CN114369060B - Indolylamine 2, 3-dioxygenase inhibitor and application thereof in preparation of antitumor drugs - Google Patents
Indolylamine 2, 3-dioxygenase inhibitor and application thereof in preparation of antitumor drugs Download PDFInfo
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- CN114369060B CN114369060B CN202011100808.9A CN202011100808A CN114369060B CN 114369060 B CN114369060 B CN 114369060B CN 202011100808 A CN202011100808 A CN 202011100808A CN 114369060 B CN114369060 B CN 114369060B
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- nicotinic acid
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Classifications
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
The invention belongs to the technical field of biological medicines, and discloses an inhibitor of indoleamine 2, 3-dioxygenase IDO1, namely a nicotinic acid derivative (a derivative of 3-pyridine propionic acid). The derivative of the 3-pyridine propionic acid can effectively inhibit the metabolism of tryptophan catalyzed by indoleamine 2, 3-dioxygenase IDO1, can obviously inhibit the activity of high-expression IDO1 enzyme in human cancer cells, and has low cytotoxicity. The nicotinic acid derivatives can be used as an IDO1 enzyme inhibitor singly to obviously inhibit the growth of transplanted tumors of mice, and can be used in combination with an innate immune channel STING agonist or an immune checkpoint inhibitor, so that the effect of inhibiting the growth of the tumors is better, and the safety is also good. Therefore, the nicotinic acid derivative has wide application prospect in preparing immune anti-tumor medicaments.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to an inhibitor of nicotinic acid derivatives p-indoleamine 2, 3-dioxygenase IDO1 and application thereof in preparation of immune antitumor drugs
Background
Tumors are one of a serious group of diseases seriously jeopardizing human life health, and are manifested by cell hyperproliferation and abnormal differentiation. Cancer cases may increase to 2400 ten thousand yearly worldwide, according to WHO statistics. At the same time, cancer places a great burden on the global economy. Tumor immunotherapy is an emerging tumor treatment modality following surgery, radiation therapy, and chemotherapy. It is a cancer treatment method that prevents, controls and eliminates cancer by stimulating or enhancing the strength of the human autoimmune system. Compared with the traditional tumor treatment method, the immunotherapy has the unique advantages, can improve the curative effect of the traditional treatment, and lighten adverse reactions caused by the traditional treatment, and the like. Innate immune system agonists, immunocheckpoint blockers and cellular immunotherapy are the primary areas of research for current immunotherapy. The tumor immunotherapy strategy based on metabolic regulation can improve the effectiveness of immunotherapy, benefit more patients, and opens up a new direction for improving tumor immunotherapy.
The immune system of the human body is responsible for recognizing itself and not itself, thereby protecting the human body from exogenous and endogenous diseases. The human immune system is composed of white blood cells and lymphoid organs, lymphoid tissues, including thymus, spleen, tonsils, lymph nodes, lymphatic vessels, and bone marrow, and the immune system maintains a sustained homeostasis of the body by recognizing and eliminating various threats. Cancer immunotherapy refers to the stimulation of the immune system against cancer cells by the introduction of vaccines, cytokines, antibodies or the metastatic immune cells themselves. The success of immunotherapy in tumor therapy, such as immune checkpoint inhibitors and CAR-T cell therapies, has established its role in cancer therapy. Cancer is the choice of host-tumor immune interactions using a variety of mechanisms, leading to immune escape. Over the past few years, there has been a continual new advance in our investigation of host-tumor interactions, leading to a variety of promising immunotherapeutic approaches.
