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WO2025037870A1 - Composé benzofurane et composition pharmaceutique le comprenant pour prévenir ou traiter des maladies cancéreuses et des métastases cancéreuses - Google Patents

Composé benzofurane et composition pharmaceutique le comprenant pour prévenir ou traiter des maladies cancéreuses et des métastases cancéreuses Download PDF

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Publication number
WO2025037870A1
WO2025037870A1 PCT/KR2024/011923 KR2024011923W WO2025037870A1 WO 2025037870 A1 WO2025037870 A1 WO 2025037870A1 KR 2024011923 W KR2024011923 W KR 2024011923W WO 2025037870 A1 WO2025037870 A1 WO 2025037870A1
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Prior art keywords
cancer
methyl
benzofuran
dihydrooxepino
alkyl
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English (en)
Korean (ko)
Inventor
이경
성낙균
한호진
시바라만애니시
류인자
한준열
김민경
송모은
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Korea Research Institute of Bioscience and Biotechnology KRIBB
Industry Academic Cooperation Foundation of Dongguk University
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Korea Research Institute of Bioscience and Biotechnology KRIBB
Industry Academic Cooperation Foundation of Dongguk University
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Publication of WO2025037870A1 publication Critical patent/WO2025037870A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention relates to a novel benzofuran compound and a pharmaceutical composition containing the same for preventing or treating cancer and cancer metastasis.
  • Hypoxia-inducible factor-1 is a transcription factor involved in cellular adaptation and regulates various biological processes such as cell proliferation, angiogenesis, cellular energy metabolism, apoptosis resistance, and metastasis.
  • HIF-1 is a heterodimeric protein composed of HIF-1 ⁇ and HIF-1 ⁇ subunits.
  • HIF-1 ⁇ is a protein that is normally present in cells called aryl hydrocarbon nuclear translocator (ARNT), and HIF-1 ⁇ is a protein that is expressed and activated by intracellular O 2 concentration. More specifically, HIF-1 ⁇ is degraded under normal oxygen concentration, but stably accumulates in cells under hypoxic conditions and activates the expression of various genes that help cells adapt to hypoxia. Therefore, HIF-1 ⁇ plays an important role in cell adaptation under hypoxic conditions.
  • HIF-1 is known as the most important molecule that regulates the adaptation of cancer cells to these hypoxic conditions, and in particular, the amount of HIF-1 ⁇ protein and the prognosis of cancer patients are known to be closely correlated.
  • active activity of HIF-1 protein promotes tumor growth and interferes with the effectiveness of chemotherapy or radiotherapy, worsening the condition of patients.
  • Ras-associated factor-1 belongs to the RAF protein kinase family, also known as C-Raf. It is an important part of the human RAS/RAF/MEK/ERK signaling pathway and is closely related to the regulation of cell proliferation and differentiation.
  • RAF-1 is positively correlated with the occurrence, development, and clinical prognosis of various cancers, and RAF-1 is recognized as a cancer metastasis drug target.
  • the inventors of the present invention prepared a novel benzofuran compound and confirmed that the compound can prevent or treat cancer and cancer metastasis by effectively inhibiting the accumulation of HIF-1 ⁇ and the expression of RAF-1, thereby completing the present invention.
  • the purpose of the present invention is to provide a novel benzofuran compound or a pharmaceutically acceptable salt thereof.
  • the purpose of the present invention is to provide a novel benzofuran compound and a pharmaceutical composition containing the same for preventing or treating cancer.
  • halogen in the present invention means a substituent selected from fluorine (F), chloro (Cl), bromo (Br) and iodo (I).
  • the halogen may be fluorine.
  • C x -C y means having x or more and y or less carbon atoms.
  • substituted refers to a moiety having a substituent replacing a hydrogen on one or more carbon atoms of the main chain.
  • substituted or substituted with ⁇ is defined to include the implicit condition that such substitution is dependent on the permissibility of the substituted atom and the substituent, and that the substitution leads to a stable compound, for example, a compound that does not undergo spontaneous transformation by rearrangement, cyclization, elimination, etc.
  • single bond means that two connected radicals are directly connected.
  • L represents a single bond in A-L-Z, this structure is essentially A-Z.
  • C 1 -C 6 alkyl as used herein means a straight or branched C 1 -C 6 saturated hydrocarbon group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, and the like.
  • Preferred alkyl groups contain about 1, 2, 3, 4, 5 or 6 carbon atoms in the chain.
  • a side chain means that one or more lower alkyl groups, for example, methyl, ethyl or propyl, are attached to a linear alkyl chain.
  • “Lower alkyl” means a group having from about 1 to about 6 carbon atoms in the chain, which may be straight or branched.
  • C 6 -C 12 aryl refers to an aromatic hydrocarbon containing 6 to 12 carbon atoms.
  • it can refer to a ring system such as monocyclic (e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl).
  • aryl can be a phenyl group having a chemical formula of C 6 H 5 and having 6 carbon atoms arranged in a cyclic ring structure.
  • the phenyl group is very stable and is a type of aromatic hydrocarbon found in many organic compounds.
  • C 3 -C 12 heteroaryl refers to an optionally substituted aromatic ring containing 3 to 12 carbon atoms, wherein at least one of the ring carbon atoms is replaced by a heteroatom selected from oxygen (O), nitrogen (N) and sulfur (S), or an aromatic ring (e.g., a bicyclic or tricyclic ring system) fused to one or more rings such as a heteroaryl ring, an aryl ring, a heterocyclic ring, or a carbocyclic ring, each of which may have an optional substituent.
  • C 3 -C 8 heterocycloalkyl includes a saturated monocyclic or polycyclic heterocycle containing 1 to 4 heteroatoms independently selected from nitrogen (N), oxygen (O) and sulfur (S), or a ring structure in which two or more rings share one or more pairs of carbon atoms (e.g., a fused ring, a spiro ring, a bridged ring, etc.).
  • nitrogen When nitrogen is present in the heterocycloalkyl ring, it may exist in an oxidized state (i.e., N + -O-) as long as the properties of the adjacent atoms and groups permit.
