New application of benzofuran terphenyl compound as HIF inhibitor

Abstract

The invention discloses a novel medical application of a micromolecular benzofuran terphenyl compound for inhibiting HIF transcriptional activity. The compound provided by the invention has obvious HIF transcriptional inhibition activity, and is used for preparing medicines for preventing or treating related diseases caused by HIF, and HIF-mediated related diseases comprise tumor growth and metastasis, tumor drug resistance and the like.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and particularly relates to a benzofuran terphenyl compound, a composition and an application thereof. The compound or composition has the activity of being a hypoxia-inducible factor (HIF) inhibitor and can be used for treating HIF-related diseases. Background Art

[0002] Hypoxia-inducible factor (HIF) is a nuclear protein with transcriptional activity, which plays a key role in the process of cell adaptation to hypoxia. It is a heterodimer composed of HIF-1α and HIF-1β subunits. Under normal oxygen partial pressure, the HIF-α subunit will be hydroxylated by prolyl hydroxylase (PHD) and then rapidly degraded by the ubiquitin-proteasome pathway (Bruick, R.K. Science. 2001, 294: 1337-1340; Kamura, T. Proc. Natl. Acad. Sci. U.S.A. 2000, 97: 10430-10435). However, under hypoxic conditions, the activity of PHD is inhibited, the HIF-α subunit is stabilized and binds to the HIF-1β subunit to form an active HIF transcription factor, which translocates into the nucleus and initiates the transcription of a series of hypoxia-responsive genes, such as the erythropoietin (EPO) gene, the vascular endothelial growth factor (VEGF) gene, matrix metalloproteinases (MMPs), etc. (Semenza, G.L. Trends Pharmacol. Sci. 2012, 33: 207-214; Wigerup, C. Pharmacol. Ther. 2016, 164: 152-169). These gene products play a crucial role in improving hypoxia, promoting angiogenesis, regulating energy metabolism, etc.

[0003] HIF is associated with a variety of diseases, and the abnormal activation or inactivation of HIF is closely related to the occurrence and development of many diseases. In tumor diseases, tumor cells activate the HIF signaling pathway in order to adapt to the hypoxic environment caused by rapid proliferation (Ke, Q. Molecular Pharmacology 2006, 70(5): 1469-1480; Li, H. Adv. Sci. 2023, 2301071). HIF can promote tumor angiogenesis, enabling tumor cells to obtain sufficient oxygen and nutrients. At the same time, it can also regulate the metabolism of tumor cells, enabling them to adapt to the hypoxic environment and enhancing their invasion and metastasis abilities. For example, in various solid tumors such as breast cancer, liver cancer, and lung cancer, high expression of HIF-1α has been found to be associated with poor prognosis of tumors (Moon, E. J. Antioxid. Redox Signaling. 2007, 9: 1237-1294; Chen, C. OncoTarget. 2017, 8: 46691-46703; Kim, B. J. Transl. Med. 2013, 11: 185). Therefore, HIF-1 is considered a promising target for developing new anti-cancer metastasis therapies. In addition, in ischemic diseases such as myocardial ischemia and cerebral ischemia, moderate activation of the HIF pathway can promote angiogenesis and tissue repair, with potential therapeutic value (Zimna, A. BioMed Research International 2015, 1-14). There are also research reports on HIF-1 as a target for neurodegenerative diseases (Zhang, Z. Current Medicinal Chemistry. 2011, 18(28): 4335-4343).

[0004] Terphenyls are mainly derived from fungi and actinomycetes and mainly exist in the form of p-terphenyls in nature. The structural feature of terphenyl is composed of a central benzene ring B and two phenyl groups (ring A and C) substituted at the para positions of benzene ring B. So far, more than 230 terphenyls have been identified, and the number is still increasing. This compound exhibits various biological activities, such as anti-inflammatory, antibacterial, antioxidant, and α-glucosidase inhibitory effects (Zhou G. Marine Life Science & Technology. 2022, 4: 62–73). In recent years, a large number of bioactive p-terphenyls have been reported. Chen et al. reported that the benzofuran terphenyl compound candidusin A found from the marine compound library is a potent AMPK activator and can be used as a new potential candidate for the treatment of non-alcoholic steatohepatitis (NASH) (Chen J. Marine Life Science & Technology. 2023, 5: 196). However, the inhibitory activity of this type of compound against HIF has not been reported, and its application in the preparation of drugs for preventing or treating HIF-mediated diseases has not been seen either. Summary of the Invention

[0005] Only some aspects of the present invention are briefly described below and are not limited thereto. These aspects and other parts are more fully described later. All references in this specification are incorporated herein by reference in their entirety. When there are differences between the disclosure of this specification and the cited literature, the disclosure of this specification shall prevail.

[0006] The present invention provides a benzofuran terphenyl compound for treating diseases related to HIF activation, including but not limited to tumor growth and metastasis, tumor drug resistance, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), diabetic nephropathy, non-alcoholic fatty liver disease (NAFLD), etc. The compounds of the present invention are easy to prepare, have stable properties and strong activities, and thus have good clinical application prospects.