Indoleamine 2, 3-dioxygenase (IDO 1) is a monomeric heme protein with a molecular weight of 45KD. IDO1 catalyzes molecules with an indole ring and is therefore known as indoleamine 2, 3-dioxygenase. IDO1 is a key rate-limiting metabolic enzyme in the tryptophan metabolic pathway. Numerous studies have shown that IDO1 is highly expressed in many types of human cancers, which subsequently leads to accumulation of tryptophan metabolites, resulting in immune tolerance of the body to tumor antigens, and ultimately to immune escape of the tumor. Many preclinical and clinical trial studies have shown that IDO1 inhibitors are effective tools against a variety of cancers. At present, clinical researches on IDO1 inhibitors for treating tumors are ongoing, and the IDO1 inhibitors can effectively activate tumor-infiltrating T cells and/or reduce tumor-resident immunosuppressive regulatory T cells, so that the human immunity is improved, and the purpose of resisting tumors is achieved. Based on the important role of IDO1 in tumor immunotherapy and the fact that IDO1 inhibitors are not currently marketed for tumor therapy, the screening of new IDO1 inhibitors and the research of antitumor drugs based on IDO1 enzyme inhibitors are of great significance.
Cyclic dinucleotide synthases (cGAS) are important cytoplasmic DNA receptors in the innate immune pathway. cGAS catalyzes the synthesis of cGAMP from ATP and GTP in vivo, and cGAMP induces production of interferon IFN- β and other cytokines as a secondary messenger molecule through STING protein pathway on the endoplasmic reticulum membrane, regulates downstream protein expression, induces cell growth arrest and apoptosis, and produces antiviral effects. STING pathway can regulate innate immune recognition of immunogenic tumors, promoting anti-tumor effects of interferon. IFN-gamma plays an anti-tumor role in vivo through TRAIL (tumor necrosis factor-related apoptosis-reducing ligand) and promotes apoptosis of tumor cells. cGAMP is a key stimulator of innate immune response, is an endogenous activator of STING, and has immune and antitumor effects.
The invention provides an innovative inhibitor of indoleamine 2, 3-dioxygenase IDO1, namely a nicotinic acid derivative (derivative of 3-pyridine propionic acid). The derivative of the 3-pyridine propionic acid can effectively inhibit the metabolism of tryptophan catalyzed by indoleamine 2, 3-dioxygenase IDO1, can obviously inhibit the activity of high-expression IDO1 enzyme in human cancer cells, and has lower cytotoxicity. The nicotinic acid analogues can be used as the inhibitors of IDO1 enzyme alone to obviously inhibit the growth of transplanted tumors of mice, and are used in combination with an innate immune channel STING agonist or an immune checkpoint inhibitor and/or an anti-tumor drug, so that the effect of inhibiting the growth of the tumors is better, and the safety is also good. Therefore, the nicotinic acid derivative has wide application prospect in preparing immune anti-tumor medicaments.
Disclosure of Invention
The invention provides an innovative inhibitor of indoleamine 2, 3-dioxygenase IDO1, namely a nicotinic acid derivative (derivative of 3-pyridine propionic acid). The derivative of the 3-pyridine propionic acid can effectively inhibit the metabolism of tryptophan catalyzed by indoleamine 2, 3-dioxygenase IDO1, can obviously inhibit the activity of high-expression IDO1 enzyme in human cancer cells, and has lower cytotoxicity. The nicotinic acid derivatives can be used as an IDO1 enzyme inhibitor singly to obviously inhibit the growth of transplanted tumors of mice, and the nicotinic acid derivatives are used in combination with an innate immune channel STING agonist or an immune checkpoint inhibitor, so that the effect of inhibiting the growth of the tumors is better, and the safety is also good. Therefore, the nicotinic acid derivative has wide application prospect in preparing immune anti-tumor medicaments.
The specific invention is characterized in that:
1. nicotinic acid derivatives (derivatives of 3-pyridinepropionic acid) are novel inhibitors of indoleamine 2, 3-dioxygenase IDO 1. The nicotinic acid derivative is characterized in that: the nicotinic acid is used as a structural parent nucleus, and atoms such as S, N, O, F and the like which are easy to form hydrogen bonds are introduced in a carboxylic acid isostere mode, so that the binding force of the inhibitors and IDO1 enzyme protein molecules is enhanced, the compound formed by the inhibitors and the IDO1 protein molecules is stabilized, and the effect of inhibiting the IDO1 enzyme activity is improved. The specific nicotinic acid derivatives are shown in figure 1 (nicotinic acid derivatives (1-10) and their names).
