WO2019242687A1 - Composé 1,3-dioxane-4,6-dione, procédé de préparation, composition pharmaceutique et utilisation de celui-ci - Google Patents

Composé 1,3-dioxane-4,6-dione, procédé de préparation, composition pharmaceutique et utilisation de celui-ci Download PDF

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WO2019242687A1
WO2019242687A1 PCT/CN2019/092080 CN2019092080W WO2019242687A1 WO 2019242687 A1 WO2019242687 A1 WO 2019242687A1 CN 2019092080 W CN2019092080 W CN 2019092080W WO 2019242687 A1 WO2019242687 A1 WO 2019242687A1
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substituted
unsubstituted
compound
sirt1
alkyl
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刘东祥
柳红
王敏
李淳朴
杨利生
陈凯先
蒋华良
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中国科学院上海药物研究所
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    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/00—Drugs for disorders of the metabolism
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
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    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to 1,3-dioxane-4,6-dione compounds, a preparation method thereof, a pharmaceutical composition, and applications thereof.
  • Sirtuin is a class of NAD + -dependent protein deacetylases, which have a high degree of homology in amino acid sequence and structure.
  • Sirtuin protein is widely present in various organisms such as archaea, nematodes, fruit flies, yeast, and mammals, and regulates a variety of cells including cell senescence, transcription, apoptosis, inflammation, stress, mitochondrial synthesis, and the body's biological clock. Important biological processes.
  • the yeast Sir2 gene was the first sirtuin protein discovered. As early as the 1970s, it was discovered that the Sir2 gene can maintain the length of yeast telomeres and regulate the generation of DNA repeats encoded by rDNA. It was later discovered that the Sir2 gene can prolong the lifespan of yeast by suppressing genomic instability. Knockout of the Sir2 gene can significantly shorten the yeast's lifespan, while overexpression of the Sir2 gene can extend the yeast's lifespan by about 40%. Similarly, overexpression of Sir2.1 (a homologous gene of Sir2) in nematodes can extend the lifespan of nematodes by about 50%, and a similar phenomenon occurs in fruit flies. These findings have made research on sirtuin family proteins more popular.
  • the mammalian genome encodes seven sirtuin proteins, named SIRT1-7, which contain a highly conserved core region consisting of a NAD + binding region and an enzyme catalytic region, as well as a variable length N-terminus and a C-terminus. end. Differences in the N- and C-termini of Sirtuin proteins can affect protein-ligand binding, mediate protein interactions with other sirtuin isoforms, or affect their subcellular localization.
  • SIRT1, SIRT6, and SIRT7 are nuclear proteins, but SIRT1 can also pass from the nucleus into the cytoplasm through nuclear transport, thereby regulating the target proteins in the cytoplasmic stress response.
  • SIRT2 is mainly located in the cell matrix, but SIRT2 can be transported into the nucleus through nuclear transport, while SIRT3, SIRT4, and SIRT5 are mainly located in the mitochondria.
  • Mammalian sirtuins are distributed in different subcellular layers, which is closely related to the substrates and biological functions they act on.
  • SIRT1 is the mammalian sirtuin family protein that is closest in sequence to yeast Sir2 and is the earliest member of the mammalian sirtuin family to be studied. SIRT1 regulates heterochromatin formation by deacetylating H1K26, H3K9, and H4K16. In addition, SIRT1 is also involved in the deacetylation of non-histones.
  • the non-histone substrates of SIRT1 can be divided into three categories: (1) transcription factors: such as p53, FOXO3a, E2F2, BCL6, etc .; (2) DNA repair proteins: such as Ku70 and MRE11-RAD50-NBS1 (MRN); 3) Signal factor: Smad7 and so on. SIRT1 participates in regulating a variety of physiological functions including gene expression, energy metabolism, and aging by deacetylating histone substrates and non-histone substrates.
  • SIRT1 is closely related to the occurrence and development of various diseases. It can control the development of Alzheimer's disease (AD) by deacetylating the P65 / RelA subunit of NF- ⁇ B and inhibiting the accumulation of A ⁇ in microglia. . SIRT1 can also protect nerve cells in Huntington's disease (HD) disease models by deacetylating PGC-1 ⁇ and increasing PGC-1 ⁇ activity. It is known that the tumor suppressor p53 protein is involved in many physiological processes including DNA repair, cell growth arrest, aging and apoptosis, and has become one of the important targets for cancer treatment. SIRT1 can deacetylate the lysine residue at position 382 of p53.
