CN117362286B - Compounds with SIRT6 agonistic activity and uses thereof - Google Patents
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- CN117362286B CN117362286B CN202311679118.7A CN202311679118A CN117362286B CN 117362286 B CN117362286 B CN 117362286B CN 202311679118 A CN202311679118 A CN 202311679118A CN 117362286 B CN117362286 B CN 117362286B
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Abstract
The invention discloses a compound which is a compound shown in a formula (I) or stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof. The compound has SIRT6 agonistic activity, can be used as SIRT6 agonist or medicine for promoting the expression or activity of SIRT6 protein in cells, and is effective in preventing and/or treating SIRT6 protein mediated related diseases.(I)。
Description
Technical Field
The invention belongs to the technical field of biological pharmacy, and particularly relates to a compound with SIRT6 agonistic activity and application thereof.
Background
SIRT6 is used as histone deacetylase and is a key protein for regulating and controlling key biological processes such as DNA repair, cell metabolism, apoptosis and the like through epigenetic modification. SIRT6 is also called as longevity protein and is a key drug target of diseases such as aging-related diseases, inflammations, cancers and the like. Therefore, the development of the medicine with the SIRT6 deacetylase activation effect has important significance for delaying senescence and treating senescence-associated diseases and realizing healthy aging.
Although there are many agonists that target SIRT6 deacetylase, such as MDL-800 and MDL-811, and have been shown to have anti-inflammatory effects. But screening SIRT6 agonists with lower toxicity or better efficacy is still of great scientific value. Therefore, development of a drug with better SIRT6 agonistic activity is needed.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems existing in the prior art to at least some extent. Therefore, the invention provides a compound with SIRT6 agonistic activity and application thereof, and the compound has SIRT6 agonistic activity and can be used as SIRT6 agonist to effectively prevent and/or treat SIRT6 protein mediated related diseases.
In a first aspect of the present invention, the present invention provides a compound of formula (I) or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt thereof:
(I)；
wherein R is 1 And R is 2 Each independently selected from H, halogen, C 1~6 Alkyl, C 1~6 Oxyalkyl, C 1~6 Haloalkyl or C 1~6 A haloalkoxy group;
each X is 1 Each independently selected from C, O, S or N;
n is any integer between 1 and 6.
The compound provided by the invention has SIRT6 agonistic activity, can be used as SIRT6 agonist, and is effective in preventing and/or treating SIRT6 protein mediated related diseases.
According to an embodiment of the invention, R 1 Selected from C 1~6 Alkyl, C 1~6 Oxyalkyl, C 1~6 Haloalkyl or C 1~6 Halogenated oxyalkyl groups.
According to an embodiment of the invention, R 1 Selected from C 1~3 Alkyl or C 1~3 An oxyalkyl group.
According to an embodiment of the invention, R 2 Selected from H, halogen or C 1~6 An alkyl group.
According to an embodiment of the invention, R 2 Selected from halogen.
According to an embodiment of the invention, each X 1 Each independently selected from C or S.
According to an embodiment of the invention, n is 1, 2,3 or 4.
According to an embodiment of the invention, n is 1, 2 or 3.
According to an embodiment of the present invention, the compound represented by formula (I) has a structure represented by formula (II):
(II)。
according to an embodiment of the present invention, the compound represented by formula (I) has the structure shown below:
、、
。
in a second aspect of the invention, the invention provides a pharmaceutical composition. According to an embodiment of the invention, the pharmaceutical composition comprises a compound according to the first aspect. From the foregoing, it is apparent that the compounds of the first aspect have SIRT6 agonistic activity and are useful as SIRT6 agonists. Thus, the pharmaceutical composition containing the compound can effectively prevent and/or treat SIRT6 protein mediated related diseases.
According to an embodiment of the invention, the pharmaceutical composition further comprises pharmaceutically acceptable excipients.
In a third aspect of the invention, the invention provides the use of a compound of the first aspect as a SIRT6 agonist. From the foregoing, it is apparent that the compound according to the first aspect has SIRT6 agonistic activity, and can promote the expression or activity of SIRT6 protein in cells or effectively prevent and/or treat SIRT6 protein-mediated related diseases by using the compound as a SIRT6 agonist.