2. Application of nicotinic acid derivative (3-pyridine propionic acid derivative) in preparing antitumor drug is provided. The antitumor drug is applied to treat various types of tumors, including but not limited to colorectal cancer, breast cancer, testicular cancer, ovarian cancer, prostate cancer, lung cancer, nasopharyngeal cancer, esophageal cancer, malignant lymphoma, head and neck cancer, thyroid cancer, osteogenic sarcoma, bladder cancer, cervical cancer, germ cell tumor and the like.
3. Use of nicotinic acid derivatives (derivatives of 3-pyridinepropionic acid) in combination (including complexes) with immune pathway STING agonists for the manufacture of an antitumor medicament. STING agonists include, but are not limited to cGAMP and derivatives thereof. The antitumor drug is applied to treat various types of tumors.
4. Application of nicotinic acid derivative (derivative of 3-pyridine propionic acid) and immune checkpoint inhibitor in preparing antitumor drug. Immune checkpoint inhibitors include, but are not limited to, anti-PD 1/PD-L1, anti-CD-47, anti-VEGF, anti-CTLA-4 and like monoclonal antibodies and nanobodies of monoclonal antibodies thereof; the antitumor drug is applied to treat various types of tumors.
5. The application of nicotinic acid derivatives (3-pyridine propionic acid derivatives) in preparing antitumor drugs by combined administration of chemotherapy antitumor drugs. Chemotherapeutic drugs including but not limited to platinum-based metal drugs, 5-fluorouracil, violaxanthin and other antitumor drugs are used for treating various types of tumors.
6. The application of the nicotinic acid derivative (3-pyridine propionic acid derivative) in preparing antitumor drugs comprises unit preparations with different specifications and pharmaceutically acceptable pharmaceutical preparations, including but not limited to one or more of intravenous injection, intramuscular injection, subcutaneous injection, intravenous drip, nasal drip, oral administration and the like, and the treatment of the related tumors is carried out.
Drawings
FIG. 1 shows the structural formula and names of nicotinic acid derivatives (1-10).
Detailed Description
The following is a detailed description of the present invention by way of examples. In the present invention, the following examples are given for better illustration of the present invention and are not intended to limit the scope of the present invention.
Example 1: inhibition study of nicotinic acid derivatives on IDO1 metalloenzyme
All biochemical reagents were analytically pure and purchased from Sigma-Aldrach. The structural formula of nicotinic acid derivatives 1-10 and the English name thereof are shown in figure 1.
1. Indoleamine 2, 3-dioxygenase 1 (IDO 1) was prepared according to literature procedures
pGEX-6P-1 is selected as a vector for constructing a humanized IDO1 expression plasmid, IDO1 protein with GST fusion tag can be expressed in escherichia coli, the IDO1 fusion protein is adsorbed and purified by using a GST affinity column, the protein purity is extremely high, GST tag protein is digested by adopting recombinant HRV 3C protease, enzyme is carried out overnight at 16 ℃, and the digested IDO1 protein is purified by using a Glutathione Sepharose affinity column for the second time to obtain electrophoresis pure protein, and is identified by SDS-Page and mass spectrometry. SDS-PAGE showed IDO1 protein purity higher than 95%, MALDI-TOF mass spectrometry further confirmed that IDO1 molecular weight was 45KD, which is consistent with the theoretical molecular weight; characterization of the ultraviolet visible spectrum shows that the characteristic absorption peak is 404nm, and the electrochemical reduction potential is-0.37V. Experimental results prove that the high-purity humanized IDO1 protein is successfully obtained, and a foundation is laid for subsequent IDO1 inhibitor screening and smooth performance of enzyme activity related experiments.
