CN116554263A - SIRT1 agonists and their use in the treatment of related diseases - Google Patents

SIRT1 agonists and their use in the treatment of related diseases Download PDF

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CN116554263A
CN116554263A CN202210106886.2A CN202210106886A CN116554263A CN 116554263 A CN116554263 A CN 116554263A CN 202210106886 A CN202210106886 A CN 202210106886A CN 116554263 A CN116554263 A CN 116554263A
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sirt1
compound
amino acid
arginine
cysteine
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刘东祥
余年达
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Shanghai Institute of Materia Medica of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/081—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1013—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a compound which has a structure shown as a formula I, wherein the definitions of X0, X1, X2 and X3 are described in the specification and the claims. The compound provided by the invention, which is used as an SIRT1 agonist, has high subtype selectivity on SIRT1, and can be used for treating related diseases such as inflammation, covid-19, septicemia, diabetes, cancer, cardiovascular diseases, acute kidney injury, nerve injury, neurodegenerative diseases and the like. X0-X1-X2-X3 (I).

Description

SIRT1 agonists and their use in the treatment of related diseases
Technical Field
The invention relates to the field of biological medicine, in particular to an SIRT1 agonist and application thereof in the treatment of related diseases.
Background
Sirtuins deacetylase is expressed as Nicotinamide Adenine Dinucleotide (NAD) + ) Catalytic protein deacetylation as cofactor with simultaneous NAD addition + To Nicotinamide (NAM) and 2' -O-acyl-ADP-ribose (OAADPr). Sirtuins have been found in humans in seven subtypes (SIRT 1-SIRT 7) which have distinct subcellular localization and functions, with SIRT1 being distributed in brain, heart, kidney, liver, retina, uterus, skeletal muscle, blood vessels, and adipose, etc., located primarily in the nucleus, and also transported through the nucleus to the cytoplasm, playing an important role in physiological processes, mainly in several ways: 1) SIRT1 affects chromatin condensation by deacetylating histones, regulating expression and activity of histones and their modifying enzymes, regulating transcription and expression of genes; 2) SIRT1 participates in DNA damage repair and body aging processes by regulating the acetylation levels of FOXO3a, LKB1 and p 53; 3) SIRT1 is very important for embryo and brain development, and only 20% of mouse fertilized eggs with SIRT1 gene deletion can develop and mature, but the development is slow, eyes and hearts are malformed, and brain infants appear or not; in addition, SIRT1 also has protective effects on neurons in traumatic brain injury and Alzheimer's disease; 4) The SIRT1 tissue specificity high expression in the myocardial cells can reduce the range affected by myocardial infarction and promote the recovery of the organism; 5) PGC-1 alpha inhibits the expression of glycolytic genes and the activities of glucokinase G6P and pyruvate kinase PEPCK, SIRT1 forms a compound with HNF4 alpha through deacetylation of PGC-1 alpha so as to regulate the expression of gluconeogenesis related genes and the activities of PEPCK and G6P and promote hepatic glucose metabolism; 6) Upregulation of SIRT1 promotes FOXO3a deacetylation, thereby inhibiting PUMA and alleviating Acute Kidney Injury (AKI); 7) SIRT1 is demonstrated by increasing lysosomal numbers and depletionAcetylation of lysosomal related proteins promotes degradation of beta-amyloid peptide (aβ) in primary astrocytes, which is beneficial for alleviating symptoms of Alzheimer's Disease (AD). Furthermore, in Huntington's Disease (HD) mouse models, specific knockouts of SIRT1 may lead to worsening brain pathology, while overexpression of SIRT1 may increase survival. It follows that the pleiotropic nature of SIRT1 makes it a hotspot target of interest in alleviating symptoms of aging, preventing and treating diseases associated with aging (such as inflammation, cardiovascular disease, neurodegenerative disease, diabetes and cancer). Therefore, a strong and high-selectivity SIRT1 agonist is developed to promote SIRT1 deacetylase reaction, and the SIRT1 agonist can be applied to the treatment of related diseases.