In a fourth aspect of the invention, the invention provides the use of a compound of the first aspect in the preparation of an agent for promoting expression or activity of a SIRT6 protein. From the foregoing, it is apparent that the compound according to the first aspect has SIRT6 agonistic activity, and the compound can be used as an agent to effectively promote the expression or activity of SIRT6 protein, especially to enhance the expression or activity of SIRT6 protein in cells in vitro, for example, to construct a desired cell model.
In a fifth aspect of the invention, the invention provides the use of a compound as described in the first aspect or a pharmaceutical composition as described in the second aspect in the manufacture of a medicament for the prevention and/or treatment of a SIRT6 protein mediated related disease. From the foregoing, it can be seen that the compound of the first aspect has SIRT6 agonistic activity, and can be used as a SIRT6 drug to effectively prevent and/or treat SIRT6 protein-mediated related diseases or symptoms.
According to embodiments of the invention, the SIRT6 protein-mediated related diseases or symptoms include aging-related diseases, cancers, inflammation, aging.
According to an embodiment of the invention, the aging-related diseases include osteoarthritis, herniated disc, osteoporosis, alzheimer's disease, atherosclerosis, liver fibrosis, age-related macular degeneration, diabetic nephropathy, idiopathic pulmonary fibrosis.
In a sixth aspect of the invention, the invention provides a method of activating and/or promoting SIRT6 protein activity in a cell in vitro. According to an embodiment of the invention, the method comprises: contacting the cell with a compound according to the first aspect. From the foregoing, it is apparent that the compounds of the first aspect have SIRT6 agonistic activity. Thus, contacting the above-described compound with a cell can promote expression or activity of a SIRT6 protein in the cell.
Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Drawings
The foregoing and/or additional aspects and advantages of the invention will become apparent and may be better understood from the following description of embodiments taken in conjunction with the accompanying drawings in which:
FIG. 1 is a hydrogen spectrum of compound 1 of example 1;
FIG. 2 is a hydrogen spectrum of compound 2 of example 1;
FIG. 3 is a graph showing the results of the detection of SIRT6 enzyme activity of compound 1 of example 2;
FIG. 4 is a graph showing the results of the detection of SIRT6 enzyme activity of Compound 2 of example 2;
FIG. 5 shows the measurement results of the dose-response curve of Compound 1 in example 2;
FIG. 6 shows the measurement results of the dose-response curve of Compound 2 in example 2;
FIG. 7 shows the toxicity test results of compound 1 using CCK-8 in example 2;
FIG. 8 shows the toxicity test results of compound 2 using CCK-8 in example 2;
FIG. 9 is a graph showing the results of a Western blot to detect the activation of SIRT6 protein activity in a cell line from Compound 1 in example 2;
FIG. 10 is a graph showing the results of the detection of the activating effect of compound 2 on SIRT6 protein activity in a cell line using Western blot in example 2.
Detailed Description
Embodiments of the present invention are described in detail below. The following examples are illustrative only and are not to be construed as limiting the invention.
It should be noted that the terms "first," "second," and "second" are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or implying a number of technical features being indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include one or more such feature. Further, in the description of the present invention, unless otherwise indicated, the meaning of "a plurality" is two or more.
Description
Definitions and general terms
In this document, the terms "comprise" or "include" are used in an open-ended fashion, i.e., to include what is indicated by the present invention, but not to exclude other aspects.
In this document, the terms "optionally," "optional," or "optionally" generally refer to the subsequently described event or condition may, but need not, occur, and the description includes instances in which the event or condition occurs, as well as instances in which the event or condition does not.
Stereoisomers are defined and convention herein generally in accordance with s.p. parker, ed., mcGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, new York; and Eliel, e.and Wilen, s., "Stereochemistry of Organic Compounds", john Wiley & Sons, inc., new York,1994. The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers (attopiomers) and mixtures thereof, such as racemic mixtures, are also included within the scope of the present invention. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefix D and L or R and S are used to denote the absolute configuration of the molecule in terms of chiral center (or chiral centers) in the molecule. The prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light by a compound, where (-) or l indicates that the compound is left-handed. The compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are generally referred to as mixtures of enantiomers. Enantiomer 50: the 50 mixture is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.