2. IC of nicotinic acid derivative inhibiting IDO1 enzyme activity 50 Value determination
The experimental method comprises the following steps:
by KH 2 PO 4 (100 mM, pH 6.5) buffer solution, and the UV absorbance at 404nm of 1. Mu.M protein was calculated from the molar extinction coefficient of IDO1 to prepare a protein sample. Preparing an EP tube with the volume of 1.5mL, and marking each concentration gradient of the compound; then 1mL and 1 mu M protein are taken in an EP tube to be used as the volume of a reaction system; then methylene blue, catalase and L-ascorbic acid are respectively added into the mixturepH was adjusted to 6.5 with NaOH) and final concentrations of reagents were 10. Mu.M, 200. Mu.g/mL and 10mM, respectively; adding a compound with a corresponding concentration gradient into each tube, setting blank holes without adding the compound, mixing the two tubes upside down, and incubating the tubes in a water bath at 37 ℃ for 10min; subsequently, 100. Mu.M substrate L-tryptophan was added before the kinetic test, and the absorbance of the reaction product N' -formylkynurenine at 320nm was immediately monitored for a reaction time of 60s. Experimental selection of IC for calculating inhibitor of inhibition ratio at tryptophan concentration of 100. Mu.M 50 Values.
And (3) data processing:
in data processing, firstly, linear fitting is carried out on dynamics experiment data of each reaction, and an initial rate V is obtained; then, the corresponding inhibition rates at different compound concentrations are calculated according to a formula, the inhibition rate is plotted against the Log10 value of the niacin derivative inhibitor concentration, and the inhibition rate is calculated according to IC 50 Fitting the data by using the formula to obtain the IC of each compound 50 Values.
Experimental results: IC (integrated circuit) 50 The value measurement shows that 10 nicotinic acid derivatives have inhibitory effect on IDO 1. Compounds 6, 7, 8,9, 10, their IC 50 The values were all around 10. Mu.M. All 8 compounds showed a higher positive control compound 4-PI (IC 50 49.03.+ -. 6.67. Mu.M) higher IDO1 inhibition, with compounds 9 and 10 having the best effect, their inhibition was highest at a maximum concentration of 200. Mu.M, whereas the inhibition of compound 9 could reach 90%.
TABLE 1 IC of nicotinic acid derivatives for inhibiting IDO1 metalloenzyme 50 And K i Value of
3. Nicotinic acid derivative inhibition IDO1 inhibition constant K i Measurement
Experimental method and data processing:
parallel inhibition activity kinetics experiments were performed on the same nicotinic acid derivative inhibitor at three substrate concentrations of 50. Mu.M, 100. Mu.M and 150. Mu.M, respectively. Firstly, carrying out linear fitting on kinetic experimental data of each reaction to obtain an initial rate V, then adopting a Cornish-Bowden drawing method, taking the concentration of the inhibitor as an abscissa and the ratio (S/V) of the concentration of the substrate to the initial rate V as an ordinate in the same numerical axis, finally carrying out linear fitting on three groups of data, wherein the absolute value of the intersection point of the fitting straight lines is the inhibition constant Ki, and judging the inhibition type of the inhibitor through the position of the coordinate axis where the intersection point Ki is positioned. The derived experimental data were plotted using Origin 7.5.
Experimental results:
the Ki value was measured by selecting compounds whose inhibition rate was 60% or more at a concentration of 100 μm, compounds 2,4,5,8,9 and 10, respectively. Experiments parallel experiments were performed with different inhibitor concentrations at 50. Mu.M, 100. Mu.M and 150. Mu.M of the nicotinic acid derivative substrate concentrations, and S/V was plotted against the nicotinic acid derivative inhibitor concentration, and the absolute value of the intersection point of the straight lines of the linear fitting of the three groups of data was the inhibition constant Ki.
As shown in Table 1, the Ki values of the three potent IDO1 nicotinic acid derivative inhibitors 8 (15.56. Mu.M), 9 (8.68. Mu.M) and 10 (9.93. Mu.M) are in the range of 15. Mu.M. The lower the Ki value, the stronger the inhibitory effect, and thus, niacin derivative inhibitor 9 has the strongest inhibitory effect on IDO 1. The above results indicate that two fluorine-containing compounds 9 and 10 are the most potent in IDO1 inhibitory activity as compounds having 3-pyridinepropionic acid as a parent nucleus. The lowest IC of both 50 And Ki is about 10. Mu.M. The inhibitory effect of inhibitor 9 is most pronounced mainly due to two reasons, on the one hand, the introduction of F, with only 9 having oxygen and three fluorine atoms, can enhance the hydrogen bonding force between IDO1 and the inhibitor, as compared to other inhibitors. In particular, 9 contains trifluoroethyl groups, which can significantly increase the binding capacity of the inhibitor. On the other hand, the carboxylic acid in 9 is substituted with fluorine, which increases the hydrophobicity of the inhibitor and favors 9 occupying the hydrophobic cavity of IDO 1. In summary, compounds containing elements that readily form hydrogen bonds, especially trifluoroethyl groups, have the potential advantage of inhibiting IDO 1.
