CN112402425B - Application of 3, 5-dinitrophenyl-pyrazolo [3,4-d ] [1,3] oxazine as tumor drug resistance reversal agent - Google Patents

Application of 3, 5-dinitrophenyl-pyrazolo [3,4-d ] [1,3] oxazine as tumor drug resistance reversal agent Download PDF

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CN112402425B
CN112402425B CN202011350126.3A CN202011350126A CN112402425B CN 112402425 B CN112402425 B CN 112402425B CN 202011350126 A CN202011350126 A CN 202011350126A CN 112402425 B CN112402425 B CN 112402425B
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tumor
dinitrophenyl
pyrazolo
pharmaceutical composition
oxazine
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类红旭
盛卸晃
赵子婧
郝梦珠
卢佳澳
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Shanghai Xianglihe Pharmaceutical Co ltd
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Shandong Normal University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin

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Abstract

本发明属于医药技术领域，涉及3,5‑二硝基苯基‑吡唑并[3,4‑d][1,3]恶嗪作为肿瘤耐药逆转剂的应用。本发明研究表明1‑苯基‑6‑(3,5‑二硝基苯基)‑吡唑并[3,4‑d][1,3]恶嗪‑4(1H)‑酮能够显著提高肿瘤细胞对抗肿瘤药物的敏感性，逆转肿瘤细胞耐药性，并且治疗剂量安全无毒性，具有潜力成为新型的肿瘤耐药逆转剂类药物。基于该研究结果，上述化合物可用于化疗方案的辅助治疗及配合其他抗肿瘤药物共同用药，具有良好的临床用药意义。The invention belongs to the technical field of medicine, and relates to the application of 3,5-dinitrophenyl-pyrazolo[3,4-d][1,3]oxazine as a tumor resistance reversing agent. The present research shows that 1-phenyl-6-(3,5-dinitrophenyl)-pyrazolo[3,4-d][1,3]oxazine-4(1H)-one can significantly improve the The sensitivity of tumor cells to anti-tumor drugs, the reversal of tumor cell drug resistance, and the safe and non-toxic therapeutic dose, has the potential to become a new type of tumor drug resistance reversal agent. Based on the results of this study, the above compounds can be used for adjuvant therapy of chemotherapy regimens and co-administration with other antitumor drugs, and have good clinical significance.