Depending on the choice of starting materials and methods, the compounds according to the invention may be present in the form of one of the possible isomers or mixtures thereof, for example as pure optical isomers or as isomer mixtures, for example as racemic and non-corresponding isomer mixtures, depending on the number of asymmetric carbon atoms. Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may be in cis or trans (cis-or trans-) configuration.
The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers (attospimers) and geometric (or conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.
Herein, the term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can be converted to each other by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers (prototropic tautomer)) include interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence tautomers (valance tautomers) include interconversions by recombination of some of the bond-forming electrons. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
As used herein, the term "solvate" refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules that are water.
As used herein, the term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. Preferably, the term "pharmaceutically acceptable" as used herein refers to use in animals, particularly humans, approved by the federal regulatory agency or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia.
Herein, the term "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as in the literature: s.m. Berge et al describe pharmaceutically acceptable salts in detail in j Pharmaceutical Sciences, 1977, 66: 1-19.
In this context, the term "halogen" refers to a fluorine, chlorine, bromine or iodine atom.
Herein, the term "C 1~6 Alkyl "means a straight or branched saturated monovalent hydrocarbon group having 1, 2,3, 4, 5 or 6 carbon atoms, e.g. C 1~5 Alkyl, C 1~4 Alkyl, C 1~3 Alkyl, C 2~5 Alkyl, C 2~4 Alkyl, C 2~3 An alkyl group. Including but not limited to methyl, ethyl, n-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) Isopropyl (i-Pr, -CH (CH) 3 ) 2 ) N-butyl (n-Bu, -CH) 2 CH 2 CH 2 CH 3 ) Isobutyl (i-Bu, -CH) 2 CH(CH 3 ) 2 ) Sec-butyl (s-Bu, -CH (CH) 3 )CH 2 CH 3 ) Tert-butyl (t-Bu, -C (CH) 3 ) 3 ) N-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) N-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 )、4-Methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2, 3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3, 3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 ) Wherein the alkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.
Herein, the term "haloalkyl" means that one or more H of an alkyl group is replaced with any halogen.
Herein, the term "C 1~6 Alkoxy "means C containing the formula" -O-alkyl 1~6 Alkyl, wherein the term "alkyl" is as defined above. For example: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentoxy, isopentoxy and n-hexoxy, or isomers of the foregoing. In particular, the "C 1~6 Alkoxy "may contain 1, 2,3, 4 or 5 carbon atoms (" C 1~5 Alkoxy "), preferably, may contain 1, 2,3 or 4 carbon atoms (" C) 1~4 Alkoxy ").
In this context, the term "haloalkoxy" means that one or more H's of the oxyalkyl are replaced by any halogen.
As used herein, the term "pharmaceutically acceptable excipients" may include any solvent, solid excipient, diluent or other liquid excipient, etc., suitable for the particular dosage form of interest. In addition to the extent to which any conventional adjuvant is incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other component of the pharmaceutically acceptable composition in a deleterious manner, their use is also contemplated by the present invention.
In this context, the term "treatment" refers to the use to obtain a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing the disease or symptoms thereof, and/or may be therapeutic in terms of partially or completely curing the disease and/or adverse effects caused by the disease. As used herein, "treating" encompasses diseases in mammals, particularly humans, including: (a) Preventing the occurrence of a disease or disorder in an individual susceptible to the disease but not yet diagnosed with the disease; (b) inhibiting disease, e.g., arresting disease progression; or (c) alleviating a disease, e.g., alleviating symptoms associated with a disease. As used herein, "treating" or "treatment" encompasses any administration of a drug or compound to an individual to treat, cure, alleviate, ameliorate, reduce or inhibit a disease in the individual, including, but not limited to, administration of a drug comprising a compound described herein to an individual in need thereof.
As used herein, the term "cancer" or "tumor" can be any unregulated cell growth. Illustratively, non-small cell lung cancer, papillary thyroid cancer, glioblastoma multiforme, colon cancer, rectal cancer, lung cancer, head and neck cancer, kidney cancer, bladder cancer, nasopharyngeal cancer, glioblastoma, breast cancer, ovarian cancer, liver cancer, cholangiocarcinoma or sarcoma, acute myelogenous leukemia, large cell neuroendocrine cancer, neuroblastoma, prostate cancer, neuroblastoma, pancreatic cancer, melanoma, head and neck squamous cell carcinoma, cervical cancer, skin cancer, glioma, esophageal cancer, oral squamous cell carcinoma or gastric cancer, and the like.