Example 2: research on inhibiting effect of nicotinic acid derivative on cancer cell IDO1 enzyme
1. Experimental reagent consumable
0.25 Xpancreatin-EDTA, double antibody (penicillin/streptomycin) from Gibco company; 1640 medium, FBS fetal bovine serum was purchased from the company of vitamin biotechnology (south kyo); isopropyl alcohol, DMSO, glacial acetic acid, absolute ethanol, copper sulfate were purchased from national pharmaceutical group chemical agents limited; the Nalgene program cooling box is purchased from beijing solibao technologies limited; sterile PBS buffer, sterile 0.22 μm aqueous filter, available from Biotechnology (Shanghai) Co., ltd; the CCK-8 kit was purchased from Biyun Tian Biotechnology Co., ltd; 60mm and 100mm cell culture dishes and cell cryopreservation tubes were purchased from Corning corporation; 96-well plates were purchased from NEST company; human cervical cancer cells (Hela), human liver cancer cells (HepG-2), human breast cancer (MCF-7) and human normal liver cells (L02) are purchased from a cell bank of Shanghai department of science; IFNγ was purchased from Sigma-Aldrich; p-dimethylaminobenzaldehyde, trichloroacetic acid, 4-phenylimidazole were all purchased from ala Ding Shiji (Shanghai) limited.
2. Experimental instrument
-80 ℃ refrigerator (ambi, department of science, mitsubishi commercial electric parts limited); an electric heating thermostatic water bath (Shanghai department Hengshi development Co., ltd.); vertical pressure steam sterilizing pot (Shanghai Bosch & Co., ltd. Medical equipment factory); double single-sided vertical air supply clean bench (Shanghai Tianheng medical instruments limited company); carbon dioxide incubator (model: BPN-50CH, shanghai-Heng science instruments Co., ltd.); microscope (Shanghai optical instruments factory); vertical refrigerator (Hefei Meishi Co., ltd.); a centrifuge (Sorvall Legend Micro R/21R,Thermo Fisher Scientific); microplate reader (BioTek CytationTM 3).
3. Experiment content and experiment method
The assay employs ifnγ to induce IDO1 production by cancer cells, thereby performing an activity assay of IDO1 inhibitors at the level of viable cells.
Experiment first day: heLa, hepG-2 and MCF-7 cancer cells cultured to a certain cell density with 100mm were digested with trypsin, observed under a microscope, and after the cell morphology was rounded, the digestion was stopped with complete medium, the cells were gently blown down with a pipette, and pancreatin was removed by centrifugation. At 5X 10 4 Cell number of cells per mL were seeded into 96-well plates and a blank was placed. Placing at 37deg.C, 5% CO2Culturing in a carbon dioxide incubator for 12 hours.
The following day of the experiment: cells in 96-well plates were plated and 200. Mu.L of medium was added, followed by co-cultivation for 48h with 10ng/mL IFNγ, 100. Mu.M tryptophan and inhibitor at different concentration gradients at each culture space. The final concentration of inhibitor was 0. Mu.M, 0.5. Mu.M, 1. Mu.M, 5. Mu.M, 10. Mu.M, 20. Mu.M, 40. Mu.M, 60. Mu.M, 80. Mu.M, 100. Mu.M, 150. Mu.M, 200. Mu.M, respectively. The final concentrations of the positive control drug 4-PI were 0. Mu.M, 10. Mu.M, 20. Mu.M, 40. Mu.M, 6. Mu.M, 100. Mu.M, 150. Mu.M, 200. Mu.M, respectively. 3 wells were multiplexed for each sample concentration.
