CN114105752A - CYP1B1 inhibitor and application thereof - Google Patents
CYP1B1 inhibitor and application thereof Download PDFInfo
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- CN114105752A CN114105752A CN202111294375.XA CN202111294375A CN114105752A CN 114105752 A CN114105752 A CN 114105752A CN 202111294375 A CN202111294375 A CN 202111294375A CN 114105752 A CN114105752 A CN 114105752A
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- inhibitor
- cyp1b1
- chrysophanol
- physcion
- emodin
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- 101000725164 Homo sapiens Cytochrome P450 1B1 Proteins 0.000 title claims abstract description 53
- 239000003112 inhibitor Substances 0.000 title claims abstract description 49
- 102100027417 Cytochrome P450 1B1 Human genes 0.000 title claims abstract description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 5
- 206010014733 Endometrial cancer Diseases 0.000 claims abstract description 5
- 206010014759 Endometrial neoplasm Diseases 0.000 claims abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 4
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 4
- LQGUBLBATBMXHT-UHFFFAOYSA-N chrysophanol Chemical group C1=CC=C2C(=O)C3=CC(C)=CC(O)=C3C(=O)C2=C1O LQGUBLBATBMXHT-UHFFFAOYSA-N 0.000 claims description 42
- FFWOKTFYGVYKIR-UHFFFAOYSA-N physcion Chemical group C1=C(C)C=C2C(=O)C3=CC(OC)=CC(O)=C3C(=O)C2=C1O FFWOKTFYGVYKIR-UHFFFAOYSA-N 0.000 claims description 42
- PKUBGLYEOAJPEG-UHFFFAOYSA-N physcion Natural products C1=C(C)C=C2C(=O)C3=CC(C)=CC(O)=C3C(=O)C2=C1O PKUBGLYEOAJPEG-UHFFFAOYSA-N 0.000 claims description 26
- UGNZSMZSJYOGNX-UHFFFAOYSA-N Isoviocristine Natural products O=C1C=C(C)C(=O)C2=CC3=CC(OC)=CC(O)=C3C(O)=C21 UGNZSMZSJYOGNX-UHFFFAOYSA-N 0.000 claims description 21
- WLXGUTUUWXVZNM-UHFFFAOYSA-N anthraglycoside A Natural products C1=C(C)C=C2C(=O)C3=CC(OC)=CC(O)=C3C(=O)C2=C1OC1OC(CO)C(O)C(O)C1O WLXGUTUUWXVZNM-UHFFFAOYSA-N 0.000 claims description 21
- NZPQWZZXRKZCDU-UHFFFAOYSA-N chrysophanol Natural products Cc1cc(O)c2C(=O)c3c(O)cccc3Oc2c1 NZPQWZZXRKZCDU-UHFFFAOYSA-N 0.000 claims description 21
- YDQWDHRMZQUTBA-UHFFFAOYSA-N Aloe emodin Chemical group C1=CC=C2C(=O)C3=CC(CO)=CC(O)=C3C(=O)C2=C1O YDQWDHRMZQUTBA-UHFFFAOYSA-N 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 11
- 230000000259 anti-tumor effect Effects 0.000 claims description 10
- VWDXGKUTGQJJHJ-UHFFFAOYSA-N Catenarin Natural products C1=C(O)C=C2C(=O)C3=C(O)C(C)=CC(O)=C3C(=O)C2=C1O VWDXGKUTGQJJHJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000010282 Emodin Substances 0.000 claims description 5
- RBLJKYCRSCQLRP-UHFFFAOYSA-N Emodin-dianthron Natural products O=C1C2=CC(C)=CC(O)=C2C(=O)C2=C1CC(=O)C=C2O RBLJKYCRSCQLRP-UHFFFAOYSA-N 0.000 claims description 5
- YOOXNSPYGCZLAX-UHFFFAOYSA-N Helminthosporin Natural products C1=CC(O)=C2C(=O)C3=CC(C)=CC(O)=C3C(=O)C2=C1O YOOXNSPYGCZLAX-UHFFFAOYSA-N 0.000 claims description 5
- NTGIIKCGBNGQAR-UHFFFAOYSA-N Rheoemodin Natural products C1=C(O)C=C2C(=O)C3=CC(O)=CC(O)=C3C(=O)C2=C1O NTGIIKCGBNGQAR-UHFFFAOYSA-N 0.000 claims description 5
- RHMXXJGYXNZAPX-UHFFFAOYSA-N emodin Chemical group C1=C(O)C=C2C(=O)C3=CC(C)=CC(O)=C3C(=O)C2=C1O RHMXXJGYXNZAPX-UHFFFAOYSA-N 0.000 claims description 5
- VASFLQKDXBAWEL-UHFFFAOYSA-N emodin Natural products OC1=C(OC2=C(C=CC(=C2C1=O)O)O)C1=CC=C(C=C1)O VASFLQKDXBAWEL-UHFFFAOYSA-N 0.000 claims description 5
- BPIUIOXAFBGMNB-UHFFFAOYSA-N 1-hexoxyhexane Chemical compound CCCCCCOCCCCCC BPIUIOXAFBGMNB-UHFFFAOYSA-N 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 229910052725 zinc Inorganic materials 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