Detailed description of Compounds of SIRT6 agonistic Activity and their use according to the invention
The invention provides a compound with SIRT6 agonistic activity and application thereof, and the compound and the application are respectively described in detail below.
Compounds of formula (I)
In a first aspect of the present invention, the present invention provides a compound of formula (I) or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt thereof:
(I)；
wherein R is 1 And R is 2 Each independently selectFrom H, halogen, C 1~6 Alkyl, C 1~6 Oxyalkyl, C 1~6 Haloalkyl or C 1~6 A haloalkoxy group;
each X is 1 Each independently selected from C, O, S or N;
n is any integer between 1 and 6.
The compound provided by the invention has SIRT6 agonistic activity, can be used as SIRT6 agonist, and is effective in preventing and/or treating SIRT6 protein mediated related diseases.
According to an embodiment of the invention, R 1 Selected from C 1~6 Alkyl, C 1~6 Oxyalkyl, C 1~6 Haloalkyl or C 1~6 Halogenated oxyalkyl groups.
According to an embodiment of the invention, R 1 Selected from C 1~3 Alkyl or C 1~3 An oxyalkyl group.
According to an embodiment of the invention, R 1 Is C 1~3 An oxyalkyl group.
According to an embodiment of the invention, R 1 is-O-CH 3 。
According to an embodiment of the invention, R 2 Selected from H, halogen or C 1~6 An alkyl group.
According to an embodiment of the invention, R 2 Selected from halogen.
According to an embodiment of the invention, R 2 Is Cl.
According to an embodiment of the invention, each X 1 Each independently selected from C or S.
According to an embodiment of the invention, X 1 Is C.
According to an embodiment of the invention, X 1 S.
According to an embodiment of the invention, n is 1, 2,3 or 4.
According to an embodiment of the invention, n is 1, 2 or 3.
According to an embodiment of the invention, n is 1.
According to an embodiment of the invention, n is 2.
According to an embodiment of the invention, n is 3.
According to an embodiment of the present invention, the compound represented by formula (I) has a structure as described by formula (II) below:
(II)。
according to an embodiment of the present invention, the compound represented by formula (I) has a structure described by the following formula (IIa), formula (IIb) or formula (IIc):
(IIa)；
(IIb)；
(IIc)。
according to an embodiment of the present invention, the compound represented by formula (I) has the structure shown below:
、
、
。
use of the same
In a second aspect of the invention, the invention provides a pharmaceutical composition. According to an embodiment of the invention, the pharmaceutical composition comprises a compound according to the first aspect. From the foregoing, it is apparent that the compounds of the first aspect have SIRT6 agonistic activity and are useful as SIRT6 agonists. Thus, the pharmaceutical composition containing the compound can effectively prevent and/or treat SIRT6 protein mediated related diseases.
According to an embodiment of the invention, the pharmaceutical composition further comprises pharmaceutically acceptable excipients.
Administration of the pharmaceutical compositions of the present invention may be carried out by any acceptable mode of administration. The pharmaceutical compositions of the present invention may be formulated as solid, semi-solid, liquid or gaseous forms of preparations such as tablets, capsules, injections, freeze-dried powders, the current methods of preparing such dosage forms being known or obvious to a person skilled in the art. Typical routes of administration of such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal and intranasal routes. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intradermal, intrasternal injection or infusion techniques. The pharmaceutical composition of the present invention is formulated so as to allow the biologically active ingredient contained therein to be bioavailable upon administration of the composition to a patient.
In a third aspect of the invention, the invention provides the use of a compound of the first aspect as a SIRT6 agonist. From the foregoing, it is apparent that the compound according to the first aspect has SIRT6 agonistic activity, and can promote the expression or activity of SIRT6 protein in cells or effectively prevent and/or treat SIRT6 protein-mediated related diseases by using the compound as a SIRT6 agonist.
In a fourth aspect of the invention, the invention provides the use of a compound of the first aspect in the preparation of an agent for promoting expression or activity of a SIRT6 protein. From the foregoing, it can be seen that the compound of the first aspect has SIRT6 agonistic activity, and when used as a reagent, the compound can effectively promote the expression or activity of SIRT6 protein, especially can improve the expression or activity of SIRT6 protein in cells in vitro, and can construct a desired cell model.