Several SIRT1 agonists have been reported to date, one of which is the natural product resveratrol, and there has been controversy in the past as to whether resveratrol is a true SIRT1 activator, because resveratrol shows activity that is actually caused by its interaction with a fluorescent group behind the substrate acetylated lysine, and if there is no fluorescent group or chemical group of a similar nature on the acetylated substrate, resveratrol has no effect on SIRT1 enzyme activity. In addition, some so-called SIRT1 agonists, such as SRT1720, that are synthesized artificially, can increase insulin sensitivity, decrease blood glucose levels, increase mitochondrial capacity in diet-induced obese or genetically mutated (Lepob/ob) mice, but in vivo it does not act directly on SIRT1 but via other signaling pathways; compound SRT2104, which has the same chemical backbone, exhibits poor pharmacokinetic properties when administered orally. In addition, 1, 4-dihydropyridine derivatives, 15-oxazolo [4,5-b ] pyridine and related heterocyclic analogs have also been reported as SIRT1 agonists. The activity exhibited by these compounds on SIRT1 depends on the fluorescent group behind the acetylated lysine, and only when the substrate's acetylated lysine residue is followed by a coumarin (AMC), rhodamine (TAMRA) fluorescent group or other similar chemical group, the promotion of SIRT1 enzyme activity by these compounds is observed in enzymatic experiments and therefore these compounds are now considered to be not real SIRT1 agonists. Even though these compounds are capable of promoting deacetylation of SIRT1 physiological substrates in a cellular or animal model, they are caused by other signaling pathways and do not act on SIRT1. Some of these compounds have entered phase I clinic on behalf of SIRT1 agonists, suggesting that SIRT1 agonists do have clinical application prospects, as well as the importance and urgency of developing true SIRT1 agonists.
Disclosure of Invention
The invention aims to provide an SIRT1 agonist which can promote SIRT1 enzyme activity.
In a first aspect of the present invention, there is provided a compound represented by the general formula (I),
X0-X1-X2-X3 (I)
wherein X0 is cysteine or a cysteine precursor procysteine;
x1 is any amino acid or amino acid analog;
x2 is arginine or lysine;
x3 is absent or is any chemical group, amino acid analog or amino acid analog modified with a chemical group at the carboxy terminus.
In another preferred embodiment, the chemical group is selected from the group consisting of: amidation, glycosylation, alcoholization, hydroformylation, ketonization, epoxyketonization, hydroxamate peptide, esterfication, N-alkylation, mercaptoethylamination, AMC, AFC, pNA, PEG, dap (Dnp), lys (Dye), rh110.
In another preferred embodiment, X1 is selected from: glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or an amino acid analog of the above type having a protecting group in the side chain or a non-protein derived amino acid analog thereof.
In another preferred embodiment, X3 is selected from: glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or an amino acid analog of the above type having a protecting group in the side chain or a non-protein derived amino acid analog thereof.
In another preferred embodiment, the amino acid analog is selected from the group consisting of: beta-amino acids, alpha-disubstituted amino acids, non-alpha-amino acids, secondary amine type amino acids, alpha, beta-double amino acids, sulfur containing amino acids, halogen containing amino acids, freidinger type amino acids.
In another preferred embodiment, the substituents in the α, α -disubstituted amino acids are each independently halogen, cyano, nitro, amino, hydroxy, carboxy, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 unsaturated hydrocarbyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 acyl, substituted or unsubstituted C3-C12 cycloalkyl, -L1- (CH) 2 ) m-substituted or unsubstituted C6-C12 aryl, -L1- (CH) 2 ) m-substituted or unsubstituted 3-12 membered heterocyclyl, -L1- (CH) 2 )m-C(＝O)-N(R 8 )(R 9 ) Wherein L1 is none, -O-, or-S-; m is 0, 1, 2, 3, 4 or 5; r is R 8 And R is 9 Each independently selected from: hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl, or substituted or unsubstituted C6-C12 aryl;
each of the above substitutions is meant to comprise 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 cyclic hydrocarbon, 3-12 membered heterocyclic, cyano, nitro, hydroxymethyl, carboxyl, mercapto.
In another preferred embodiment, X0, X1, X2, X3 are each independently L-form, D-form or DL-form.
In another preferred embodiment, X0 is cysteine, X1 is tryptophan, X2 is arginine, and X0, X1, X2 are not L-forms at the same time when X3 is absent.
In another preferred embodiment, X0 is cysteine;
x1 is tryptophan, aspartic acid, arginine, lysine, glutamine, glutamic acid, leucine, glycine, cysteine, proline, serine, threonine, histidine, alanine, methionine, tyrosine, or phenylalanine;
x2 is arginine or asparagine;
x3 is arginine, glutamic acid or tryptophan.
In a second aspect of the invention there is provided a pharmaceutical composition comprising a compound of the first aspect and a pharmaceutically acceptable carrier.
The novel compounds provided by the invention can be used singly or mixed with pharmaceutically acceptable auxiliary materials (such as excipient, diluent and the like) to prepare tablets, capsules, granules, syrups and the like for oral administration. The pharmaceutical composition can be prepared according to a conventional pharmaceutical method.
In another preferred embodiment, the pharmaceutical composition further comprises at least one additional therapeutic agent. Preferably, the at least one other therapeutic agent comprised in the pharmaceutical composition is selected from the group consisting of other anticancer agents, immunomodulators, anti-inflammatory agents, hypoglycemic agents, antiallergic agents, antiemetic agents, pain relieving agents, cytoprotective agents and combinations thereof.