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- 239000000243 solution Substances 0.000 description 22
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 10
- 238000003032 molecular docking Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000000284 extract Substances 0.000 description 9
- 238000010298 pulverizing process Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
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- 238000001914 filtration Methods 0.000 description 6
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- 231100000673 dose–response relationship Toxicity 0.000 description 3
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- 238000000967 suction filtration Methods 0.000 description 2
- LCSYBHAMRRYYLC-UHFFFAOYSA-N 2-ethoxybenzene-1,3-diol Chemical compound CCOC1=C(O)C=CC=C1O LCSYBHAMRRYYLC-UHFFFAOYSA-N 0.000 description 1
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- 229910052720 vanadium Inorganic materials 0.000 description 1
- LEONUFNNVUYDNQ-UHFFFAOYSA-N vanadium atom Chemical compound [V] LEONUFNNVUYDNQ-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
- C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
- C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/06—Zinc compounds
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/005—Compounds of elements of Group 5 of the Periodic Table without metal-carbon linkages
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Abstract
The invention discloses a CYP1B1 mixed type (competition)Sexual and non-competitive) inhibitor having the structure:
wherein: r1＝H、OCnH2n+1，n＝1～6；R2＝H、CH3、C2H5OH can effectively inhibit CYP1B1 enzyme, has potential application value in preparing antitumor drugs, and can be applied in drug development for treating breast cancer and endometrial cancer.
Description
Technical Field
The invention relates to the field of medicines, in particular to a CYP1B1 inhibitor, and specifically relates to an application of a compound capable of inhibiting CYP1B1 in preparation of an anti-tumor medicine.
Background
The CYP1 family is a heme-containing monooxygenase series that catalyzes the hydroxylation and oxygen dealkylation of substrates. The CYP1 family has three members: CYP1B1, CYP1a1 and CYP1a 2. The CYP1B1 enzyme is a subtype of CYP1 family, is a key enzyme involved in prostaglandin catalysis and partial drug epoxidation, and plays an important role in tumor development. Estrogen-related tumors are increasingly recognized as a serious global public health problem.
Research shows that 17-beta-estradiol promotes the occurrence and development of breast cancer and endometrial cancer. The long-term effects of 17- β -estradiol are thought to be the major cause of 17- β -estradiol related cancer. Two common metabolic pathways catalyzed by CYP1 enzymes and 17-beta-estradiol (E2,1) are shown in figure 1. CYP1A1 and CYP1A2 catalyze 2-position hydroxylation of E2 to generate 2-hydroxy-17-beta-estradiol (2), and then the 2-hydroxy-17-beta-estradiol is oxidized into nontoxic 17-beta-estradiol-2, 3-diketone (3); another pathway of E2 metabolism is that it is metabolized by the extracellular enzyme CYP1B1 to produce 4-hydroxy-17- β -estradiol (4), which is then metabolized by peroxidase to produce 17- β -estradiol-3, 4-dione (5). This metabolite can be added to DNA by Michael, resulting in DNA mutation.