In a fifth aspect of the invention, the invention provides the use of a compound as described in the first aspect or a pharmaceutical composition as described in the second aspect in the manufacture of a medicament for the prevention and/or treatment of a SIRT6 protein mediated related disease. From the foregoing, it can be seen that the compound of the first aspect has SIRT6 agonistic activity, and can be used as a SIRT6 drug to effectively prevent and/or treat SIRT6 protein-mediated related diseases or symptoms.
According to embodiments of the invention, the SIRT6 protein-mediated related diseases or symptoms include aging-related diseases, cancers, inflammation, aging.
According to an embodiment of the invention, the aging-related diseases include osteoarthritis, herniated disc, osteoporosis, alzheimer's disease, atherosclerosis, liver fibrosis, age-related macular degeneration, diabetic nephropathy, idiopathic pulmonary fibrosis.
As used herein, "anti-aging" refers to the ability to prevent aging in an individual organism, such as to combat skin aging, combat cellular aging, or delay shortening of telomere length.
Method for activating SIRT6 protein activity of cells in vitro
In a sixth aspect of the invention, the invention provides a method of activating and/or promoting SIRT6 protein activity in a cell in vitro. According to an embodiment of the invention, the method comprises: contacting the cell with a compound according to the first aspect. From the foregoing, it is apparent that the compounds of the first aspect have SIRT6 agonistic activity. Thus, contacting the above-described compound with a cell can promote expression or activity of a SIRT6 protein in the cell.
In a seventh aspect of the invention, the invention provides a method of preventing and/or treating a SIRT6 protein mediated related disease. According to an embodiment of the invention, the method comprises: administering to a subject a pharmaceutically acceptable amount of a compound of the first aspect or a pharmaceutical composition of the second aspect. From the foregoing, it is apparent that the compounds of the first aspect have SIRT6 agonistic activity. Thus, the compounds can be used for effectively preventing and/or treating SIRT6 protein mediated related diseases or symptoms.
The effective amount of the compounds of the present invention may vary depending upon the mode of administration and the severity of the condition being treated, etc. The selection of the preferred effective amount can be determined by one of ordinary skill in the art based on a variety of factors (e.g., by clinical trials). Such factors include, but are not limited to: pharmacokinetic parameters of the active ingredient such as bioavailability, metabolism, half-life etc.; the severity of the disease to be treated in the patient, the weight of the patient, the immune status of the patient, the route of administration, etc. For example, separate doses may be administered several times per day, or the dose may be proportionally reduced, as dictated by the urgent need for the treatment of the condition.
The compounds of the invention may be incorporated into medicaments suitable for parenteral administration (e.g. intravenous, subcutaneous, intraperitoneal, intramuscular). These drugs can be prepared in various forms. Such as liquid, semi-solid, and solid dosage forms, and the like.
According to embodiments of the invention, the SIRT6 protein-mediated related diseases or symptoms include aging-related diseases, cancers, inflammation, aging.
According to an embodiment of the invention, the aging-related diseases include osteoarthritis, herniated disc, osteoporosis, alzheimer's disease, atherosclerosis, liver fibrosis, age-related macular degeneration, diabetic nephropathy, idiopathic pulmonary fibrosis.
In some alternative embodiments of the invention, the cancer is bladder cancer, nasopharyngeal cancer, glioblastoma.
The scheme of the present invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1: acquisition of Compounds
1. Compound 1 was synthesized by Shanghai Tao Shu biology (TOPScience) technology, inc., and the hydrogen spectrum of compound 1 is shown in fig. 1, which is characterized by:
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.37 (s, 1H), 9.80 (s, 1H), 8.10 (s, 1H), 7.74 (d, 1H), 7.65 (d, 1H), 7.40 (d, 1H), 7.31 (d, 1H), 7.06 (d, 1H), 3.80 (s, 3H), 3.71-3.60 (m, 2H), 2.43-2.21 (m, 3H), 1.92-1.81 (m, 2H), 1.73-1.58 (m, 2H).