In a third aspect of the invention there is provided the use of a compound according to the first aspect or a pharmaceutical composition according to the second aspect, (a) for the preparation of a SIRT1 agonist; or (b) for preparing a medicament for treating a disease associated with SIRT1 enzyme activity.
In another preferred embodiment, the disease associated with SIRT1 enzyme activity is selected from the group consisting of: inflammation, covid-19, sepsis, diabetes, cancer, cardiovascular disease, acute kidney injury, nerve injury, and neurodegenerative disease.
In a fourth aspect of the invention there is provided a method of non-therapeutically agonizing a SIRT1 enzyme in vitro comprising adding to a system in need thereof a compound as described in the first aspect or a pharmaceutical composition as described in the second aspect.
The present application provides chemical structures containing the amino acid sequence of X0-X1-X2-X3 (e.g., (Cys/procysteine) -X1- (Arg/Lys) -X3) and peptidomimetics thereof or compounds comprising these amino acid sequence formulae or peptidomimetics thereof, wherein X1 is any amino acid or amino acid analogue,x3 is not present or is any chemical group, amino acid analogue or amino acid analogue with modified chemical group at the carboxyl end, and the amino acid residue in the sequence can be L-type amino acid or D-type amino acid; the patent does not cover all L-type amino acids Cys-Trp-Arg polypeptides (the N-terminal and C-terminal of which are not chemically modified), but covers a peptide mimetic of Cys-Trp-Arg or a compound comprising such an amino acid sequence or peptide mimetic thereof, wherein the amino acid residues may be L-type amino acids or D-type amino acids. The compounds of the present application act as SIRT1 agonists, unlike the so-called "SIRT1 agonists" reported previously, whose promoting effect on SIRT1 enzymatic activity is independent of the chemical groups following the acetylation of lysine on the substrate, are true SIRT1 agonists, the-NH of Cys amino acid residues 2 and-SH on the side chain promotes dissociation of the reaction product from the enzyme complex by forming reversible covalent bonding with the C1' atom on the OAADPr sugar ring of the SIRT1 enzyme reaction product, thereby promoting SIRT1 enzyme reaction. The compound has high subtype selectivity to SIRT1 and can be used for treating related diseases such as inflammation, covid-19, septicemia, diabetes, cancer, cardiovascular diseases, acute kidney injury, nerve injury, neurodegenerative diseases and the like.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. Each feature disclosed in the description may be replaced by alternative features serving the same, equivalent or similar purpose. And are limited to a space, and are not described in detail herein.
Drawings
In FIG. 1A) shows the principle of a fluorescence experiment for detecting SIRT1 to catalyze the deacetylation reaction of AMC labeled acetyl peptide. Trypsin is Trypsin; b) To determine the dose-response curves of the compounds of the present application and resveratrol (resveratrol) to promote SIRT1 enzymatic reactions using the AMC fluorescence detection method. The relative activities are shown in the figure, the initial enzyme activity (i.e.without compound) is set to 1, and when the value reaches 1.5, the EC is the compound 1.5 。
FIG. 2A) shows detection of SIRT1 catalyzed Abz markersThe principle of fluorescence experiments of the deacetylation reaction of the acetyl peptide is recorded. Trypsin is Trypsin; b) To determine the dose-response curve of the compounds of the present application and resveratrol (resveratrol) to promote SIRT1 enzymatic reaction using the Abz fluorescence detection method; c) As a result of HPLC analysis, the compound CERW is shown to promote SIRT1 to GQSTSRHKK ac Deacetylation of LM polypeptides.
FIG. 3A) is a dose-response curve of compound CWR to SIRT1, SIRT2, SIRT3, SIRT5, SIRT6 enzyme responses determined by AMC fluorescence assay; b) Determination of CWR versus SIRT3, SIRT3 for AMC fluorescence detection methods R158M Dose-effect histogram of enzyme response.
The mechanism by which compounds promote SIRT1 enzymatic reactions is shown in a) in fig. 4: the N-terminal alpha-amino nitrogen and side chain sulfhydryl of Cys amino acid residue of the compound form reversible covalent bonding with C1' atom on the OAADPr sugar ring of SIRT1 enzyme reaction product to promote dissociation of the reaction product from the enzyme complex, thereby promoting SIRT1 enzyme reaction; b) The dose-response curve of CWR and its N-terminal acetylated analogs to SIRT1 enzyme response was determined for the AMC fluorescence detection method. Wherein Ac-CWR is N-terminal acetylated CWR.