  • AD Alzheimer's disease
  • HD Huntington's disease
  • SIRT1 can also deacetylate DNA repair factor Ku70 and forkhead transcription factor FOXOs to enhance cell DNA repair and inhibit apoptosis caused by DNA damage. Studies have shown that inhibition of SIRT1 activity can induce tumor cell growth arrest and promote tumor cell apoptosis. In addition, SIRT1 can regulate the transcription of tumor suppressor genes by deacetylating histone H1 at position 26, H3 at position 9, and H4 at position 16 to participate in the regulation of tumor cell cycle. The study found that overexpression of SIRT1 protein was detected in most solid tumors and hematological malignancies including breast, colon, prostate, liver and leukemia.
  • SIRT1 Since the overexpression of SIRT1 is related to the occurrence of cancer, inhibiting the activity of SIRT1 can effectively inhibit the proliferation of cancer cells and induce apoptosis of cancer cells at the same time. Therefore, SIRT1 may become a new target for tumor therapy, and SIRT1 inhibitors may become potential anticancer drug candidates.
  • An object of the present invention is to provide a 1,3-dioxane-4,6-dione compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, an enantiomer, Enantiomers or racemates.
  • Another object of the present invention is to provide a method for preparing the compound represented by the general formula (I).
  • It is still another object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds represented by the general formula (I) or a pharmaceutically acceptable salt thereof.
  • Yet another object of the present invention is to provide the use of the compound represented by the general formula (I) in the preparation of a medicament for treating diseases related to the activity level of SIRT1 deacetylase, such as cancer, immune disorders and inflammation.
  • a compound represented by Formula I or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, diastereomer or racemate thereof, or mixture:
  • R 1 and R 7 are each independently hydrogen, C1-C6 alkyl or C2-C12 unsaturated hydrocarbon group
  • substitution refers to including one or more substituents selected from the group consisting of halogen, hydroxy, phenyl, C1-C12 alkyl, C1-C12 haloalkyl, C2-C12 unsaturated hydrocarbon, C1-C6 alkoxy , C1-C6 haloalkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, cyano, nitro, methylol, carboxyl, mercapto;
  • R 6 is 1-3.
  • R 1 and R 7 are each independently hydrogen, C1-C4 alkyl, or C2-C4 unsaturated hydrocarbon group.
  • substitution refers to including one or more substituents selected from the group consisting of halogen, hydroxy, phenyl, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 unsaturated hydrocarbon, C1-C4 alkoxy , C1-C4 haloalkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, cyano, nitro, methylol, carboxyl, mercapto.
  • R 2 and R 4 are each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, or -L1- (CH 2 ) m-C6-C10 aryl, wherein: L1 is none, -O- or -S-; m is 0, 1, 2 or 3.
  • R 5 is hydrogen or C1-C4 alkoxy.
  • the compound is:
  • a method for preparing a compound according to the second aspect including the following steps:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as described in the first aspect.
  • the method for preparing the compound includes the following steps:
  • a pharmaceutical composition comprising the compound described in the first aspect, or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, diastereomer Enantiomers or racemates, or mixtures thereof; and pharmaceutically acceptable carriers.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must have sufficient purity and low enough toxicity. "Compatibility” here means that each component in the composition can blend with the active ingredient of the present invention and each other without significantly reducing the medicinal effect of the active ingredient.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as Tween
  • Wetting agents such as sodium lauryl sulfate
  • the compound described in the first aspect or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, diastereomer or racemate thereof, or The use of their mixture, (a) for the preparation of inhibitors of SIRT1 deacetylase; or (b) for the preparation of drugs for treating diseases related to abnormal expression of SIRT1 protein or its enzyme activity level.
  • the abnormal expression of SIRT1 protein or a disease associated with its enzyme activity level is selected from the group consisting of: neurodegenerative disease, cancer, metabolic disease, immune disorder, and inflammation.
  • Figure 1 shows the results of SIRT1 enzyme activity in vitro experiments, illustrating that compound S3 inhibits SIRT1 activity in a concentration-dependent manner.
  • Figure 2 shows the inhibition type of compound S3 on SIRT1 protein.
  • A) and B) are the fixed NAD + concentration.
  • C) and D) are the concentrations of the fixed substrate Abz polypeptide, respectively.