In summary, the CYP1B1 enzyme is a promising biomarker and therapeutic target. Therefore, CYP1B1 inhibitor is expected to be a potential anti-tumor drug. Therefore, the effective CYP1B1 inhibitor has important significance for the research of anti-tumor theory and the research of drug development.
Disclosure of Invention
The present invention is directed to a novel CYP1B1 inhibitor to solve the problems set forth in the background art described above.
In order to achieve the purpose, the invention provides the following technical scheme:
a CYP1B1 inhibitor, said inhibitor having the formula:
wherein: r1＝H、OCnH2n+1，n＝1～6；R2＝H、CH3、C2H5OH。
The other CYP1B1 inhibitor in the technical scheme also contains metal M, is obtained by combining the CYP1B1 inhibitor with the metal M, and has the following structure:
wherein: r1＝H、OCnH2n+1，n＝1～6；R2＝H、CH3、C2H5OH；M＝V、Zn、Fe。
As further preferred in this embodiment: the inhibitor is physcion, and has the structure as follows:
as further preferred in this embodiment: the inhibitor is emodin hexyl ether, and has the structure as follows:
as further preferred in this embodiment: the inhibitor is chrysophanol and has the structure as follows:
as further preferred in this embodiment: the inhibitor is aloe-emodin and has the structure as follows:
the invention also aims to provide application of the CYP1B1 inhibitor in preparing an anti-tumor medicament.
As further preferred in this embodiment: the anti-tumor medicine is applied to treating breast cancer and endometrial cancer.
As further preferred in this embodiment: the anti-tumor medicine contains CYP1B1 inhibitor, and the CYP1B1 inhibitor is one or more of physcion, chrysophanol and aloe-emodin.
As further preferred in this embodiment: the anti-tumor medicine comprises a mixture of physcion, chrysophanol and aloe-emodin, the above substances are obtained by extracting plant species, and the extraction method comprises the following steps:
s1: freeze-drying and crushing, namely freeze-drying the plants and crushing the plants by a wall breaking machine;
s2: pulverizing the extract, soaking in ethanol water solution, heating and reflux extracting, filtering the extractive solution, and recovering ethanol to obtain extract;
s3: acidolysis, hydrolyzing the extract with inorganic acid water solution, filtering the acid water solution to remove residues;
s4: and (3) column chromatography separation: extracting with chloroform, recovering chloroform from the extractive solution to near dryness, passing through silica gel chromatographic column, gradient eluting with ethyl acetate and acetone mixed solution, collecting eluate by stages, and recovering solvent under reduced pressure to obtain mixture.
The plant is one or more of radix et rhizoma Rhei, Aloe, and rhizoma Polygoni Cuspidati.
As further preferred in this embodiment: the anti-tumor medicine contains a CYP1B1 inhibitor, and the CYP1B1 inhibitor has the structure:
wherein: r1＝H、OCnH2n+1，n＝1～6；R2＝H、CH3、C2H5OH；M＝V、Zn、Fe。
The preparation method of the CYP1B1 inhibitor comprises the following steps:
s1: dissolving the raw materials in an organic solvent, and heating and refluxing;
the raw materials are as follows:
wherein: r1＝H、OCnH2n+1，n＝1～6；R2＝H、CH3、C2H5OH。
S2: slowly adding the metal ion solution into the raw material solution, reacting for 12-24 h at 60-120 ℃, and carrying out suction filtration while the solution is hot to obtain a solid;
s3: the solid is washed thick by hot ethanol and ice water, and is dried in vacuum at low temperature to obtain the product.
Compared with the prior art, the invention has the beneficial effects that: provides a CYP1B1 mixed (competitive and non-competitive) inhibitor, can effectively inhibit CYP1B1 enzyme, has potential application value in preparing antitumor drugs, and can be applied to drug development for treating breast cancer and endometrial cancer.