In fig. 5 a) shows the interaction of compound CWR with SIRT1, red representing the acetylated peptide; green, blue, yellow and red represent C, N, S, O atoms, respectively. The N-terminal alpha-amino nitrogen of cysteine residue, side chain sulfhydryl and OAADPr form thiazolidine ring, arginine in the compound is surrounded by Glu214, asp292 and Asp298 of SIRT1, and salt bridge (or electrostatic) interaction is formed. Dashed box inside: the distance between the conserved arginine Arg274 of SIRT1 and the carbon atom of the ADPr ribocyclic C1'; B-E) shows the distances between the conserved arginine corresponding to SIRT2, SIRT3, SIRT5, SIRT6 and the ADPr ribocyclic C1' carbon atom in sequence.
FIG. 6 shows that compounds affect intracellular p53 acetylation levels by acting on SIRT1, wherein A-B) control groups were treated with 5%o (v/v) DMSO, experimental groups were treated with 10. Mu.M DOX with 0. Mu.M, 5. Mu.M, 10. Mu.M, and 25. Mu.M compounds, where 0. Mu.M indicates the addition of equal volumes of water; c) After SIRT1 knockdown, compound C D W D R D Effects on intracellular p53 acetylation levels. The DOX group was treated with 10. Mu.M DOX,while the control group was treated with 5%o (v/v) DMSO, the experimental group was treated with 10. Mu.M DOX, 25. Mu. M C D W D R D And si-SIRT1 treatment at different concentrations (increasing concentrations from left to right). Error bars represent mean ± SEM (n=5) p compared to control group<0.05，***p<0.001. Single-factor analysis of variance for Newman-Keuls post-hoc test.
Detailed Description
The inventor of the application researches and researches extensively and intensively develop a compound with a general structure of X0-X1-X2-X3 (such as Cys-X1- (Arg/Lys) and Cys-X1- (Arg/Lys) -X3 amino acid sequence), which adopts a brand new action mechanism to promote SIRT1 enzyme activity: i.e. -NH of Cys amino acid residues 2 and-SH on the side chain promotes dissociation of the reaction product from the enzyme complex by forming reversible covalent bonding with the C1' atom on the OAADPr sugar ring of the SIRT1 enzyme reaction product, thereby promoting SIRT1 enzyme reaction. Unlike the so-called "SIRT1 agonists" reported previously, the promotion of SIRT1 enzyme activity by the compounds of the present application, independent of the chemical groups following the acetylation of lysine on the substrate, is a true SIRT1 agonist, and the change of residues from L-type amino acids to D-type amino acids does not lead to the loss of compound activity, which is beneficial for improving its metabolic stability. In addition, the compounds have high subtype selectivity to SIRT1, and have no influence on SIRT2, SIRT3, SIRT5 and SIRT6 enzyme activities. The compound of the present application, as an SIRT1 agonist, can be used for the treatment of inflammation, covid-19, sepsis, diabetes, cancer, cardiovascular disease, acute kidney injury, nerve injury, neurodegenerative disease and other related diseases. On this basis, the present invention has been completed.
Compounds of formula (I)
The compound has a structure shown in the following general formula:
X0-X1-X2-X3(I)
wherein X0 is procysteine or Cys;
since procysteine (CA: 19771-63-2; designation L-2-OXOTHIAZOLIDINE-4-CARBOXYLIC ACID) can be converted in vivo by 5-Oxo-L-procline (5-Oxo-L-prolinase) into Cysteine, this application covers chemical structures containing the amino ACID sequence formula (Cys/procysteine) -X1- (Arg/Lys), (Cys/procysteine) -X1- (Arg/Lys) -X3 and peptidomimetics thereof, or compounds containing these amino ACID sequence formulae or peptidomimetics thereof.
X1 is any amino acid or amino acid analog; in another preferred embodiment, X1 is selected from: glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or an amino acid analog of the above type having a protecting group in the side chain or a non-protein derived amino acid analog thereof.
X2 is arginine or lysine.
X3 is absent or is any chemical group, amino acid analog or amino acid analog modified with a chemical group at the carboxy terminus. In another preferred embodiment, X3 is selected from: glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or an amino acid analog of the above type having a protecting group in the side chain or a non-protein derived amino acid analog thereof.
The amino acid residues in the sequence may be L-type amino acids, D-type amino acids. In another preferred embodiment, X0, X1, X2, X3 are each independently of the other L-or D-form.
The general formula I does not cover all L-type amino acid Cys-Trp-Arg polypeptide (the N-end and the C-end of the polypeptide are not chemically modified), but covers a peptide mimetic of Cys-Trp-Arg or a compound containing the amino acid sequence or the peptide mimetic, wherein the amino acid residue can be L-type amino acid or D-type amino acid.
The compound adopts a brand new action mechanism to promote the activity of SIRT1 enzyme: i.e. -NH of Cys amino acid residues 2 and-SH on the side chain promotes dissociation of the reaction product from the enzyme complex by forming reversible covalent bonds with C1 atoms on the OAADPr sugar ring of the SIRT1 enzyme reaction productAnd (3) performing SIRT1 enzyme reaction.
