypanosomiasis and leishmaniasis. While several of these disease states could benefit from the inhibition of HDACs activities, much attention has been directed towards cancers (Gryder, B.; Sodji, Q. H.; Oyelere, A. K. Targeted Cancer Therapy: Giving Histone Deacetylase Inhibitors All They Need to Succeed. Future Med. Chem. 4, 505-524 (2012)). Specifically, upregulation of HDAC activities, which results in silencing of tumor suppressor genes and uncontrolled proliferation, predominates in malignant tumors. One of the early examples of small molecule HDAC inhibitor (HDACi) was reported by Yoshida et al. who showed that the natural product (R)-trichostatin A induced cell differentiation of murine erythroleukemia cells and hyperacetylation of histone proteins at nanomolar concentrations (Yoshida, M.; Kijima, M.; Akita, M.; Beppu, T., J. Biol. Chem. 265, 17174-17179 (1990); Yoshida, M.; Hoshikawa, Y.; Koseki, K.; Mori, K.; Beppu, T., J. Antibiot. 43, 1101-1106 (1990)). Subsequently, several HDAC inhibitors (HDACi) have been reported by other researchers (West, A. C.; Johnstone, R. W. J. Clin. Invest. 124, 30-39 (2014); Eckschlager, R.; Plch, J.; Stiborova, M.; Hrabeta, J. Histone Deacetylase Inhibitors as Anticancer Drugs. Int. J. Mol. Sci. 18, 1414 (2017)). These prior reports have contributed to the clinical validation of HDAC inhibition as cancer therapy strategy with the approval of Vorinostat, Romidepsin, Belinostat, Chidamide and Panabinostat (Tapadar, S.; Fathi, S.; Raji, I.; Omesiete, W.; Kornacki, J. R.; Mwakwari, S. C.; Miyata, M.; Mitsutake, K.; Li, J.-D.; Mrksich, M.; Oyelere, A. K. A structure-activity relationship of non-peptide macrocyclic histone deacetylase inhibitors and their antiproliferative and anti-inflammatory activities. Bioorg. Med. Chem. 23, 7543-7564 (2015)). However, current HDACi have elicited limited therapeutic benefit against most solid tumors. HDACi have elicited antiproliferative activities against nearly all transformed cell types, including epithelial (melanoma, lung, breast, pancreas, ovary, prostate, colon and bladder) and hematological (lymphoma, leukemia and multiple myeloma) tumors (Kelly, W. K; O'Connor, O. A.; Marks, P. A., Expert. Opin. Investig. Drugs, 11, 1695-1713 (2002)). Similar to other cancers, liver cancers including hepatocellular carcinoma (HCC) and cholangiocarcinoma, are driven by genetic mutations and epigenetic dysfunctions including gene-silencing chromatin histone hypoacetylation (Rikimaru, T.; Taketomi, A.; Yamashita, Y.; Shirabe, K.; Hamatsu, T.; Shimada, M.; Maehara, Y. Clinical significance of histone deacetylase 1 expression in patients with hepatocellular carcinoma. Oncology 72, 69-74 (2007); Ma, B. B.; Sung, F.; Tao, Q.; Poon, F. F.; Lui, V. W.; Yeo, W.; Chan, S. L.; Chan, A. T. The preclinical activity of the histone deacetylase inhibitor PXD101 (belinostat) in hepatocellular carcinoma cell lines. Invest New Drugs 28, 107-114 (2010); Yeo, W.; Chung, H. C.; Chan, S. L.; Wang, L. Z. et al Epigenetic Therapy Using Belinostat for Patients With Unresectable Hepatocellular Carcinoma: A Multicenter