  • Examples include piperidinyl N-oxide and morpholinyl-N-oxide. Additionally, when sulfur is present in the heterocycloalkyl ring, it may exist in an oxidized state (i.e., S + -O- or -SO 2 -) as long as the properties of the adjacent atoms and groups permit. Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. Additionally, one ring of the polycyclic heterocycloalkyl group can be aromatic (e.g., aryl or heteroaryl) if the polycyclic heterocycloalkyl group is attached to the parent structure through a non-aromatic carbon or nitrogen atom.
  • alkoxy is an alkyl group (a chain of carbon and hydrogen) bonded to oxygen, and means a straight or branched chain alkoxy of C 1 -C 6 such as methoxy, ethoxy, etc.
  • amino means a form in which hydrogen is bonded to a nitrogen atom, and this hydrogen atom may be substituted with a C 1 -C 6 straight chain or branched chain alkyl, aryl, etc.
  • “carboxy” means a substituent represented by -COOH or -CO 2 H.
  • haloalkyl means an alkyl group substituted with one or more halogens (e.g., fluoride, chloride, bromide, or iodide).
  • halobenzyl means a benzyl group substituted with one or more halogens (e.g., fluoride, chloride, bromide, or iodide).
  • a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof is provided.
  • R 1 is a hydrogen atom, -OH, or C 1 -C 6 alkyl
  • R 6 is independently a hydrogen atom, a halogen atom, -OH, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, -R 2 OH, , , -NHR 7 or a heteroatom selected from oxygen, nitrogen and sulfur,
  • R 2 is C 1 -C 6 alkyl
  • R 3 is a hydrogen atom or C 1 -C 6 alkyl
  • R 7 is a hydrogen atom or C 1 -C 6 alkyl
  • n is an integer from 0 to 5, and when n is 2 or greater, R 6 are equal or different.
  • R6a, R6b, R6c and R6e are the same or different and each independently represents a hydrogen atom, a halogen atom, -OH, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, -R 2 OH, , , -NHR 7 or a heteroatom selected from oxygen, nitrogen and sulfur,
  • R6d is hydrogen atom, halogen atom, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, -R 2 OH, , , -NHR 7 or may contain a heteroatom selected from oxygen, nitrogen and sulfur.
  • R 1 in the chemical formula 1 is methyl
  • R6b and R6d are not OH.
  • the compound represented by the chemical formula 1 may be a compound represented by the following chemical formula 2.
  • R 1 is a hydrogen atom, -OH, or C 1 -C 6 alkyl
  • R 6 is hydrogen atom, halogen atom, -OH, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, -R 2 OH, , , -NHR 7 or a heteroatom selected from oxygen, nitrogen and sulfur,
  • R 2 is C 1 -C 6 alkyl
  • R 7 is a hydrogen atom or C 1 -C 6 alkyl
  • n is an integer from 0 to 4, and when n is 2 or greater, R 6 are identical or different.
  • R 1 is hydrogen, OH, methyl, ethyl, or isobutyl
  • Is , , , , , , , , , , , , , , or It could be.
  • R 1 is methyl, Is , , , , , , , , , , , , , , , , , , , , , or It could be.
  • Is , , , , , , , , , , , , , , or It could be.
  • the compound of the chemical formula 1 may be any one selected from the group consisting of compounds of the following Table 1:
  • the compound of the chemical formula 1 may be any one selected from the group consisting of the following compounds:
  • the compound represented by chemical formula 1 of the present invention or a pharmaceutically acceptable salt thereof may target hnRNPA2B1.
  • hnRNPA2B1 refers to a heterogeneous nuclear ribonucleoprotein A2B1, which is localized in the nucleus and cytoplasm and is a member of the RNA binding protein group associated with early pre-mRNA.
  • the expression of hnRNPA2B1 is increased in cancer patients and is closely related to apoptosis.
  • hnRNPA2B1 is a putative proto-oncogene in glioblastoma and regulates several tumor suppressors and oncogenes. Under hypoxic conditions, the expression of HIF-1 ⁇ protein is efficiently promoted through the interaction of hnRNPA2B1.
  • Figure 1 is a schematic diagram showing the role of MO-2097 (compound 1a of Example 1) in inhibiting HIF-1 ⁇ mRNA translation in cancer tissues mediated by hnRNPA2B1.
  • the compound represented by the chemical formula 1 of the present invention or a pharmaceutically acceptable salt thereof can exhibit excellent therapeutic efficacy against cancer by binding to hnRNPA2B1 and inhibiting the translation of HIF-1 ⁇ .
  • the compound represented by the chemical formula 1 of the present invention or a pharmaceutically acceptable salt thereof can bind to hnRNPA2B1, inhibit the activity of RAF-1, and prevent and treat cancer metastasis.
  • pharmaceutically acceptable salts mean salts commonly used in the pharmaceutical industry, and include, for example, inorganic ion salts manufactured with calcium, potassium, sodium, and magnesium; inorganic acid salts manufactured with hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid, and sulfuric acid; organic acid salts manufactured with acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, and hydroiodic acid; sulfonic acid salts manufactured with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic
  • the compound represented by the chemical formula 1 of the present invention includes not only pharmaceutically acceptable salts, but also all salts, hydrates, and solvates that can be prepared by conventional methods.
  • a pharmaceutical composition comprising a compound represented by formula 1 as defined in any embodiment described herein or a pharmaceutically acceptable salt thereof is provided.
  • R 1 is a hydrogen atom, -OH, or C 1 -C 6 alkyl
  • R 6 is independently a hydrogen atom, a halogen atom, -OH, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, -R 2 OH, , , -NHR 7 or a heteroatom selected from oxygen, nitrogen and sulfur,
  • R 2 is C 1 -C 6 alkyl
  • R 3 is a hydrogen atom or C 1 -C 6 alkyl
  • R 7 is a hydrogen atom or C 1 -C 6 alkyl
  • n is an integer from 0 to 5, and when n is 2 or greater, R 6 are equal or different.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising a compound represented by the following chemical formula 3 or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for preventing or treating cancer comprising a compound represented by formula 1 as defined in any embodiment described in the present invention or a pharmaceutically acceptable salt thereof.