Unlike the so-called "SIRT1 agonists" reported previously, the promotion of SIRT1 enzyme activity by the compounds of the present application, independent of the chemical groups following the acetylation of lysine on the substrate, is a true SIRT1 agonist, and the change of residues from L-type amino acids to D-type amino acids does not lead to the loss of compound activity, which is beneficial for improving its metabolic stability.
In addition, the compounds have high subtype selectivity to SIRT1, and have no influence on SIRT2, SIRT3, SIRT5 and SIRT6 enzyme activities.
Research has reported that promoting SIRT1 has positive protective effect on inflammation, covid-19, diabetes, breast cancer, cardiovascular diseases, acute kidney injury, nerve injury caused by cerebral ischemia, and neurodegenerative diseases. The compound of the present application, as an SIRT1 agonist, can be used for the treatment of inflammation, covid-19, sepsis, diabetes, cancer, cardiovascular disease, acute kidney injury, nerve injury, neurodegenerative disease and other related diseases.
Pharmaceutical composition
The invention also provides a pharmaceutical composition comprising an active ingredient in a safe and effective amount, and a pharmaceutically acceptable carrier.
The "active ingredient" as used herein refers to the compound of formula I as described herein.
The active ingredient and the pharmaceutical composition can promote SIRT1 enzyme activity, have high subtype selectivity on SIRT1, have no influence on SIRT2, SIRT3, SIRT5 and SIRT6 enzyme activity, and can be used for treating related diseases such as inflammation, covid-19, septicemia, diabetes, cancer, cardiovascular diseases, acute kidney injury, nerve injury, neurodegenerative diseases and the like.
"safe and effective amount" means: the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 1-2000mg of active ingredient per dose, more preferably 10-200mg of active ingredient per dose. Preferably, the "one dose" is a tablet.
"pharmaceutically acceptable salt thereofAcceptable carrier "refers to: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatibility" as used herein means that the components of the composition are capable of blending with and between the active ingredients of the present invention without significantly reducing the efficacy of the active ingredients. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, and the like), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g.) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
The mode of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and the like.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like. In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active ingredient, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the present invention may be administered alone or in combination with other therapeutic agents (e.g., antineoplastic agents, anti-inflammatory agents, etc.).
When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 20 to 500mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions (e.g.those described in Sambrook et al, molecular cloning: A laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989)) or under conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
Amino acids and abbreviations are shown in the following table.
Name of the name English Three letters Single letter
Glycine (Gly) Glycine Gly G
Alanine (Ala) Alanine Ala A
Valine (valine) Valine Val V
Leucine (leucine) Leucine Leu L
Isoleucine (Ile) Isoleucine Ile I
Proline (proline) Proline Pro P
Phenylalanine (Phe) Phenylalanine Phe F
Tyrosine Tyrosine Tyr Y
Tryptophan Tryptophan Trp W
Serine (serine) Serine Ser S
Threonine (Thr) Threonine Thr T
Cysteine (cysteine) Cystine Cys C
Methionine Methionine Met M
Asparagine derivatives Asparagine Asn N
Glutamine Glutarnine Gln Q
Aspartic acid Aspartic acid Asp D
Glutamic acid Glutamic acid Glu E
Lysine Lysine Lys K
Arginine (Arg) Arginine Arg R
Histidine Histidine His H
Preparation of polypeptide Compounds
All polypeptides of the invention were synthesized using Wang resin, fmoc-based solid phase method, and the amino acid residues were coupled in sequence from the carboxy-terminus to the amino-terminus (i.e., right to left). Fmoc deprotection and coupling of amino acids are as follows: treating Wang resin with Fmoc-protected polypeptide rightmost amino acid residue with 20% piperidine to remove Fmoc protection; the second amino acid residue at the right end of the Fmoc-protected polypeptide was activated by 2- (1H-benzotriazole-1-oxy) -1, 3-tetramethyluronium Hexafluorophosphate (HBTU) in the presence of N-methylmorpholine (NMM) and reacted with the resin for 1 hour to couple with the Fmoc-deprotected amino acid on the resin. Repeating the Fmoc deprotection and coupling steps until all amino acid residues of the polypeptide are coupled to the resin, finally removing Fmoc on the polypeptide by trifluoroacetic acid (TFA) and cutting the Fmoc from the resin, and purifying the sample by High Performance Liquid Chromatography (HPLC) by using a C18 Pep RPC reverse phase column to obtain the pure target polypeptide (solvent A:0.1% TFA/water, solvent B:0.1% TFA/MeCN, flow rate: 10.0 ml/min, elution gradient: 10% -90% solvent B,30 min).