  • the NAD + concentration is changed, the Mie constant curve and the double reciprocal curve of the compound S3 against NAD + are detected.
  • This shows that compound S3 is a competitive inhibitor of the substrate polypeptide Abz and a non-competitive inhibitor of NAD + .
  • Figure 3 is a graph showing the binding curve of compound S3 and protein detected by a microthermophoresis test (MST). Result chart illustrating that compound S3 competitively binds to the binding site of the substrate polypeptide Abz.
  • FIG. 4 A) the molecular simulation results of compound S3 and SIRT1 binding; B) the results of SIRT1 mutant enzyme kinetic experiment.
  • Figure 5 shows the effect of compounds on p53 acetylation levels in SH-SY5Y human neuroblastoma cells.
  • the control group Con, control
  • DMSO 10 ⁇ M
  • the SIRT1 inhibitor Ex527 reported in the literature was used as a positive control
  • ⁇ -actin was used as an internal reference.
  • anti-p53 (acetyl K381) antibody article number: ab61241)
  • anti-p53 antibody article number: ab26
  • Antibodies were purchased from LICOR.
  • the present inventors Based on long-term and in-depth research, the present inventors have prepared a class of compounds having a structure represented by Formula I and found that they have SIRT1 inhibitory activity. In addition, the compound has an inhibitory effect on SIRT1 at a low concentration, and the inhibitory activity is quite excellent. Therefore, it can be used to treat diseases related to SIRT1 activity or expression, such as neurodegenerative diseases, metabolic diseases, and tumors. Based on this, the present invention has been completed.
  • C1-C12 alkyl refers to a straight or branched chain alkyl group having 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, S-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl, or similar groups.
  • C1-C6 alkyl refers to a straight or branched chain alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms
  • C1-C4 alkyl refers to a group having 1, 2, 3, or 4 Straight or branched chain alkyl groups of one carbon atom, and so on.
  • C1-C12 haloalkyl refers to a straight or branched chain alkyl group having 1 to 12 carbon atoms, such as trifluoromethyl, etc., which is substituted with 1, 2, 3 or more halogens.
  • C2-C12 unsaturated hydrocarbon group refers to a linear or branched alkenyl or alkynyl group having 2 to 12 carbon atoms, such as vinyl, propynyl, and the like.
  • C1-C6 alkoxy refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso Butoxy, sec-butoxy, and tert-butoxy, or similar groups.
  • the definition of "C1-C6 alkoxy” includes “C1-C4 alkoxy”.
  • C3-C12 cycloalkyl refers to a saturated or unsaturated hydrocarbon group having 3-12 carbon atoms on the ring, such as cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl and the like.
  • C3-C8 cycloalkyl refers to a saturated hydrocarbon group having 3 to 8 carbon atoms on the ring, such as cyclopropyl, cyclobutyl, cyclohexyl and the like.
  • C6-C12 aryl refers to a monocyclic or fused bicyclic ring having 6 to 12 carbon atoms, a substituent having a conjugated pi electron system, such as phenyl and naphthyl, or the like.
  • the definition of “C6-C12 aryl” includes “C6-C10 aryl”.
  • 3-12 membered heterocyclyl refers to a monocyclic or fused bicyclic ring having 3-12 ring atoms and having one or more (preferably 1-5) ring systems selected from O, S, N or Heteroatoms of P, such as piperidinyl, pyrrolidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, benzodioxolyl, tetrahydropyrrolyl or the like.
  • the definition of "3-12 membered heterocyclic group” includes “4-10 membered heterocyclic group”.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • substituted refers to the replacement of one or more hydrogen atoms on a group with a substituent selected from the group consisting of halogen, carboxyl, unsubstituted or halogenated C1-C6 alkyl , Unsubstituted or halogenated C2-C6 acyl, unsubstituted or halogenated C1-C6 alkyl-hydroxy.
  • each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • the term "compound of the invention” refers to a compound of formula I.
  • the term also includes various crystalline forms of the compounds of Formula I, pharmaceutically acceptable salts, hydrates or solvates.
  • the term "pharmaceutically acceptable salt” refers to a salt of a compound of the present invention and an acid or base suitable for use as a medicament.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • One preferred type of salt is a salt of a compound of the invention with an acid.
  • Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,
  • Organic acids such as maleic acid, lactic acid, mal
  • the compounds of the invention inhibit the activity of one or more sirtuin proteins.