Drawings
FIG. 1 shows two common metabolic pathways catalyzed by CYP1 enzyme for 17- β -estradiol;
FIG. 2 is a dose response curve of chrysophanol (chrysophanol) and physcion (physcion) to CYP1B 1;
FIG. 3 is a Michaelis-Menten enzyme kinetic model catalyzed by CYP1B1 at physcion and chrysophanol IC50 concentrations;
FIG. 4 is a Lineweaver-Burk plot of the effect of physcion and chrysophanol on CYP1B 1;
FIG. 5 is a molecular docking diagram of physcion, chrysophanol and CYP1B 1.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
CYP1B1 inhibitor 1:
s1: freeze-drying and pulverizing, freeze-drying rhizoma Polygoni Cuspidati, and pulverizing with wall breaking machine;
s2: pulverizing the extract, soaking in ethanol water solution, heating and reflux extracting, filtering the extractive solution, and recovering ethanol to obtain extract;
s3: acidolysis, hydrolyzing the extract with inorganic acid water solution, filtering the acid water solution to remove residues;
s4: and (3) column chromatography separation: extracting with chloroform, recovering chloroform from the extractive solution to near dryness, passing through silica gel chromatographic column, gradient eluting with mixed solution of ethyl acetate and acetone, collecting eluate by stages, and recovering solvent under reduced pressure to dry to obtain physcion and chrysophanol respectively.
Example 2
CYP1B1 inhibitor 2:
s1: freeze drying and pulverizing, freeze drying radix et rhizoma Rhei, Aloe and rhizoma Polygoni Cuspidati, mixing, and pulverizing with wall breaking machine;
s2: pulverizing the extract, soaking in ethanol water solution, heating and reflux extracting, filtering the extractive solution, and recovering ethanol to obtain extract;
s3: acidolysis, hydrolyzing the extract with inorganic acid water solution, filtering the acid water solution to remove residues;
s4: and (3) column chromatography separation: extracting with chloroform, recovering chloroform from the extractive solution to near dryness, passing through silica gel chromatographic column, gradient eluting with mixed solution of ethyl acetate and acetone, and recovering solvent under reduced pressure to dry to obtain mixture of physcion, chrysophanol and aloe-emodin.
Example 3
CYP1B1 inhibitor 3:
s1: dissolving physcion in chloroform solvent, heating and refluxing;
s2: slowly adding the vanadium metal ion solution into the raw material solution, reacting for 12-24 h at 60-120 ℃, and carrying out suction filtration while the solution is hot to obtain a solid;
s3: the solid is washed thick by hot ethanol and ice water, and is dried in vacuum at low temperature to obtain CYP1B1 inhibitor 3.
Example 4
CYP1B1 inhibitor efficacy test:
(1) enzyme inhibition kinetics study
The kinetics of inhibition of the target compound (CYP1B1 inhibitor) on CYP1B1 were determined by the EROD method (0mM,0.02mM,0.05mM,0.10mM,0.20mM,0.50mM,0.80mM) with increasing concentration of ethoxyresorcinol. The concentrations were set at the cell half inhibitory concentrations, respectively. After preincubation at 37 ℃ for 10min, the reaction mixture was initiated by adding CYP1B 1. The enzymatic reaction was carried out under these conditions for 20 minutes. The resorcinol concentration was then determined as described above and the data were fit to the Michaelis-Menten equation and Km and Vmax values were calculated by non-linear regression analysis.
The IC50 was estimated using a sigmoidal dose-response curve as shown in figure 2.
The IC50 value of physcion to CYP1B1 is 0.35 + -0.09 mM, and the IC50 value of chrysophanol is 0.47 + -0.10 mM. Physcion and chrysophanol can inhibit the activity of CYP1B1 in a dose-dependent manner, but the effect of chrysophanol on the activity of CYP1B1 is slightly less than physcion.