Example 1
Compounds containing Cys-X- (Arg/Lys) and Cys-X- (Arg/Lys) -X amino acid sequence general structure promote SIRT1 enzyme reaction
The literature experiments for screening SIRT1 agonists generally used a "Fluor de Lys" (FdL) peptide RHKKAc AMC as substrate (FIG. 1A). RHKK is derived from amino acid residues 379-382 of the SIRT1 physiological substrate p53 protein, wherein lysine 382 is acetylated, and 7-amino-4-methylcoumarin (AMC) is connected at the C-terminal, thus forming the so-called FdL. However, a disadvantage of this assay is that the compound interacts with the fluorophore AMC, resulting in a false positive result that the compound promotes SIRT1 enzyme activity. Thus, when using the "SIRT1 agonist" found using the FdL assay, agonist activity may not be observed in vivo because the natural state of the acetyllysine of the SIRT1 physiological substrate is not followed by a fluorescent or similar chemical moiety.
By usingFdL method (A in FIG. 1), 0.5. Mu.M SIRT1, 750. Mu.M NAD + Compounds of 31.25. Mu.M RHKKAcAMC and different concentrations (0.5. Mu.M, 1.5. Mu.M, 4.5. Mu.M, 13.5. Mu.M, 40.5. Mu.M, 121.5. Mu.M) were placed in enzyme reaction buffers (i.e.25 mM Tris-HCl, pH 8.0, 137mM NaCl, 2.7mM KCl, 1mM MgCl2) and reacted at 37℃for 45 minutes. Then, trypsin (0.5 mg/ml) containing 10mM nicotinamide was added and incubated at 37℃for 30min. The effect of the polypeptide compound CWR on SIRT1 enzyme activity was evaluated by measuring fluorescence at 340nm excitation wavelength and 490nm emission wavelength using a microplate reader (POLARstar OPTIMA, BMG Labtech) 1.5 At 3.16. Mu.M (B in FIG. 1), resveratrol (EC) was superior to the control compound 1.5 19.2 μm). Interestingly, peptide C containing amino acid form D D W D R D Is equivalent to CWR in activity, and the reverse D-form peptide R D W D C D Does not exhibit any activity. This suggests that the amino acid sequence of the compound is critical for activity, even a simple inversion of the amino acid sequence will result in a loss of activity.
To further verify the effect of amino acid chirality on activity, cysteines (Cys, C), tryptophan (Trp, W) and arginines (Arg, R) with different chiralities were combined without altering the amino acid sequence (including C D WR、CW D R、CWR D 、C D W D R、C D WR D 、CW D R D Wherein subscript D represents a D-form amino acid, and an L-form amino acid is not subscripted), and their activities are measured, it was found that the amino acid residue was changed from L-form to D-form without causing the loss of CWR activity (Table 1). These results indicate that the activity of compound CWR is largely dependent on amino acid sequence rather than amino acid chirality.
Agonistic activity of the compounds of Table 1 on SIRT1
a EC 1.5 : concentration of compound required to increase enzyme Activity by 50%
b Max A: maximum activation fold;
c NA: "non active", no activity
Example 2
The activity of the compound is independent of the fluorescent group AMC on the acetylated substrate
To exclude that the activating effect of compound CWR is due to the interaction of compound and AMC, compound activity was further verified using other assays and substrates.
Use of the acetylated polypeptide Abz-GVLKacAY NO2 GV-NH 2 As substrate, the peptide is derived from carbamoyl phosphate synthetase 1 (CPS 1) (a in fig. 2). 0.05. Mu.M SIRT1, 500. Mu.M NAD + 、10μMAbz-GVLKacAY NO2 After reaction of GV-NH2 and compounds of different concentrations (0.5. Mu.M, 1.5. Mu.M, 4.5. Mu.M, 13.5. Mu.M, 40.5. Mu.M, 121.5. Mu.M) at 37℃for 30 minutes, trypsin (0.01 mg/ml) containing 10mM nicotinamide was added, incubation at 37℃for 15 minutes, and fluorescence of the enzyme reaction product Abz-GCLK was measured at 320nm excitation wavelength, 420nm emission wavelength (A in FIG. 2) and the effect of the compounds on SIRT1 enzyme activity was evaluated.
Experimental results show that CWR and C D W D R D Is still present, and R D W D C D Remain inactive (B in fig. 2). In contrast, no activity of the control compound resveratrol was observed, which further confirms: unlike resveratrol, the promoting effect of compounds containing Cys-X1- (Arg/Lys) and Cys-X1- (Arg/Lys) -X3 amino acid sequence general structure on SIRT1 enzyme activity is irrelevant to the fluorescent group AMC.