  • the compound of the present invention can be used to inhibit the activity of the sirtuin enzyme in a cell or a patient, and the inhibitory function of the sirtuin protein can be achieved by applying an inhibitory amount of the compound of the present invention to the cell, individual or patient. .
  • the compounds of the present invention are suitable for treating various diseases associated with abnormal expression or activity of SIRT1.
  • the abnormal proliferation diseases related to the activity or expression of SIRT1 include but are not limited to the following diseases: histiocytic lymphoma, ovarian cancer, head and neck phosphorous epithelial cell cancer, gastric cancer, breast cancer, childhood hepatocellular carcinoma, colorectal cancer , Cervical cancer, lung cancer, sarcoma, nasopharyngeal cancer, pancreatic cancer, glioblastoma, prostate cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, thyroid cancer, testicular cancer, cervical cancer, lung adenocarcinoma , Colon cancer, papillary renal cell carcinoma, glioblastoma, endometrial cancer, esophageal cancer, leukemia, renal cell carcinoma, bladder cancer, liver cancer and astrocytoma, glioma, non-malignant skin cancer,
  • the compounds and compositions of the present invention are used to treat, prevent or regulate metabolic related diseases, including diabetes, hyperlipidemia, obesity, hyperglycemia and hypertonic syndrome.
  • the compounds and compositions of the present invention are used to treat, prevent or regulate neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinocerebellar ataxia and spinal sex Muscular atrophy.
  • neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinocerebellar ataxia and spinal sex Muscular atrophy.
  • the 1,3-dioxane-4,6-dione compounds of the present invention have low toxicity and good solubility.
  • the preparation method of the 1,3-dioxane-4,6-dione compound and its derivatives has the advantages of mild reaction conditions, abundant raw materials, easy operation and post-treatment, and good corresponding selectivity.
  • the 1,3-dioxane-4,6-dione compounds and derivatives thereof according to the present invention have very good inhibitory activity and excellent selectivity on SIRT deacetylase.
  • the compounds of the present invention can be used to treat various diseases related to abnormal expression or activity of SIRT1 protein, such as neurodegenerative diseases, diabetes, tumors and other diseases.
  • Step 2 preparing S1
  • Step 2 preparing S2
  • the compound S5 was prepared in the same manner as in Example 1 except that 4- (benzylphenoxy) methyl) benzoic acid was used instead of 4-chlorobenzaldehyde, and the final reaction yield was 23%.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 8.24 (s, 1H), 8.08-7.92 (m, 2H), 8.05-8.01 (m, 1H), 7.95-7.85 (m, 1H), 7.62-7.50 (m, 3H), 7.48-7.38 (m, 4H), 7.10-7.01 (m, 2H), 6.88 (s, 1H), 5.20 (s, 2H).
  • Compound S6 was prepared in the same manner as in Example 1 except that 4-chlorobenzaldehyde was replaced with 4-hydroxy-3-iodo-5-methoxybenzaldehyde, and the reaction yield in the last step was 70%.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 10.65 (s, 1H), 8.14 (s, 1H), 8.08-7.92 (m, 2H), 7.56-7.48 (m, 2H), 7.42-7.38 (m 3H), 6.82 (s, 1H), 3.83 (s, 3H).
  • Compound S10 was prepared in the same manner as in Example 1 except that 4-chloro-3-chlorobenzaldehyde was replaced with 4-hydroxy-3-chloro-5-methoxybenzaldehyde, and the reaction yield in the last step was 72%.
  • 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 8.15 (s, 1H), 7.90-7.82 (m, 1H), 7.80-7.74 (m, 1H), 7.58-7.45 (m, 2H), 7.42-7.36 (m, 3H), 6.82 (s, 1H), 3.84 (s, 3H).
  • the compound S20 was prepared in the same manner as in Example 1 except that 4- (1-tetrahydropyrrolyl) benzaldehyde was used instead of 4-chlorobenzaldehyde, and the final step yield was 22%.
  • 1 H NMR 400MHz, CDCl 3 ) ⁇ 8.32 (s, 1H), 8.28-8.19 (m, 2H), 7.68-7.58 (m, 2H), 7.52-7.40 (m, 3H), 6.64-6.52 (m , 3H), 3.58-3.40 (m, 4H), 2.18-1.97 (m, 4H).
  • the inhibitory activity of 1,3-dioxane-4,6-dione compounds on SIRT deacetylase activity is determined.