Description

Application of 3, 5-dinitrophenyl-pyrazolo [3,4-d ] [1,3] oxazine as tumor drug resistance reversal agent
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an application of a 3, 5-dinitrophenyl-pyrazolo [3,4-d ] [1,3] oxazine compound, namely 1-phenyl-6- (3, 5-dinitrophenyl) -pyrazolo [3,4-d ] [1,3] oxazine-4 (1H) -ketone as a tumor drug resistance reversal agent, and an application of a pharmaceutical composition comprising 1-phenyl-6- (3, 5-dinitrophenyl) -pyrazolo [3,4-d ] [1,3] oxazine-4 (1H) -ketone in preparation of an antitumor agent.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
Multidrug resistance (MDR) of tumors has been a worldwide problem that plagues cancer treatment, and MDR refers to the long-term exposure of tumor cells to a certain chemotherapeutic drug, which results in drug resistance, and may also result in cross-resistance of other multiple chemotherapeutic drugs with different functions, which is one of the main causes of chemotherapy failure. The mechanism of MDR in tumors is complex, with overexpression of ABC transporters being the major cause of MDR. Therefore, efforts to find and develop MDR reversal agents to restore sensitivity of MDR cells to traditional anticancer drugs are considered as the main strategy to overcome MDR.
ABCG2 is one of the key proteins responsible for MDR and belongs to the second-position member of the G subfamily of the ABC transporter superfamily. The ABCG2 transporter can pump antitumor drugs such as mitoxantrone, gefitinib, adriamycin and imatinib from the inside to the outside of cells, thereby reducing the antitumor effect of the drugs. The research finds that the ABCG2 has direct clinical relevance to the staging, metastasis and prognosis of the breast cancer, and has clear connection with the survival rate and treatment response of patients with diffuse large B-cell lymphoma, acute myelogenous leukemia and non-small cell lung cancer. Therefore, blocking the efflux of ABCG2 is of great significance in the treatment of drug resistant tumors.
Disclosure of Invention
Based on the research background, the invention discovers that the compound 1-phenyl-6- (3, 5-dinitrophenyl) -pyrazolo [3,4-d ] [1,3] oxazine-4 (1H) -ketone can target ABCG2, has an inhibiting effect, improves the sensitivity of tumor cells to drugs, and is expected to be applied to the treatment of drug-resistant tumors.
In order to achieve the technical purpose, the invention adopts the following technical scheme:
in a first aspect of the invention, there is provided the use of 3, 5-dinitrophenyl-pyrazolo [3,4-d ] [1,3] oxazines as reversal agents of tumour resistance.
Wherein the 3, 5-dinitrophenyl-pyrazolo [3,4-d ] [1,3] oxazine is 1-phenyl-6- (3, 5-dinitrophenyl) -pyrazolo [3,4-d ] [1,3] oxazine-4 (1H) -ketone, and the structural formula is as follows:
Figure BDA0002801145890000021
the research of the invention shows that the compound shown in the formula I can reverse the drug resistance of tumor cells and improve the sensitivity of the tumor cells to antitumor drugs. Preferably, the compound can inhibit the activity of ABCG2 in tumor cells, reduce the pumping out of anticancer drugs and improve the sensitivity of the antitumor drugs related to the ABCG2 drug resistance route. In addition, cytotoxicity experiments also confirmed that there was no significant toxicity at therapeutic doses. The results show that the 1-phenyl-6- (3, 5-dinitrophenyl) -pyrazolo [3,4-d ] [1,3] oxazine-4 (1H) -ketone can reverse the drug resistance degree of tumor cells, and has adjuvant therapy effect on tumors and drug-resistant tumors.
In a second aspect, the invention provides the application of 3, 5-dinitrophenyl-pyrazolo [3,4-d ] [1,3] oxazine in preparing a medicament with an inhibitory effect on drug-resistant protein (ABCG 2).
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising: compound a and a pharmaceutically acceptable carrier;
wherein the compound A is 3, 5-dinitrophenyl-pyrazolo [3,4-d ] [1,3] oxazine.
In a fourth aspect of the present invention, there is provided an application of any one of the above pharmaceutical compositions in the preparation of an anti-tumor agent.
The invention has the beneficial effects that:
(1) the research of the invention proves that the therapeutic dose of the compound is far lower than the minimum toxic dose through in vitro cell experiments, and the use is safe.
(2) The research result of the invention proves that 1-phenyl-6- (3, 5-dinitrophenyl) -pyrazolo [3,4-d ] [1,3] oxazine-4 (1H) -ketone (a compound shown in a formula I) inhibits the expression of ABCG2 in tumor cells, and realizes the reversal effect of drug-resistant tumor cells. The research result of the invention provides the effect of the compound in resisting tumors, particularly drug-resistant tumors for the first time.