Due to the acetylated polypeptide Abz-GVLKacAY NO2 GV-NH 2 The fluorescent group Abz is still arranged at the amino end, and in order to examine the influence of the compound on SIRT1 enzyme reaction under the condition that an acetylated substrate is in an unmodified state, the activity of the compound is evaluated by quantitatively analyzing the amount of SIRT1 enzyme reaction products by adopting a High Performance Liquid Chromatography (HPLC) method. Fluorescent-free acetylated substrates (GQSTRHKKAcLM) and deacetylated substrates(GQSTSRHKKLM) retention times on HPLC were 6.8 min and 6.0min, respectively. In preliminary experiments, the retention times of compound CWR and deacetylated substrate GQSTSRHKKLM were found to be very close and difficult to distinguish, which prevented quantitative analysis of the enzyme reaction product GQSTSRHKKLM in the presence of compound CWR, and therefore, another compound, CERW, was designed to be synthesized with a retention time that was significantly different from that of GQSTSRHKKLM, and showed similar activity to CWR as measured by FdL method (fig. 1 a) (table 1). The results of the HPLC experiments are shown in FIG. 2C, and the peak area at 6.0min of the retention time is significantly greater for the experimental group with compound CERW than for the control group without CERW, indicating that compound CERW promotes SIRT1 enzyme reaction, and that under the same reaction conditions, the experimental group produced a greater amount of deacetylated peptide GQSTSRHKKLM than the control group, which clearly demonstrated that the activity of the compound was independent of the fluorescent group behind the acetylated lysine residue of the substrate.
Example 3
Mechanism of promoting SIRT1 enzyme reaction by compounds and reason for SIRT1 selective action
Each sirtuins has its unique role in the physiological process, and therefore the development of SIRT1 agonists should take into account their selectivity.
The activity of compound CWR on SIRT2/3/5/6 (SIRT 2, SIRT3, SIRT5, SIRT6 concentrations of 0.62. Mu.M, 1.0. Mu.M, 1.2. Mu.M, 5.0. Mu.M, respectively) was determined using the assay method described in example 1 and was found to have no effect on these enzymes (FIG. 3A). Based on the structure-activity relationship of the compounds, it was deduced that the high selectivity of compound CWR for SIRT1 should originate from the fact that the cysteine of the compound covalently binds to SIRT1 amino acid residues in the vicinity of SIRT1 enzyme reaction product oadpr (fig. 4 a), and therefore, based on the N-terminal α -amino nitrogen of the cysteine residue of compound CWR, the side chain thiol and oadpr, a thiazolidine ring is formed and CWR is docked into SIRT1 using a molecular modeling method (fig. 5 a). Arginine in CWR was found to be surrounded by acidic amino acids of Glu214, asp292 and Asp298 and to form a salt bridge (or electrostatic) interaction with these residues, thus the side chain of the amino acid residue at the third position of the compound is positively charged (e.g., arg, lys) and the interaction of the compound with SIRT1 can be enhanced.
Based on the model of the binding of the compound to SIRT1, amino acid residues around the thiazolidine ring were found to be very conserved in SIRT 1/2/3/5/6. However, the distance between the C1' carbon atom of the ADPr (adenosine diphosphate ribose) ribose ring in SIRT1 and the conserved arginine (i.e., arg274 in SIRT 1) is significantly different from other sirtuins, as compared to SIRT 2/3/5/6. The distance between Arg274 of SIRT1 and C1' of ADPr ribose ring isWhile SIRT2 (PDB ID:5D 7O), SIRT3 (PDB ID:4BN 4), SIRT5 (PDB ID:4F 56), SIRT6 (PDB ID:3 PKI) correspond to arginine at a distance from C1', respectively And->(B-E in FIG. 5). It is speculated that in SIRT2/3/5/6, this conserved arginine residue competes with the alpha-amino nitrogen N-terminal to the cysteine residue of the compound, attacking the C1' carbon atom of the ribose ring in OAADPr, thereby preventing thiazolidine ring formation, which is why the compounds of the present application selectively promote SIRT1 enzymatic reactions.
To confirm this view, mutation of Arg158, a conserved arginine residue in SIRT3, to Met, interestingly mutant SIRT3 R158M The disappearance of the enzyme activity of (2) suggests that conserved Arg158 is critical for SIRT3 enzyme activity, consistent with the above presumption. When the compound CWR is added into the reaction system, the CWR restores the mutant SIRT3 R158M Enzyme activity and promote SIRT3 in a concentration dependent manner R158M Enzymatic reaction (B in FIG. 3). This suggests that the selectivity of the compounds of the present application for SIRT1 is indeed due to the difference in distance between this conserved arginine residue in SIRT1/2/3/5/6 and C1' of the OAADPr ribose ring.