  • the experimental materials used in pharmacological experiments are commercially purchased except for special instructions.
  • the peptide Abz-GVLK (Ac) AY (NO2) GV-NH2 was prepared into a 10 mM storage solution with DMSO, and then frozen in a -80 ° C refrigerator after being dispensed; NAD + enzyme-activated reaction buffer (25 mM Tris, pH 8.0) (137 mM sodium chloride, 2.7 mM potassium chloride, 1 mM magnesium chloride) was prepared into a 50 mM stock solution; small molecule compounds were prepared into a 10 mM stock solution with DMSO.
  • the reaction system was 100 ⁇ L.
  • the system contained 1 ⁇ M SIRT1, 500 ⁇ M NAD + , 10 ⁇ M substrate peptide, and compounds at corresponding concentrations.
  • Each reaction condition had 3 auxiliary wells, and each experiment was repeated 3 times.
  • 50 ⁇ L of 10 mM nicotinamide and 0.01 mg / mL trypsin were added to each well to terminate the reaction and perform digestion.
  • the fluorescence value was read with a microplate reader, and the excitation and emission wavelengths were 320 nm and 420 nm, respectively.
  • these compounds are all 1,3-dioxane-4,6-dione with a phenyl group at the C2 position and a benzylidene structure at the C5 position.
  • the SIRT1 enzyme activity test was used to test the IC 50 (Table 2) of SIRT1 deacetylase activity inhibition by these batches of compounds, indicating that these compounds have inhibitory effects on SIRT1 deacetylase activity.
  • SI527 inhibitor EX527 was selected as the positive compound.
  • the IC 50 detection method for determining the inhibitory effect of small molecule compounds on SIRT1 and the concentration ratio of each component, the inhibitory effect of these compounds on SIRT1 homologous proteins was detected.
  • these compounds are selective inhibitors of SIRT1 and have better selectivity than the positive compound EX527. It can be seen that the compounds of the present invention have very good inhibitory activity on SIRT1 and have good selectivity.
  • a and B are respectively the Mie constant curve and the double reciprocal curve of compound S3 to the Abz polypeptide when the concentration of NAD + is fixed and the substrate Abz polypeptide concentration is changed.
  • C and D in FIG. 2 are respectively the Mie constant curve and the double reciprocal curve of compound S3 versus NAD + when the concentration of Abz polypeptide is fixed and the NAD + concentration is changed.
  • the curve intersects the horizontal axis at different compound concentrations, indicating that as the concentration of compound S3 increases, the initial velocity V 0 decreases and the apparent Mie constant K m ′ does not Therefore, the compound S3 is a non-competitive inhibitor of NAD + , and the binding of S3 to SIRT1 is not at the NAD + binding site.
  • mini-hSIRT1 protein was centrifuged at high speed (12,000 rpm, 10 min) to remove gas, it was left at room temperature for 30 min.
  • the labeled SIRT1 Cy5 protein was centrifuged at high speed (13,000 rpm, 5 min) to remove aggregates.
  • the labeled SIRT1 Cy5 protein was diluted to 200 nM with MST optimized buffer (50 mM Tris, pH 7.4, 150 mM sodium chloride, 10 mM magnesium chloride, 0.05% Tween-20).
  • MST optimized buffer 50 mM Tris, pH 7.4, 150 mM sodium chloride, 10 mM magnesium chloride, 0.05% Tween-20.
  • the concentration of SIRT1 Cy5 was fixed at 100 nM, the compound was set to an initial concentration of 500 ⁇ M, the dilution ratio was 16 gradients, and the DMSO content in the system was maintained at 10%.
  • Monolith NT115 (Nano Temper Technologies) was used to determine the MST curve under three conditions (Monolith NT115 parameters were set to 20% Red, MST Power 40.0%, excitation power 20%):
  • SIRT1 / EX527 complex crystal complex structure (PDB ID: 4I5I) from the RCSB-PDB database (www.rcsb.org), remove the EX527 molecules in the structure, extract the coordinates of a SIRT1 protein molecule, and save it as a pdb file .
  • Compound S3 was docked into the SIRT1 protein structure and the binding model was analyzed based on structure-activity relationship. As shown in Figure 4A, compound S3 binds to phenylalanine at position 273, asparagine at position 346, isoleucine at position 347, aspartic acid at position 348, and phenylalanine at position 414.