  • prevention means any act of inhibiting or delaying the onset of cancer formation or cancer metastasis by administering a composition
  • treatment means any act of improving or beneficially changing the symptoms of a disease by administering a composition.
  • the cancer may be any one selected from the group consisting of colon cancer, breast cancer, brain cancer, neurological cancer, lung cancer, small cell lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, colon cancer, breast cancer, fallopian tube carcinoma, endometrial carcinoma, cervical cancer, vaginal cancer, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvic carcinoma, CNS tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, and pituitary adenoma
  • the cancer may be any one selected from the group consisting of colon cancer, uterine cancer, endometrial cancer and cervical cancer.
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier, and may be formulated in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injectable solutions, respectively, according to conventional methods.
  • oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injectable solutions, respectively, according to conventional methods.
  • the pharmaceutically acceptable carriers include, but are not limited to, those commonly used in the art, such as lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil.
  • composition of the present invention may include, but is not limited to, diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, surfactants, and other pharmaceutically acceptable additives.
  • diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, surfactants, and other pharmaceutically acceptable additives.
  • the pharmaceutical composition of the present invention when formulated as an oral solid preparation, it includes tablets, pills, powders, granules, capsules, etc., and such solid preparations may include at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., and include, but are not limited to, lubricants, such as magnesium stearate and talc.
  • excipient for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc.
  • lubricants such as magnesium stearate and talc.
  • the pharmaceutical composition of the present invention when formulated as an oral liquid, it includes a suspension, an oral solution, an emulsion, a syrup, etc., and includes, but is not limited to, a diluent such as water or liquid paraffin, a wetting agent, a sweetener, an air freshener, a preservative, etc.
  • a diluent such as water or liquid paraffin, a wetting agent, a sweetener, an air freshener, a preservative, etc.
  • the pharmaceutical composition of the present invention when formulated for parenteral use, it includes a sterile aqueous solution, a non-aqueous solvent, a suspension, an emulsion, a lyophilized preparation, and a suppository.
  • Non-aqueous solvents and suspensions include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • Suppository bases include, but are not limited to, witepsol, macrogol, Tween 61, cacao butter, laurin butter, and glycerogelatin.
  • compositions of the present invention may be prepared by any well-known pharmaceutical technique, such as effective formulation and administration procedures.
  • the composition may be administered in single or multiple doses in a pharmaceutically effective amount.
  • pharmaceutically effective amount of the present invention means an amount sufficient to prevent or treat a disease at a reasonable benefit/risk ratio applicable to medical prevention or treatment, and the effective dosage level may be determined according to factors including the severity of the disease, the activity of the drug, the patient's age, weight, health, sex, the patient's sensitivity to the drug, the time of administration of the composition of the present invention used, the route of administration and the excretion rate, the treatment period, drugs combined with or co-used with the composition of the present invention used, and other factors well known in the medical field.
  • the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof may be administered at 0.0001 to 100 mg/kg per day, and the administration may be administered once a day or in several divided doses.
  • the pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, and humans by various routes, for example, but not limited to, oral administration, intrathecal, intra-auricular, intraperitoneal or intravenous, intramuscular, subcutaneous, intrauterine epidural, sublingual, or intracerebrovascular injection.
  • the pharmaceutical composition of the present invention may contain 0.01 to 95 wt%, preferably 1 to 80 wt%, of the compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof based on the total weight of the composition.
  • the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents.
  • the pharmaceutical composition of the present invention may be administered singly or in multiple doses. It is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects by taking all of the above factors into consideration, and this can be easily determined by those skilled in the art.
  • subject of the present invention includes an animal or human whose symptoms can be improved by administration of the pharmaceutical composition according to the present invention.
  • cancer can be effectively prevented and treated.
  • administration means introducing a given substance into a human or animal by any appropriate method, and the route of administration of the therapeutic composition according to the present invention may be oral or parenteral administration through any common route as long as it can reach the target tissue.
  • the therapeutic composition according to the present invention may be administered by any device through which the active ingredient can move to the target cell.
  • a method for treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by formula 1 or a pharmaceutically acceptable salt thereof, as defined in any embodiment described herein;
  • a method for inhibiting cancer metastasis comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by formula 1 or a pharmaceutically acceptable salt thereof as defined in any embodiment described herein;
  • subject of the present invention means any animal that has developed or may develop cancer, and typically may be an animal that can exhibit a beneficial effect by treatment with the compound represented by Chemical Formula 1 of the present invention, or a pharmaceutically acceptable salt thereof, but includes, without limitation, any subject that has symptoms of cancer or is likely to have such symptoms.
  • the pharmaceutical composition of the present invention can be administered as an individual therapeutic agent, or can be administered in combination with existing cancer therapeutic agents, and can be administered sequentially or simultaneously with the existing therapeutic agents.
  • a food composition for preventing or improving cancer comprising a compound represented by chemical formula 1 as defined in any embodiment described in the present invention or a pharmaceutically acceptable salt thereof.
  • “improvement” means any act of improving cancer by administering a composition according to the present invention.
  • the food composition of the present invention may be, for example, any one selected from among noodles, gum, dairy products, ice cream, meat, grains, caffeinated beverages, general beverages, chocolate, bread, snacks, confectionery, candy, pizza, jelly, alcoholic beverages, alcohol, vitamin complexes, and other health supplements, but is not limited thereto.
  • the food composition of the present invention when used as a food additive, it can be added as is or used together with other foods or food ingredients, and can be used appropriately according to a conventional method.
  • the food composition of the present invention includes a health functional food.
  • health functional food refers to food manufactured and processed using raw materials or ingredients with functionality useful to the human body according to Act No. 6727 on Health Functional Foods, and “functionality” refers to consumption for the purpose of obtaining a useful effect for health purposes, such as regulating nutrients for the structure and function of the human body or physiological effects.
  • the food composition of the present invention may include additional ingredients.