Experiment day four: after 48h of cell dosing culture, 140 mu L of supernatant is taken from each culture well to a 1.5mL centrifuge tube, 10 mu L of 30% (w/v) trichloroacetic acid solution is added, the culture well is incubated for 15min under the water bath condition of 65 ℃ to terminate the catalytic reaction of IDO1 on tryptophan, and N' -formylkynurenine is converted into kynurenine; centrifuging at 10000rpm for 10min, taking 100 μl of supernatant into a new 96-well plate, adding 2% (w/v) acetic acid solution of p-dimethylaminobenzaldehyde with the same volume, mixing, and performing display reaction; finally, an enzyme label instrument is adopted to detect the absorption value at 492nm, and the reaction rate of the IDO1 enzyme is calculated according to the amount of the product. Data were exported in excel format and then plotted with GraphPad 7.00. Cell experiments were performed in duplicate. Calculation formula of inhibition ratio on IDO1 living cells: inhibition% = [1- (a/B) ] ×100% (1) (a represents an absorption value when the inhibitor is contained, and B represents an absorption value when the inhibitor is not contained.)
4. Experimental results
In order to evaluate the inhibitory activity of nicotinic acid derivatives on IDO1 enzyme in living cells, we performed cell assay analysis on six inhibitors screened in the enzyme inhibition assay of example 1 with an inhibition rate greater than 60%, three human cancer cell lines were selected. The drug inhibition of IDO1 in three cancer cells was first measured at the same inhibitor concentration of 20. Mu.M, and the experimental results are shown in Table 2, wherein the highest IDO1 inhibition rates of 9 and 10 were 14.70% and 20.06%, respectively, in the Hela cell line, 9 and 10 also gave the best inhibition effects in the HepG-2 cell line, 45.61% and 29.52%, respectively, and the inhibition in the MCF-7 cell lineThe preparation effect is weaker, inhibitor 9 is slightly obvious and is 13.54%, and other 5 inhibitors are all about 10%. We used 9 and 10 inhibitors to determine their EC on IDO1 of HepG-2 cells 50 . The results show EC of 9 and 10 50 The values were found to be 11.04. Mu.M and 14.06. Mu.M, respectively. EC of other inhibitors 50 The values were all over 100. Mu.M (Table 2).
TABLE 2 inhibition of IDO1 inhibitory Activity parameters by nicotinic acid derivatives in human cancer cells
Example 3: detection of antitumor effect of nicotinic acid derivatives by using tumor-bearing murine model
Animals
BALB/C common mice, male, body weight 20-22g,7-8 weeks old, SPF grade, purchased from Shanghai Laek laboratory animal Limited [ laboratory animal quality elike Scale: SCXK (Shanghai) 2007-0005].
Feeding conditions
All mice were free to feed and drink water and were kept at room temperature (25.+ -. 2). Degree.C. The feed and water are subjected to high-pressure sterilization treatment, and all experimental feeding processes are SPF level.
Dose setting
(1) Nicotinic acid derivative (compound 9) 1 dose group 20mg/kg;
(2) Niacin derivatives and cGAMP in combination: nicotinic acid derivative 20mg/kg+cGAMP20
mg/kg;
(3) Niacin derivatives and anti-PD-L1 combinations: nicotinic acid derivative 20 mg/kg/day + anti-PD-L1 mab, 200 μg/time, once a week;
test control
Negative control: physiological saline solution
Positive control:
(1)cGAMP,20mg/kg;
(2) anti-PD-L1 mab, 200 μg/time, once a week;
administration method
Route of administration: tail vein injection
Dosing volume: 100 microliters/min; number of administrations: the administration was continued for 21 days, 1 every two days.
Number of animals per group: 10 pieces of
The mouse colorectal cancer cell strain CT26 and the mouse breast cancer cell strain 4T1 are all purchased from a cell bank of China academy of sciences.