Example 4
Compounds acting on SIRT1 promote intracellular p53 deacetylation
p53 is a physiological substrate for SIRT1 and modulation of SIRT1 enzymatic reactions alters the level of acetylation of p53. To verify the activity of the compounds of the present application at the cellular level, human breast cancer MCF-7 cells were placed at 37℃with 5% CO 2 Is grown in DMEM (Gibco, product No. 12430-054) medium containing 10% FBS (Gibco, product No. 10091-148). To examine the effect of compounds on p53 acetylation levels, MCF-7 cells were treated with various concentrations of compounds (5. Mu.M, 10. Mu.M, 25. Mu.M) and 10. Mu.M Doxorubicin (DOX) for 6 hours. As a control, MCF-7 cells without doxorubicin and compound were incubated for 6 hours. Then, the cells were washed three times with PBS, and the cells were collected for western blot analysis (p 53 antibody, abcam, product number: AB75754; p53 (K382 acetylated) antibody, abcam, product number: AB 754).
The experimental method is adopted, C is respectively adopted D W D R D The MCF-7 breast cancer cells were treated with SWR and Doxorubicin (DOX), which induced apoptosis of the MCF-7 cells to produce a large number of acetylated p53. The results show that following compound C D W D R D Increasing concentrations gradually decreased the level of p53 acetylation, while SWR did not affect the p53 acetylation level (a-B in fig. 6).
Next, it was tested by gene knock-down experiments whether compounds promote intracellular p53 deacetylation by acting on SIRT1. mu.L of opti medium containing 8. Mu.L of liposomal lipo 2000 was added to another 250. Mu.L of opti medium containing SIRT1 siRNA (12 nM,24nM,48nM,96 nM), mixed well and left to stand for 20 min, and then added to MCF-7 cells containing 4.5mL of DMEM medium at 37℃with 5% CO 2 Incubate in incubator for 4 hours. The medium was removed by centrifugation and replaced with 5mL of DMEM medium containing 10% FBS, and the culture was continued for 12 hours. The medium was removed again and replaced with 5mL serum free DMEM medium, 25 μ M C D W D R D And 10. Mu.M DOX was incubated with the cells for 6 hours. As a control, MCF-7 cells without doxorubicin, compound were incubated for 6 hours, while as DOX group, 10. Mu.M DOX was incubated with MCF-7 cells for 6 hours. These samples were collected for western blot analysis.
The knockdown experiment result shows that the SIRT1 expression level in the MCF-7 is gradually reduced along with the increase of the SIRT1-siRNA concentration (C in figure 6), which shows that the SIRT1 knockdown is successful. Furthermore, with increasing SIRT1-siRNA concentration (15 nM, 30nM, 60nM, 120 nM), the amount of acetylated p53 expression was gradually increased, which indicated that C D W D R D The effect of reducing p53 acetylation gradually decreases, and the compound reduces p53 acetylation level by selectively acting on intracellular SIRT1.
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims (10)

1. A compound of the general formula (I),
X0-X1-X2-X3 (I)
wherein X0 is cysteine or a cysteine precursor;
x1 is any amino acid or amino acid analog;
x2 is arginine or lysine;
x3 is absent or is any chemical group, amino acid analog or amino acid analog modified with a chemical group at the carboxy terminus.
2. The compound of claim 1, wherein X1 is selected from the group consisting of: glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or an amino acid analog of the above type having a protecting group in the side chain or a non-protein derived amino acid analog thereof.
3. The compound of claim 1, wherein X3 is selected from the group consisting of: glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or an amino acid analog of the above type having a protecting group in the side chain or a non-protein derived amino acid analog thereof.
4. The compound of claim 1, wherein X0, X1, X2, X3 are each independently L-form, D-form or DL-form.
5. The compound of claim 1, wherein X0 is cysteine, X1 is tryptophan, X2 is arginine, and X0, X1, X2 are not L-forms at the same time when X3 is absent.
6. The compound of claim 1, wherein X0 is cysteine;
x1 is tryptophan, aspartic acid, arginine, lysine, glutamine, glutamic acid, leucine, glycine, cysteine, proline, serine, threonine, histidine, alanine, methionine, tyrosine, or phenylalanine;
x2 is arginine or asparagine;
x3 is arginine, glutamic acid or tryptophan.
7. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
8. The use of a compound of claim 1 or a pharmaceutical composition of claim 7, (a) for the preparation of a SIRT1 agonist; or (b) for preparing a medicament for treating a disease associated with SIRT1 enzyme activity.
9. The use of claim 8, wherein the disease associated with SIRT1 enzyme activity is selected from the group consisting of: inflammation, covid-19, sepsis, diabetes, cancer, cardiovascular disease, acute kidney injury, nerve injury, and neurodegenerative disease.
10. A method of non-therapeutically agonizing a SIRT1 enzyme in vitro comprising adding a compound according to claim 1 to a system in need thereof.
CN202210106886.2A 2022-01-28 2022-01-28 SIRT1 agonists and their use in the treatment of related diseases Pending CN116554263A (en)

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