  • it may include biotin, folate, pantothenic acid, vitamins A, C, D, E, B1, B2, B6, B12, niacin, etc.
  • it may include minerals such as chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu), zinc (Zn), iron (Fe), calcium (Ca), etc.
  • it may include amino acids such as cysteine, valine, lysine, and tryptophan.
  • food additives such as preservatives (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate, etc.), coloring agents (tar color, etc.), coloring agents (sodium nitrite, sodium nitrate, etc.), bleaching agents (sodium sulfite), bactericides (bleaching powder and high-purity bleaching powder, sodium hypochlorite, etc.), leavening agents (alum, D-potassium hydrogentartrate, etc.), reinforcing agents, emulsifiers, thickeners (glucose), film-forming agents, antioxidants (butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), etc.), seasonings (MSG, monosodium glutamate, etc.), sweeteners (dulcin, cyclamate, saccharin, sodium, etc.), flavorings (vanillin, lactones, etc.), gum bases, antifoaming agents, solvent, solvent
  • the compound represented by chemical formula 1 of the present invention or a pharmaceutically acceptable salt thereof binds to hnRNPA2B1 and inhibits the translation of HIF-1 ⁇ , thereby exhibiting excellent effects in the prevention or treatment of cancer for various types of cancer. In particular, it has excellent anticancer effects by inhibiting cancer metastasis together with inhibition of cell death.
  • the pharmaceutical composition for preventing and treating cancer comprising the compound represented by the chemical formula 1 of the present invention can be usefully used as a cancer treatment agent in terms of lowering cancer cell survival rate and inhibiting cancer metastasis.
  • Figure 1 is a schematic diagram showing the role of MO-2097 (compound 1a of Example 1) in inhibiting HIF-1 ⁇ mRNA translation in cancer tissues mediated by hnRNPA2B1.
  • FIG. 2 confirms the effect of MO-2097 on HIF-1 ⁇ protein expression.
  • Figure 3 shows the results of evaluating cell death by FASC analysis of MO-2097.
  • FIG. 4 shows the results of the Live cell/Apoptosis cells staining experiment of MO-2097.
  • Figure 5 shows the results of measuring the binding affinity of hnRNPA2B1 for MO-2097 and Moracin G, respectively.
  • Figure 6 shows the results of a biotin pull-down assay using HeLa CCL2 lysate to investigate the interaction between MO-2097 and hnRNPA2B1 protein under biochemical conditions.
  • Figure 7 shows the decrease in nuclear HIF-1 ⁇ protein in HeLa CCL2 cells treated with the hnRNPA2B1-binding compound MO-2097 in HeLa CCL2 cells exposed to hypoxic conditions.
  • Figure 8 shows the decrease in nuclear HIF-1 ⁇ protein in HeLa CCL2 cells treated with the hnRNPA2B1-binding compound MO-2097 in HCT116 cells exposed to hypoxic conditions.
  • Figure 9 shows the results of transcription/translation analysis to confirm the inhibitory effect of MO-2097 on HIF-1 ⁇ protein expression.
  • Figure 10 shows the results of observing the expression of HIF-1 ⁇ target genes, including HK, MRP1, SLC1A5, IL6, and VEGF, in HeLa CCL2 cells treated with MO-2097 under hypoxic conditions.
  • Figure 11 shows the results of confirming the anticancer activity of MO-2097 in a 3D spheroid model of HCT116 cells using a Zeiss microscope.
  • Figure 12 shows the average values of the spheroid areas confirmed in Figure 10 organized by date.
  • Figure 13 shows the results of treating HCT116 spheroids with DMSO or 25 and 50 ⁇ M MO-2097, culturing the spheroids for 2 more days, fixing them in 4% paraformaldehyde, and then staining the samples with anti-cleaved caspase 3 antibody (green) and Tubulin antibody (red) after cryosectioning.
  • Figure 14 is a mouse image showing the results of a xenograft analysis when both vehicle and MO-2097 were injected into mice with tumors.
  • Figure 15 is a graph showing the mouse body weight of Figure 14.
  • Figure 16 is a graph showing the mouse tumor volume of Figure 14.
  • Figure 17 is a graph showing the relative tumor weight of the mouse in Figure 14.
  • Figure 18 shows the results of additional tumor resections following in vivo xenograft studies and staining with anti-HIF-1 ⁇ antibody (green).
  • Figure 19 shows the results of additional tumor resections following in vivo xenograft studies and staining with anti-cleaved caspase 3 antibody (green).
  • Figure 20 shows the results of microscopic observation of the growth inhibitory effect on organoids 1, 2, 3, and 4, respectively, after treatment with MO-2097.
  • Figure 21 is a graph showing the relative values for the growth inhibition effect on organoids 1, 2, 3, and 4 respectively after treatment with MO-2097.
  • Figure 22 shows the results of lysing organoids 1 and 2 in sample buffer and then blotting with the indicated antibodies.
  • Figure 23 shows the results of harvesting organoid 2 for qPCR and analyzing each primer set of the target gene.
  • Figure 24 shows the results of immunostaining with the indicated antibodies after treating organoid 1 with 25 ⁇ M MO-2097 for 24 hours, and observing with a fluorescence microscope (Carl Zeiss).
  • Figure 25 shows the results of the MTT assay for colon cancer cells (DLD-1) of MO-2097.
  • Figure 26 shows the results of the MTT assay for sorafenib on colon cancer cells (DLD-1).
  • Figure 27 shows the results of assaying cell migration with MO-2097 at various concentrations and at various time points.
  • Figure 28 shows the results of assaying cell migration with Sorafenib at various concentrations and over various time periods.
  • Figure 29 shows a graph showing the extent to which the space where cells fell off is filled according to the concentration of MO-2097 and Sorafenib.
  • Figure 30 shows the results of a migration analysis of MO-2097 using crystal violet staining.
  • Figure 31 shows the numerical results of the transport analysis of MO-2097 and Sorafenib at various concentrations.
  • Figure 32 shows the results of a mobility analysis using DAPI staining at various concentrations of MO-2097 and Sorafenib.