the structural formula of compound 1 is shown below:
。
2. compound 2 was synthesized by Shanghai Tao Shu biology (TOPScience) technology, inc., and the hydrogen spectrum of compound 2 is shown in figure 2 and characterized as:
1 H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 9.80 (s, 1H), 7.74 (d, 1H), 7.62 (dd, 2H), 7.39 (dd, 1H), 7.17 (d, 1H), 7.08 (d, 1H), 3.80 (s, 3H), 3.71-3.62 (m, 2H), 2.81 (t, 2H), 2.40-2.11 (m, 7H), 1.91-1.80 (m, 2H), 1.70-1.56 (m, 2H).
the structural formula of compound 2 is shown below:
。
example 2: activity detection of Compounds
1. SIRT6 enzyme Activity verification of Compounds
Firstly, long-chain polypeptide of lysine (RHKK-Lys (Ac) -AMC) synthesized by Fmoc solid-phase polypeptide synthesis method is subjected to acetylation modification on the last lysine and is connected with coumarin. Coumarin is a natural fluorescent group that emits fluorescence at 460nm after excitation at 360nm in the free state. Then adding a compound into a system containing lysine long-chain polypeptide, removing lysine acetylation modification by catalyzing SIRT6 protein in the system by the compound, so that coumarin is exposed, and in the subsequent operation of adding trypsin, the chemical bond of the coumarin and lysine can be cut off, so that free coumarin capable of emitting fluorescent signals is generated, the activity of SIRT6 deacetylase in the system is reflected by detecting the intensity of the fluorescent signals, and the activating effect of the added compound on SIRT6 enzyme activity is reflected. Wherein, the detailed steps are as follows:
1) Compound 1 and compound 2 in example 1 were tested for in vitro enzyme activity using well plates with transparent bottoms and black inner walls, respectively.
2) The reaction system for enzyme activity detection is shown in Table 1:
TABLE 1
The test compound was added at a final concentration of 50. Mu.M, and the above reaction system was further added. The reagents in the above table all need to be diluted to final concentration with buffer system solutions, the ratio of which is shown in table 2:
TABLE 2
The total volume was made up to 20. Mu.l with buffer solution and incubated in a constant temperature incubator at 37℃for 2 hours in the absence of light.
3) After the reaction was completed, 40mM NAM,6 mg/ml trypsin was added to each 20. Mu.l of the reaction system, and the system was thoroughly mixed in a incubator at 25℃for 30 minutes at 160 rpm.
4) The excitation wavelength of the enzyme-labeled instrument is set to be 360nm, the emission wavelength is set to be 460nm, the reaction system is detected, and the catalytic activity of SIRT6 is calculated according to the following formula:
the detection results of compound 1 are shown in fig. 3, and the detection results of compound 2 are shown in fig. 4. As a result, it was found that both compound 1 and compound 2 have a higher activating effect on SIRT6 enzyme activity than the existing agonists MDL-800 and ellagic acid.
2. Compound dose-response curve detection
Taking the compound 1 and the compound 2 in the example 1, setting up different concentration gradients, detecting the compound at each concentration according to the fluorescent reaction system of the step 2, drawing a dose-response curve, and detecting the compound 1See fig. 5, and the results of the detection of compound 2 are shown in fig. 6. As a result, it was found that log (IC) of Compound 1 in an in vitro enzyme activity detection system 50 ) 1.881, log (IC) of Compound 2 50 ) 1.556.
3. Toxicity detection of Compounds
Compound 1 and compound 2 in example 1 were taken, compound 1 and compound 2 were added to culture supernatants of mouse hippocampal neuronal cell line HT22 at different concentration gradients, respectively, and after incubation at 37 ℃ for 48 hours, inhibition of proliferation of cells at each concentration was examined using CCK8, and the results of detection of compound 1 are shown in fig. 7, and the results of detection of compound 2 are shown in fig. 8. As a result, it was found that both the toxicity of the compound 1 and the toxicity of the compound 2 were low, the cell activity was maintained by the action of the compound 1 at a concentration of 0.550 mmol/L, and the cell activity was maintained by the action of the compound 2 at a concentration of 0.989 mmol/L.