Kinetic parameters of CYP1B1 catalyzing to generate 4-hydroxy-17-beta-estradiol (4) under the concentration of physcion and chrysophanol IC50 are measured by a Michaelis-Menten enzyme kinetic model. The results are shown in FIG. 3.
For physcion, the Km and Vmax values were 0.43671. + -. 0.03855mM and 45.42269. + -. 1.99782 pmol/. mu.g protein/min. Whereas for chrysophanol the Km and Vmax values are 0.96633 + -0.29869 mM and 51.9912 + -10.05474 pmol/. mu.g protein/min.
To investigate the type of action of the inhibitors, a Lineweaver-Burk plot was plotted using the reciprocal double. As shown in fig. 4, the intersection of the two lines is in the third quadrant, consistent with the linear mixed inhibition kinetics of reversible enzyme inhibition. Thus, chrysophanol and physcion are mixed (competitive and non-competitive) inhibitors.
(2) Molecular docking study
The CYP1B1 inhibitor was docked to the active site of CYP1B1 using the automated docking procedure 4.2. Solvent molecules and protoligand molecules in the crystal structure were removed using pymol 4.3 procedure prior to the experiment. Hydrogen and part of the charge are added by auto-docking, and small molecules are hydrogenated by auto-docking. The molecular charge is then calculated and the torque center determined and then stored in the PDBQT format. The number of points in the grid frame is x-40, y-40, z-40, and the pitch is 0.581. The evaluation function is a semi-empirical free energy calculation method, and a Lamark genetic algorithm is adopted for semi-flexible docking.
The molecular docking result shows that physcion, chrysophanol, CYP1B1 inhibitor 3, emodin hexyl ether and aloe-emodin all enter the CYP1B1 site, the molecular docking binding energy is respectively-8.79 kcal/mol, -8.39kcal/mol, -8.19kcal/mol, -8.87kcal/mol and-9.29 kcal/mol, the molecular docking binding energy is lower, the stable binding can be formed with CYP1B1, and the moderate inhibition effect is realized. FIG. 5 is a molecular docking diagram of physcion and chrysophanol and CYP1B 1: chrysophanol binds with ASP-326, SER-127 and ASN-265 in CYP1B1 through hydrogen bonds. Physcion is hydrogen bonded to GLN-332, ASN-228, GLY-329 and ASN-265 in CYP1B 1.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (10)
1. An inhibitor of CYP1B1, characterized by: the structure of the inhibitor is as follows:
wherein: r1＝H、OCnH2n+1，n＝1～6；R2＝H、CH3、C2H5OH。
2. The inhibitor of CYP1B1 according to claim 1, wherein: the inhibitor also contains a metal M, and the structure of the metal M is as follows:
wherein: r1＝H、OCnH2n+1，n＝1～6；R2＝H、CH3、C2H5OH；M＝V、Zn、Fe。
3. The inhibitor of CYP1B1 according to claim 1, wherein: the inhibitor is physcion.
4. The inhibitor of CYP1B1 according to claim 1, wherein: the inhibitor is emodin hexyl ether.
5. The inhibitor of CYP1B1 according to claim 1, wherein: the inhibitor is chrysophanol.
6. The inhibitor of CYP1B1 according to claim 1, wherein: the inhibitor is aloe-emodin.
7. The use of the CYP1B1 inhibitor according to claim 1 in the preparation of an anti-tumor medicament.
8. Use according to claim 7, characterized in that: the anti-tumor medicine is applied to treating breast cancer and endometrial cancer.
9. Use according to claim 7, characterized in that: the antitumor drug contains CYP1B1 inhibitor, and the CYP1B1 inhibitor is one or more of emodin ether, emodin hexyl ether, chrysophanol and aloe-emodin.
10. Use according to claim 7, characterized in that: the anti-tumor medicine contains a CYP1B1 inhibitor, and the CYP1B1 inhibitor has the structure:
wherein: r1＝H、OCnH2n+1，n＝1～6；R2＝H、CH3、C2H5OH；M＝V、Zn、Fe。
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