  • Figure 33 shows the results of Western blotting of MO-2097 and Sorafenib.
  • Figures 34 to 36 show the results of MTT analysis of compounds 1a-1t of the examples on cervical cancer cells (HeLa CCL2).
  • Figure 37 shows the results of assaying cell migration of compounds 1a-1t of the example.
  • Figure 38 summarizes the effects of compounds 1a-1t of the examples confirmed in Figures 34 to 37.
  • 1 H-NMR and 13 C-NMR of compounds prepared according to one embodiment of the present invention were measured using a Varian (400 MHz) spectrometer (Varian Medical Systems, Inc., Palo Alto, CA, USA), respectively.
  • 1 H-NMR data are reported in terms of peak multiplicity as s for a singlet, d for a doublet, dd for a doublet of doublets, t for a triplet, q for a quartet, brs for a broad singlet, and m for a multiplet.
  • 13 C-NMR chemical shift values are reported in ⁇ (ppm), and coupling constants ( J ) in Hz.
  • the mass spectrum of the compound prepared according to one embodiment of the present invention was recorded using high-resolution mass spectrometry (HRMS, ESI-MS) obtained on a G2 QTOF mass spectrometer (Waters Corp, Milford, USA).
  • HRMS high-resolution mass spectrometry
  • ESI-MS ESI-MS
  • G2 QTOF mass spectrometer Waters Corp, Milford, USA.
  • the product was purified by column or flash chromatography (Biotage, Sweden) using silica gel 60 (230-400 mesh Kieselgel 60).
  • the purity of the compounds prepared according to one embodiment of the present invention was confirmed by reverse phase high pressure liquid chromatography (RP-HPLC) performed on a Waters Corp. HPLC system equipped with an ultraviolet (UV) detector set to 254 nm.
  • the mobile phases used were (A) H 2 O containing 0.05% trifluoroacetic acid and (B) CH 3 CN.
  • HPLC was performed using a YMC Hydrosphere C18 (HS-302) column (particle size 5 ⁇ m, pore size 12 nm), 4.6 mm in diameter x 150 mm in size, at a flow rate of 1.0 mL/min.
  • the compound purity was assessed using a gradient from 25% B to 100% B in 30 min (Method A) or from 5% B to 100% B in 30 min (Method B).
  • the purity of all compounds evaluated biologically was ⁇ 95% by Method A or Method B.
  • 2-bromo-7-methyl-5,8-dihydrooxepino[3,2-f]benzofuran (4 in the reaction scheme) was prepared from 5-allyl-2-bromobenzofuran-6-ol (2 in the reaction scheme) with reference to the above reaction scheme 1.
  • 5-allyl-2-bromobenzofuran-6-ol (2 in the reaction scheme) was mixed with allyl chloride, NaI, Cs 2 CO 3 and acetone and alkylation reaction was performed at 60° C. for 2 hours to obtain 5-allyl-2-bromo-6-[(2-methylallyl)oxy]benzofuran (3 in the reaction scheme) with a yield of about 80% (step a).
  • 2-bromo-7-methyl-5,8-dihydrooxepino[3,2-f]benzofuran (4) was prepared from 2-bromo-6-((2-methylallyl)oxy)-5-(4-methylbut-2-en-1-yl)benzofuran (7 in the reaction scheme) (step d).
  • 2-bromo-7-methyl-5,8-dihydrooxepino[3,2-f]benzofuran (4 in the reaction scheme) was prepared from 2-bromo-6-((2-methylallyl)oxy)-5-(4-methylbut-2-en-1-yl)benzofuran (7 in the reaction scheme) in a yield of about 84%, and the overall yield was 31%.
  • the 1t compound of the reaction scheme was prepared from 2-bromo-7-methyl-5,8-dihydrooxepino[3,2-f]benzofuran (4 in the reaction scheme) and 2-methyl-N-(1-methylpiperidin-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (8s in the reaction scheme) according to the Suzuki coupling procedure in Experimental Example 3. Afterwards, the product was purified by silica gel column chromatography (0-20% MeOH in DCM) to obtain 1s as a white solid (30.0 mg, 20%).
  • boronic acid esters/acids (8a-8t) required for the preparation of compounds 1a-1t of the above Example 3, boronic acid esters (8l-t) that are not commercially available were prepared as shown in Scheme 4.
  • Compounds 8l-8t were obtained through two steps of initial amide coupling from the corresponding bromo acids followed by Miyaura borylation.
  • a Reagents and conditions (a) amine, T 3 P, TEA, DCM, room temperature, 16 h, 97-65%; (b) bis(pinacolato)diboron, KOAc, Pd(dppf)Cl 2 ⁇ DCM, 1,4-dioxane or MF, 100 °C 16 h, 83-43%.
  • the above compound was prepared from (4-bromophenyl)(piperidin-1-yl)methanone (10l in the scheme) according to the Miyaura borylation procedure method A of Experimental Example 4. It was then purified by silica gel column chromatography (0-35% EtOAc in n-hexane) to obtain 8l as a white solid (0.40 g, 75%).
  • the above compound was prepared from 4-bromo-N-(1-methylpiperidin-4-yl)benzamide (10m in the scheme) according to the Miyaura borylation procedure A of Experimental Example 4. It was then purified by silica gel column chromatography (0-20% methanol in DCM) to give 8m as a white solid (0.16 g, 47%).
  • the above compound was prepared from (4-bromophenyl)(piperidin-1-yl)methanone (10o in the scheme) according to the Miyaura borylation procedure Method A of Experimental Example 4. It was then purified by silica gel column chromatography (0-30% EtOAc in n-hexane) to give 8o as a white solid (0.14 g, 41%).
  • the above compound was prepared from (4-bromophenyl)[4-(4-fluorobenzyl)piperazin-1-yl]methanone (10p in the scheme) according to the Miyaura borylation procedure method A of Experimental Example 4. It was then purified by silica gel column chromatography (0-60% EtOAc in n-hexane) to give 8p as a white solid (0.2 g, 60%).