[0007] Specifically:

[0008] On the one hand, the present invention relates to a terphenyl compound, characterized in that it is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I), especially for use as an HIF inhibitor, and the compound has the following structure:

[0009]

[0010] Compound 1 has been disclosed in the literature

[0011] Jin Chen, Li Xu, Xue-Qing Zhang, Xue Liu, Zi-Xuan Zhang, Qiu-Mei Zhu, Jian-Yu Liu, Muhammad Omer Iqbal, Ning Ding, Chang-Lun Shao, Mei-Yan Wei, and Yu-Chao Gu. Discovery of a natural small-molecule AMP-activated kinase activator that alleviates nonalcoholic steatohepatitis[J]Marine Life Science & Technology, 2023, 5, 196 - 210.

[0012] On the other hand, the present invention relates to a pharmaceutical composition comprising the compound disclosed in the present invention. The pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, solvent or a combination thereof.

[0013] The term "pharmaceutically acceptable salt" in the present invention refers to a non-toxic addition salt of an inorganic or organic acid and / or base; see "Salt selection for basic drugs", International Journal of Pharmaceutics. 1986, 33, 201–217.

[0014] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0015] The present invention discloses for the first time a benzofuran terphenyl compound as a HIF inhibitor, which has good application prospects and commercial value.

[0016] The "HIF-related disease" refers to a series of diseases caused by the overexpression or abnormal regulation of hypoxia-inducible factor (HIF), which in turn leads to disorders of the body's physiological functions, including any disease in which a decrease in HIF levels will bring beneficial effects. HIF-related diseases include, but are not limited to, tumor growth and metastasis, tumor drug resistance, diabetic nephropathy, etc. Detailed implementation mode

[0017] The following specific examples are used to further illustrate the present invention, but the present invention is by no means limited to these examples.

[0018] Example 1 HIF transcriptional inhibition activity test

[0019] (1) Active test cell model: HCT 116 (human colon cancer cells) infected with lentiviral vector.

[0020] (2) Test method: Seed HCT116 cells into 24-well plates and culture them in DMEM containing 10% FBS for 24 h. After the cells adhere to the wall, co-transfect the VEGF 5×HRE-Firefly Luciferase plasmid and the CMV-RenillaLuciferase plasmid into the cells using the transfection reagent PEI. After 24 h of plasmid expression, add the compound of the present invention and treat the cells under hypoxic conditions (1% O2) for 24 h. Then, lyse the cells using 1× cell lysis buffer and perform the Dual-Luciferase experiment using a Dual-Luciferase assay kit to detect the effect of the compound on HIF transcriptional activity.

[0021] (3) Calculate the inhibition rate according to the following formula: Inhibition rate = (1 - Luciferase value of the compound treatment group / Luciferase value of the hypoxic control group) × 100%

[0022] Table 1 Inhibitory effect of the compounds of the present invention on HIF transcription IC 50 value

[0023] Compound <![CDATA[IC 50 (μM)]]> Compound <![CDATA[IC 50 (μM)]]> 1 ++++ A +

[0024] Note: In the table, "++++" indicates IC 50 <0.1 μM; "+++" indicates 0.1 < IC 50 ≤0.5 μM; "++" indicates IC 50 is 0.5 < IC 50 ≤1 μM; "+" indicates IC 50 >1 μM. IC 50 value is the half-maximal inhibitory concentration.

[0025] Note: Compound A of the present invention was tested in parallel as a control. as a control.

[0026] Conclusion: Compound 1 of the present invention has strong inhibitory activity on HIF transcription, and the IC 50 value is less than 0.1 μM, indicating that this compound can be used to treat diseases such as tumor growth and metastasis, tumor drug resistance, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), diabetic nephropathy, non-alcoholic fatty liver disease (NAFLD), cardiovascular diseases, and neurological diseases.

[0027] Note that there are other ways to implement the present invention; accordingly, the embodiments of the present invention are illustrated by way of example and are not limited to the content described in the present invention, and may also be modifications made within the scope of the present invention or equivalent content added in the claims; all publications or patents cited in the present invention will be used as references for the present invention.

Claims

1. A benzofuran terphenyl compound, characterized in that, It is a compound represented by formula (1) or a stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof, especially for use as a HIF inhibitor, characterized in that the compound has the following structure:

2. A drug capable of treating and / or preventing diseases caused by hypoxia-inducible factor (HIF), characterized in that It contains the compound described in claim 1, or its stereoisomer, geometric isomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug as an active ingredient.

3. Use of the drug described in claim 2 in the treatment and / or prevention of diseases related to hypoxia-inducible factor (HIF), said diseases including those related to HIF such as tumor growth and metastasis, tumor drug resistance, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), diabetic nephropathy, non-alcoholic fatty liver disease (NAFLD), cardiovascular diseases, and nervous system diseases.

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