Main step of the test
Establishment and intervention of tumor model mice
Cell culture, passage, collection of cells at the logarithmic phase of cells, concentration per ml (1.0X10) 7 ) Is injected into the armpit of the right forelimb of the mouse with 0.2ml of the cell suspension (cell number 2.0X10) 6 And (2) tumor formation succeeded about 8 days. According to the experimental categories of two mouse tumor models, 6 groups are randomly divided, wherein the 6 groups comprise a model control group, a cGAMP positive medicine control group, an anti-PD-L1 positive medicine control group, a nicotinic acid derivative 9 and cGAMP combined medicine group and a nicotinic acid derivative 9 and anti-PD-L1 monoclonal antibody combined medicine group. After 21 days, mice were sacrificed and weighed for tumor weight, and tumor inhibition rate was calculated.
Preparing a colorectal cancer cell strain CT26 of the mice respectively, transplanting the colorectal cancer cell strain CT26 of the mice into BalB/C common mice, transplanting the breast cancer cell strain 4T1 of the mice into the BalB/C common mice, and observing the anti-tumor effect of different drugs.
Statistical analysis
Data are expressed as x±s, treated with SPSS10.0 software, and the significance of each group of tumor weight differences was compared using one-way ANOVA test with a significance level a=0.05.
Experimental results
The mice are inoculated with tumor cells subcutaneously to prepare a successful subcutaneous transplantation tumor model, and the nicotinic acid derivative (compound 9) can obviously inhibit the growth of the tumor, and the tumor weight after 21 days of administration is obviously lower than that of a negative control model group (P <0.05, P < 0.01); the combination of the nicotinic acid derivative (compound 9) and the cGAMP and the nicotinic acid derivative (compound 9) and the anti-PD-L1 monoclonal antibody all show the effect of inhibiting tumor obviously improved compared with the effect of independently taking the individual components. The specific results are shown in tables 2-3.
TABLE 2 inhibition of mouse colorectal cancer cell CT26 subcutaneous transplantation tumor by nicotinic acid derivatives and their combination
TABLE 3 inhibition of mouse breast cancer 4T1 subcutaneous transplantations by nicotinic acid derivatives and combination thereof
EXAMPLE 4 acute toxicity study of nicotinic acid derivatives in mice
The experimental method comprises the following steps:
ICR mice were 20 (purchased from Shanghai Laike laboratory animal Limited (laboratory animal quality eligibility: SCXK (Shanghai) 2007-0005)), each half of which had a weight of 18-22 g, and the animals were fed with pellet feed and were fed with water.
The nicotinic acid derivative (compound 9) was prepared as a solution having a concentration of 200mg/mL with physiological saline.
ICR mice were given 2g/kg of the novel complex by single intraperitoneal injection of body weight, and the toxic reaction and death of the mice within 14 days after administration were observed. As a result, it was found that the mice were normally operated after a single intraperitoneal injection. Within 14 days after administration, mice did not die, and on day 15, all mice were sacrificed, dissected, and examined visually for all organs without visible lesions.
Experimental results:
the acute toxicity test results show that the maximum tolerance MTD of intraperitoneal administration is not lower than 2g/Kg, which indicates that the acute toxicity of the nicotinic acid derivative 9 is low.
Figure 1 shows the structural formula and the name of the nicotinic acid derivative (1-10).
Claims (3)
1. The application of the nicotinic acid derivative as an anti-tumor effective component in preparing an anti-tumor medicament, wherein the anti-tumor medicament is applied to the treatment of colorectal cancer and breast cancer; the structural formula of the nicotinic acid derivative is as follows:
2. the application of nicotinic acid derivatives as anti-tumor active ingredients in combination with an immune channel STING agonist in the preparation of anti-tumor drugs, wherein the immune channel STING agonist is cGAMP; the antitumor drug is applied to the treatment of colorectal cancer and breast cancer, and the structure of the nicotinic acid derivative is as follows:
3. the use of a nicotinic acid derivative according to claim 1 as an antitumor active ingredient in the preparation of an antitumor drug, wherein the drug is a pharmaceutically acceptable pharmaceutical preparation.
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