  • the above compound was prepared from 3-bromo-N-(1-methylpiperidin-4-yl)benzamide (10r in the scheme) according to the Miyaura borylation procedure method B of Experimental Example 4. It was then purified by silica gel column chromatography (0-20% methanol in DCM) to give 8r as a brown solid (0.25 g, 43%).
  • the above compound was prepared from 4-bromo-2-methyl-N-(1-methylpiperidin-4-yl)benzamide (10s in the scheme) according to the Miyaura borylation procedure B of Experimental Example 4. It was then purified by silica gel column chromatography (0-20% methanol in DCM) to give 8s as a brown solid (0.35 g, 45%).
  • the above compound was prepared from 4-bromo-3-methyl-N-(1-methylpiperidin-4-yl)benzamide (10t in the scheme) according to the Miyaura borylation procedure, method B of Experimental Example 4. It was then purified by silica gel column chromatography (0-20% methanol in DCM) to give 8t as a brown solid (0.30 g, 45%).
  • the above compound was prepared from 4-bromobenzoic acid (scheme 10a) and piperidine according to the general procedure for amide coupling in Experimental Example 4. It was then purified by silica gel column chromatography (0-35% EtOAc in n-hexane) to give 10 l as a white solid (0.65 g, 97%).
  • the above compound was prepared from 4-bromobenzoic acid (10a in Scheme 1) and 1-methylpiperidin-4-amine according to the general procedure for amide coupling in Experimental Example 4. It was then purified by silica gel column chromatography (0-20% methanol in DCM) to give 10m as a white solid (0.55 g, 75%).
  • the compound was prepared from 4-bromobenzoic acid (scheme 10a) and tert-butyl piperazine-1-carboxylate according to the general procedure for amide coupling in Experimental Example 4. It was then purified by silica gel column chromatography (0-35% EtOAc in n-hexane) to give 10o as a white solid (0.86 g, 94%).
  • the compound was prepared from 4-bromobenzoic acid (scheme 10a) and 1-(4-fluorobenzyl)piperazine according to the general procedure for amide coupling in Experimental Example 4. It was then purified by silica gel column chromatography (0-2% methanol in DCM) to give 10p as a white solid (0.75 g, 80%).
  • the compound was prepared from 4-bromo-2-methylbenzoic acid (9s in the scheme) and 1-methylpiperidin-4-amine according to the general procedure for amide coupling in Experimental Example 4. It was then purified by silica gel column chromatography (0-20% methanol in DCM) to give 10s as a white solid (0.50 g, 69%).
  • the above compound was prepared from 4-bromo-3-methylbenzoic acid (9t in the scheme) and 1-methylpiperidin-4-amine according to the general procedure for amide coupling in Experimental Example 4. It was then purified by silica gel column chromatography (0-20% methanol in DCM) to give 10t as a white solid (0.48 g, 65%).
  • Test Example 1 Confirmation of HIF-1 ⁇ protein inhibition and cell death effect
  • HeLa CCL2 cells were seeded in 6-well plates and treated with DMSO control or compound 1a of the present invention (MO-2097) at a concentration of 25 ⁇ M for 24 h in hypoxia.
  • HIF-1 ⁇ protein levels were measured by Western blotting using anti-HIF-1 ⁇ antibody
  • hnRNPA2B1 protein levels were measured using anti-hnRNPA2B1 antibody
  • red stars indicate hnRNPA2B1 protein bands
  • black stars are from previous anti- ⁇ actin blotting signals.
  • the FASC analysis was performed as follows. HeLa CCL2 cells were cultured in 12-well culture plates for 18 h. The cells were treated with 25 ⁇ M MO-2097 for 24 h under 1% oxygen conditions. The cells were then harvested and stained with propidium iodide (PI) or anti-Annexine V-APC (eBioscience TM Annexin V Apoptosis Detection Kit APC, Invitrogen, Carlsbad, CA, USA) for 30 min to determine the percentage of cells with phosphatidylserine externalization.
  • PI propidium iodide
  • anti-Annexine V-APC eBioscience TM Annexin V Apoptosis Detection Kit APC, Invitrogen, Carlsbad, CA, USA
  • Flow cytometry was performed using a flow cytometer (CytoFLEX, Beckman Coulter, Miami, FL, USA).
  • the laser excitation and emission bandpass wavelengths were 650/660 nm or 660/780 nm, respectively.
  • Results were reported as the median of the cell fluorescence intensity distribution obtained by analyzing 10,000 cells in the gate and analyzed using Summit Software (version 6.0, Beckman Coulter, Miami, FL, USA). Internalization scores and mean fluorescence intensity values were calculated for at least 5,000 cells/sample.
  • Fig. 4 The same sample used in the FASC analysis of Fig. 3 above was stained with the Live/Dead TM Viability/Cytotoxicity kit (Life Technologies Corporation) for 30 minutes. The images were then acquired using a Zeiss Axiovert 100M microscope (Carl Zeiss MicroImaging), which are shown in Fig. 4. In Fig. 4, green, red, and blue signals represent live cells, dead cells, and DNA, respectively (Scale bar: 20 ⁇ m).
  • the binding affinity of hnRNPA2B1 to MO-2097 and Moracin G was measured by ITC analysis. Specifically, His-tagged hnRNPA2B1 protein was purified by Ni 2+ bead affinity chromatography, and 50 ⁇ M hnRNPA2B1 protein was reacted with 250 nM of each compound at room temperature for 2 h, followed by isothermal titration calorimetry (ITC) analysis.
  • ITC isothermal titration calorimetry
  • the above ITC analysis was performed using a MicroCal Auto-iTC200 (Malvern Panalytical, Malvern, UK) at the Korea Basic Science Institute (Ochang, Korea).
  • the binding affinity was measured using 40 ⁇ L of 250 ⁇ M MO-2097/Moracin G and 200 ⁇ L of 50 ⁇ M purified hnRNPA2B1 protein in 50 mM Na 2 HPO 4 buffer (pH 8.0).
  • 2 ⁇ L of ligand was injected into the target protein for 4 s at 150 s intervals at 25 °C. In total, 19 injections were performed for each experiment, and the data were analyzed using MicroCal Origin software (Malvern Panalytical).