  • the mutant SIRT1 F414A has the largest effect on the inhibitory activity of the compound.
  • the compound has a hydrophobic effect between the phenyl group at the C2 position and the phenylalanine at the 414th position, which indicates that the phenylalanine at the 414th position of the SIRT1 is a key amino acid residue bound by the "protein / S3 small molecule compound", suggesting that in the next step
  • the hydrophobicity of the phenyl compound can be appropriately increased to further improve the activity of the compound.
  • SH-SY5Y human neuroblastoma cells were seeded in a 12-well plate, overnight in the culture solution, ATRA (all-trans-retinoic acid) and compound (10 ⁇ M) were added for 2 hours, and then collected Cells were washed once with pre-chilled PBS and cell lysate was added. After the cell lysate was heated in a boiling water bath for 5 minutes. After centrifugation at 4 ° C for 10 minutes using a high-speed centrifuge (12000 rpm), the supernatant was collected.
  • the supernatant was subjected to SDS-PAGE electrophoresis.
  • the gel after electrophoresis was cut and placed in a glass dish containing electrotransformation solution.
  • the membrane and filter paper were cut according to the size of the gel, and then a transfer membrane layer was prepared. It is placed on the anode, the gel is placed on the cathode, and the filter paper is on the outermost layer, which encloses the membrane and the gel.
  • the transfer film layer is placed in an electrorotation tank filled with an electro-transfer liquid to transfer the film.
  • the membrane was washed with a TBST washing solution, put in a blocking solution (5% skimmed milk powder), and blocked at 37 ° C for 2 hours.

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Abstract

La présente invention concerne un composé 1,3-dioxane-4,6-dione, un procédé de préparation, une composition pharmaceutique et une utilisation de celui-ci. La structure du composé est représentée par la formule I, la définition de chaque groupe de substituants est telle que décrite dans la spécification et les revendications. Le composé selon la présente invention inhibe l'activité de la protéine désacétylase SIRT1 et peut être utilisé dans des médicaments pour traiter diverses maladies associées à une expression anormale de la protéine désacétylase SIRT1 et une activité enzymatique de celle-ci, telles que des maladies neurodégénératives, des maladies métaboliques, le cancer, et similaires.
PCT/CN2019/092080 2018-06-21 2019-06-20 Composé 1,3-dioxane-4,6-dione, procédé de préparation, composition pharmaceutique et utilisation de celui-ci WO2019242687A1 (fr)

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Publication number Priority date Publication date Assignee Title
EP0578849A1 (fr) * 1992-07-17 1994-01-19 Biogal Gyogyszergyar Procédé pour la préparation de dérivés de 1,3-dioxane-4,6-dione
CN108640898A (zh) * 2018-06-21 2018-10-12 中国科学院上海药物研究所 1,3-二氧六环-4,6-二酮类化合物、其制备方法、药物组合物及其应用

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Publication number Priority date Publication date Assignee Title
EP0578849A1 (fr) * 1992-07-17 1994-01-19 Biogal Gyogyszergyar Procédé pour la préparation de dérivés de 1,3-dioxane-4,6-dione
CN108640898A (zh) * 2018-06-21 2018-10-12 中国科学院上海药物研究所 1,3-二氧六环-4,6-二酮类化合物、其制备方法、药物组合物及其应用

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Title
CASADESUS, M. ET AL.: "Synthesis of 5-Alkylidene- 1, 3-Dioxane-4, 6-Diones, an Easily Accessible Family of Axially Chiral Alkenes: Preparation in Non-racemic Form and Platinum Binding Studies", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 4, no. 20, 14 September 2006 (2006-09-14), pages 3822 - 3830, XP055665214, ISSN: 1477-0520, DOI: 10.1039/b608785j *
DATABASE STNext Registry Database American Chemical Society ACS; 28 July 2006 (2006-07-28) *
LIU, RUIHUAN ET AL.: "SIRT1 Research Progress of SIRT1 Inhibitors (Non-official translation )", CENTRAL SOUTH PHARMACY, vol. 10, no. 8, 8 August 2012 (2012-08-08), pages 617 - 622, XP055665228 *
SWOBODA, J. ET AL.: "Zur Kenntnis Cyclischer Acylale, 1. Mitt", MONATSHEFTE FUER CHEMIE, vol. 91, no. 1, 1 January 1960 (1960-01-01), pages 188 - 201, XP055665221 *

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