4. Compound physiological function detection
After compound 1 and compound 2 in example 1 were co-cultured with mouse hippocampal neuronal cell line HT22 at 37 ℃ for 48 hours, protein from mouse hippocampal neuronal cell line HT22 treated for 48 hours was taken for Western blot detection of acetylation of H3K9 sites, and the activation effect of compound 1 and compound 2 on SIRT6 on cell lines was evaluated, respectively, as shown in fig. 9 for the detection results of compound 1 and as shown in fig. 10 for the detection results of compound 2. As a result, both compound 1 and compound 2 were found to be effective in enhancing SIRT6 deacetylation activity on histones in cell lines.
Example 3: verification of anti-aging Activity of Compounds at the cellular level
Considering that cell lines have the characteristics of immortalized cells and cannot well characterize senescent cells, the present example performs experiments in primary cells or C2C12 cell lines specifically used to study senescence.
Common indicators of cell senescence levels currently being examined in the academy mainly include: SA-beta-Gal staining and p16 and p21 senescence-associated gene expression are detected. The method comprises the following specific steps:
1) The aging of the C2C12 cell line was induced using beta galactose, and compound 1 and compound 2 in example 1 were added to the medium, respectively, and the cells were co-cultured for 24 hours. The cells were harvested for RNA extraction, reverse transcribed into cDNA, and the expression of the p16 and p21 genes in the cells was detected by fluorescent quantitative PCR.
2) The aging of the C2C12 cell line was induced using beta galactose, and compound 1 and compound 2 in example 1 were added to the medium, respectively, and the cells were co-cultured for 24 hours. Cells were stained for SA- β -Gal, and the effect of compound addition on the positive rate of SA- β -Gal staining of cells was examined.
3) The primary cells were induced to undergo replicative senescence by multiple passages, and compound 1 and compound 2 in example 1 were added to the medium of the primary cells, respectively, and the cells were co-cultured for 24 hours. The cells were harvested for RNA extraction, reverse transcribed into cDNA, and the expression of the p16 and p21 genes in the cells was detected by fluorescent quantitative PCR.
4) The primary cells were induced to undergo replicative senescence by multiple passages, and compound 1 and compound 2 in example 1 were added to the medium of the primary cells, respectively, and the cells were co-cultured for 24 hours. The primary cells were stained for SA-beta-Gal, and the effect of compound addition on the positive rate of cell SA-beta-Gal staining was examined.
As a result, it was found that the intervention of Compound 1 and Compound 2 caused aging-inducing C2C12 to produce primary cells with replicative aging reaching the division limit, decreased SA-. Beta. -Gal staining positive rate or decreased expression levels of p16 and p21 genes, further demonstrated that the compounds of the present invention had anti-aging activity at the cellular level.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
Claims (11)
1. A compound which is a compound of formula (I) or a pharmaceutically acceptable salt thereof:
(I)；
wherein R is 1 And R is 2 Each independently selected from H, halogen, or C 1~3 An oxyalkyl group;
X 1 s, n is 1; alternatively, X 1 C and n is any integer between 1 and 4.
2. A compound according to claim 1, wherein X 1 Selected from C, n is 2,3 or 4.
3. The compound according to claim 1, wherein the compound represented by formula (I) has a structure represented by formula (II):
(II)。
4. the compound of claim 1, wherein the compound of formula (I) has the structure shown below:
、
、
。
5. a SIRT6 agonist comprising a compound of any one of claims 1 to 4.
6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, or a SIRT6 agonist according to claim 5.
7. Use of a compound of any one of claims 1 to 4, or a SIRT6 agonist of claim 5, in the manufacture of a reagent for promoting expression or activity of a SIRT6 protein.
8. Use of a compound according to any one of claims 1 to 4, a SIRT6 agonist according to claim 5 or a pharmaceutical composition according to claim 6 in the manufacture of a medicament for the prevention and/or treatment of a SIRT6 protein mediated related disease or condition.
9. The use of claim 8, wherein the SIRT6 protein mediated related disease or condition comprises an aging related disease, cancer, inflammation, aging.
10. The use according to claim 9, wherein the aging-related disease comprises osteoarthritis, herniated disc, osteoporosis, alzheimer's disease, atherosclerosis, liver fibrosis, age-related macular degeneration, diabetic nephropathy, idiopathic pulmonary fibrosis.
11. A method of activating and/or promoting SIRT6 protein activity in vitro for non-disease diagnostic and/or therapeutic purposes, comprising:
contacting the cell with a compound of any one of claims 1-4 or a SIRT6 agonist of claim 5.
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