  • the Ka values for the binding affinity of hnRNPA2B1 to MO-2097 and moracin G were 4.13 ⁇ 10 -5 /M and 9.32 ⁇ 10 -4 /M, respectively. That is, it can be confirmed that MO-2097 has approximately 5 times higher affinity for hnRNPA2B1 than moracin G (Fig. 5).
  • HeLa CCL2 lysate was subjected to biotin pulldown assay.
  • the biotin pulldown assay was performed as follows. HeLa CCL2 cell lysate (1 mg/ml) was incubated with biotin alone or 500 ⁇ M biotinylated MO-2097 (Biotin-MO-2097) for 1.5 h. For the competitive control, 1.5 mM MO-2097 was used. Then, 35 ⁇ M streptavidin beads were added to each sample and incubated for an additional 1 h. After washing six times, the samples were harvested and Western blotting was used to evaluate the affinity, and the results are shown in Fig. 6. For reference, hnRNPI, hnRNPF/H, and Tubulin antibodies were used as negative binding controls.
  • the biotinylated MO-2097 (Biotin-MO-2097) was prepared with reference to the following reaction scheme 5. Specifically, the compound represented by 1a of the reaction scheme (MO-2097) was mixed with ethyl 2-chloroacetate, K 2 CO 3 and acetone and alkylated at 60° C. for 16 hours to prepare a compound represented by 11 of the reaction scheme in a yield of about 82% (step a). Thereafter, the compound represented by 11 of the reaction scheme was mixed with LiOH H 2 O and THF:EtOH:H 2 O (2:2:1) and hydrolyzed at room temperature for 2 hours to obtain a compound represented by 12 of the reaction scheme in a yield of about 82% (step b).
  • Biotin-MO-209 and Biotin-MO-2097 bound well to hnRNPA2B21, but did not bind to other RNA binding proteins, hnRNPI and hnRNPF/H, or the housekeeping protein, Tubulin.
  • HIF-1 ⁇ protein when HeLa CCL2 and HCT116 cells are exposed to hypoxic conditions, HIF-1 ⁇ protein accumulates, and when treated with the hnRNPA2B1-binding compound MO-2097, it can be confirmed that the protein level of HIF-1 ⁇ protein decreases.
  • Test Example 3 Confirmation of the effect of suppressing the expression of HIF-1 ⁇ protein and HIF-1 ⁇ target genes
  • HIF-1a protein was expressed more effectively by hnRNPA2B1, but was dose-dependently inhibited by MO-2097 treatment (Fig. 9).
  • HeLa CCL2 and HCT116 cells were cultured under hypoxic conditions with DMSO control or 25 and 50 ⁇ M MO-2097. 20% O2- conditioned cells were used as normoxic control. After 24 h, RNA was extracted and cDNA was synthesized. HIF-1 ⁇ , HK1, MRP1, SLCA5, IL-6, and VEGF mRNA levels were measured by qPCR.
  • HK, MRP1, SLC1A5, IL6, and VEGF were confirmed to be among the target genes regulated by HIF-1 ⁇ inhibition with MO-2097 in HeLa CCL2 and HCT116 cells (Fig. 10).
  • compound 1a of the example (MO-2097) can act as an anticancer compound.
  • Test Example 4 Confirmation of anticancer effect in 3D spheroid model
  • the anticancer effect of MO-2097 was verified in a similar microscopic cancer tissue environment under 3D culture conditions. Specifically, HCT116 cells were seeded in low attachment 96-well round bottom plates and treated with DMSO control or 25 and 50 ⁇ M MO-2097.
  • the spheroid images in Fig. 11 were acquired using a Zeiss microscope (Scale bar: 100 ⁇ m).
  • the measured spheroid area data in Fig. 12 are expressed as mean ⁇ SD, p-value ⁇ 0.0001 based on the measurement on the last day.
  • HCT116 spheroids were cultured for 8 days and treated with DMSO or 25 and 50 ⁇ M MO-2097. The spheroids were then cultured for 2 more days and fixed in 4% paraformaldehyde. After cryosectioning, the samples were stained with anti-cleaved caspase 3 antibody (green) and Tubulin antibody (red), and the results are shown in Fig. 13. In Fig. 13, the blue signal represents DNA (Scale bar: 100 ⁇ m).
  • Test Example 5 Confirmation of anticancer effect in a mouse in vivo xenograft model
  • MO-2097 25 mg/kg and 50 mg/kg were injected intraperitoneally into three mice seven times, but no obvious toxicity was observed. Therefore, in vivo experiments were performed at the highest dose (50 mg/kg). When the average tumor size reached 50 mm 3 and was palpable, MO-2097 was injected intraperitoneally into the mice together with vehicle every other day for 15 days.
  • MO-2097 progressively reduced the visceral tumor volume without significant body weight loss, indicating that MO-2097 was well tolerated in mice at the tested doses.
  • the tumor size of the vehicle treatment group was 637.04 ⁇ 115.49 mm 3
  • the tumor size of the MO-2097 treatment group was 326.7 ⁇ 51.5 mm 3 , confirming that MO-2097 significantly suppressed the tumor volume by about 49% (Figs. 16 and 17).
  • Figure 18 shows the tumor tissue stained with anti-HIF-1 ⁇ antibody (green)
  • Figure 19 shows the tumor tissue stained with anti-cleaved caspase 3 antibody (green).
  • the blue signal in Figures 18 and 19 represents DNA (Scale bar: 200 ⁇ m).
  • MO-2097-treated tumors showed increased expression of cleaved caspase 3, an apoptosis marker, suggesting that MO-2097 is a potent inducer of tumor cell apoptosis (Fig. 19).
  • Test Example 6 Confirmation of anticancer activity in organoids derived from colon cancer patients
  • Figure 20 shows the results of microscopic observation of the growth inhibition effect on organoids 1, 2, 3, and 4, respectively, after treatment with MO-2097
  • Figure 21 shows a graph showing the relative values of the growth inhibition effect on organoids 1, 2, 3, and 4, respectively, after treatment with MO-2097.
  • Figure 22 shows the results of blotting with the indicated antibodies after dissolving organoids 1 and 2 in sample buffer. According to Figure 22, among the two samples, hnRNPA2B1 expression was found to be higher in organoid 2, and HIF-1 ⁇ expression in organoid 2 reacted at a lower concentration.
  • Figure 23 shows the results of harvesting organoid 2 for qPCR and analyzing each primer set of the target gene. According to Figure 23, it can be confirmed that the target gene expression level of HIF-1 ⁇ responded to MO-2097 in a dose-dependent manner. Although it was not an artificial hypoxic condition, expression and inhibition of HIF-1 ⁇ were observed under these experimental conditions.
  • organoid 1 was treated with 25 ⁇ M MO-2097 for 24 hours, and then immunostained with the indicated antibodies (Tubulin, anti-cleaved caspase 3, DAPI, and Merge), and observed under a fluorescence microscope (Carl Zeiss), as shown in Fig. 24.
  • the suitable concentration of the 1a compound (MO-2097) of the present invention is 30 ⁇ M (cell viability of about 91%), and the concentration of Sorafenib, which shows a similar effect, is 2.5 ⁇ M (cell viability of about 92%). Therefore, the comparison will be focused on 30 ⁇ M of the 1a compound (MO-2097) of the present invention and 2.5 ⁇ M of Sorafenib.
  • FIG. 30 The results of mobility analysis using crystal violet staining of the 1a compound (MO-2097) of the present invention are shown in FIG. 30, the results of mobility analysis using various concentrations of the 1a compound (MO-2097) of the present invention and Sorafenib are numerically shown in FIG. 31, and the results of mobility analysis using DAPI staining of the 1a compound (MO-2097) of the present invention and Sorafenib are shown in FIG. 32.
  • Figure 33 shows the results of Western blotting of compound 1a (MO-2097) of the present invention and Sorafenib.
  • the compound 1a (MO-2097) of the present invention has an anti-metastatic effect on colon cancer cells DLD-1, and it was confirmed through the analysis of (4) that the compound (MO-2097) inhibits RAF-1.
  • compound 1a (MO-2097) of the present invention has an inhibitory effect on RAF-1, and also shows an excellent inhibitory effect on cancer cell metastasis, thereby showing excellent effects not only on simple inhibition of cancer cell growth but also on inhibition of cancer metastasis, and thus shows high potential for use as a cancer treatment agent.
  • Test Example 8 Confirmation of inhibition of cancer metastasis by compounds 1a-1t of the example
  • an MTT assay was performed to confirm the anticancer activity of compounds 1a-1t of the present invention against HeLa CCL2 cells.
  • HeLa CCL2 cells were seeded at 5000 cells/well (100 ⁇ l per well) in a 96-well flat bottom plate, and then treated with 20 ⁇ l of each of the 1a-1t compounds of the example the next day. Considering that the total volume after compound treatment was 120 ⁇ l, the treatment was performed at a concentration 6 times higher than the final concentration. MTT solution was treated 48 hours after treating the example compounds, and the results were measured 2 hours later.
  • compounds of Examples 1a-1e, 1g, 1m, 1n, 1p-1t have a cell killing effect on HeLa CCL2 cells, and in particular, compounds of Examples 1a, 1c, 1d, 1m, 1n, 1p-1t have an IC 50 of 30 ⁇ M or less, confirming that they have relatively strong anticancer activity.
  • HeLa CCL2 cells were seeded in a 24-well plate at 1.5 x 10 4 cells/well (500 ⁇ l per well), and the cells in the center of the well were removed the next day using a Scratcher (SPL product_CAT # 201925). After that, the cells were washed twice with DMEM culture medium and suctioned, and then treated with 500 ⁇ l of the culture medium containing each of the 1a-1t compounds of the examples. Thereafter, images after 0 hour, 24 hours, and 48 hours were taken under a microscope, and after 48 hours, the culture medium was suctioned and the images were obtained by staining for 20 minutes using Wright stain solution (CAT #45253-250ML-F) (Geimsa staining).
  • SPL product_CAT # 201925 Scratcher
  • compounds of examples 1a-1e, 1g, 1l, 1m, 1q-1t have an effect of inhibiting the metastasis of cancer cells, and in particular, it can be confirmed that compounds of examples 1a, 1c, 1d, 1m, 1q and 1t exhibit a strong metastasis inhibition effect.
  • the exemplary compounds according to the present invention exhibit excellent inhibitory effects on cancer cell metastasis, thereby demonstrating excellent effects not only in inhibiting simple cancer cell growth but also in inhibiting cancer metastasis, and thus have high potential for use as cancer treatment agents.

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Abstract

La présente invention concerne un nouveau composé benzofurane et une composition pharmaceutique le comprenant pour prévenir ou traiter le cancer. Le composé selon la présente invention ou un sel pharmaceutiquement acceptable de celui-ci se lie à hnRNPA2B1 pour inhiber la traduction de HIF-1α, présentant ainsi un excellent effet prophylactique et thérapeutique sur des maladies cancéreuses de divers carcinomes. En particulier, la présente invention a pour effet d'avoir une excellente activité anticancéreuse par l'effet d'inhibition de la métastase cancéreuse ainsi que l'effet d'inhibition de la mort cellulaire.
PCT/KR2024/011923 2023-08-11 2024-08-09 Composé benzofurane et composition pharmaceutique le comprenant pour prévenir ou traiter des maladies cancéreuses et des métastases cancéreuses Pending WO2025037870A1 (fr)

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NAIK RAVI; HARMALKAR DIPESH S.; XU XUEZHEN; JANG KYUSIC; LEE KYEONG: "Bioactive benzofuran derivatives: Moracins A–Z in medicinal chemi", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ELSEVIER MASSON, AMSTERDAM, NL, vol. 90, 25 November 2014 (2014-11-25), AMSTERDAM, NL, pages 379 - 393, XP029125974, ISSN: 0223-5234, DOI: 10.1016/j.ejmech.2014.11.047 *
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