(3) Tumors related to ABCG2 drug resistance have been reported to include non-small cell lung cancer, diffuse large B-cell lymphoma, acute myelogenous leukemia and the like. Based on the research result of the invention, the combined application treatment method of the compound and the disease treatment medicine can be correspondingly developed, and the invention has good guiding significance for clinical medication.
Detailed Description
It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. 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 to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
As introduced in the background art, aiming at the defects in the prior art, the invention provides the application of 1-phenyl-6- (3, 5-dinitrophenyl) -pyrazolo [3,4-d ] [1,3] oxazine-4 (1H) -ketone as a tumor drug resistance reversal agent in order to solve the technical problems.
In a first aspect of the invention, the invention provides a compound selected from compounds shown in formula I, or pharmaceutically acceptable salts, solvates and hydrates thereof, and the compound is used as a tumor drug resistance reversal agent.
Figure BDA0002801145890000041
In some embodiments, the tumor resistance-reversing agent is a transport pump inhibitor.
In some embodiments, the transport pump inhibitor has an inhibitory effect on drug resistance protein (ABCG 2).
In some embodiments, the tumor resistance reversal agent is an inhibitor of drug resistance protein (ABCG2) transport.
In some specific embodiments, the tumor-resistant drug is mitoxantrone or doxorubicin.
In a second aspect of the present invention, a pharmaceutical composition is provided, where the pharmaceutical composition includes one or more of the compound described in the first aspect, a pharmaceutically acceptable salt, a solvate, and a hydrate of the compound, and a pharmaceutically acceptable carrier.
In some embodiments, the pharmaceutical composition further comprises a drug for treating or assisting in treating tumors.
In some embodiments, the drugs for treating or adjunctively treating tumors include, but are not limited to, camptothecin analogs, tyrosine kinase inhibitors, anthracyclines, anti-HIV viral drugs, anti-rheumatic drugs, immunosuppressive agents, and antibiotics.
In some embodiments, the drug for treating a tumor is an ABCG2 drug resistance-related drug.
In some embodiments, the anthracycline is mitoxantrone or doxorubicin.
In some embodiments, the pharmaceutical composition includes, but is not limited to, oral dosage forms, parenteral dosage forms, topical dosage forms, and rectal dosage forms.
In some embodiments, the pharmaceutical composition may be tablets, capsules, pills, powders, sustained release formulations, solutions and suspensions for oral administration, sterile solutions, suspensions or emulsions for parenteral injection, ointments or creams for topical use, or suppositories for rectal administration.
In a third aspect of the present invention, there is provided the use of a compound according to the first aspect or a pharmaceutical composition according to the second aspect in the manufacture of an anti-neoplastic agent.
In some embodiments, the anti-tumor agent comprises drugs, nutraceuticals, and model tool drugs for treating tumors.
In a fourth aspect of the invention, there is provided a method of treatment of a tumour which comprises treatment with a compound according to the first aspect or a pharmaceutical composition according to the second aspect.
In some embodiments, the tumor is a drug-resistant tumor disease, further including, but not limited to, drug-resistant breast cancer, drug-resistant non-small cell lung cancer, drug-resistant diffuse large B-cell lymphoma, drug-resistant acute myelogenous leukemia.
The present invention is described in further detail below with reference to specific examples, which are intended to be illustrative of the invention and not limiting.
EXAMPLE 1 test for reversing drug resistance of Compounds to tumor cells
1. And (3) drug-resistant cell culture: S1-MI-80 cells are MX-induced ABCG2 overexpression resistant sublines derived from human colon cancer cell line S123. S1-MI-80 was cultured in DMEM medium. All cell lines were maintained at 37 ℃ with 5% CO2In a moist incubator.
2. Cytotoxicity test: drug sensitivity in vitro cell models was determined using MTT colorimetric cell proliferation assays. Single cell suspensions were prepared and seeded at 160. mu.L per well in 96-well plates, and CO was placed2Culturing in incubator for 24 hr, adding a series of concentrations (0, 1, 2, 4, 8, 18, 32 μmol/L) of 1-phenyl-6- (3, 5-dinitrophenyl) -pyrazolo [3,4-d][1,3]Oxazin-4 (1H) -ones. mu.L of 0.5% MTT was added to each well and incubated for an additional 4 hours. The supernatant was then removed and 150 μ L DMSO was added to each well to dissolve the MTT crystals. Absorbance was measured at 540nm using a microplate reader, and the essentially non-toxic dose was determined.
3. Drug resistance reversal activity test: single cell suspensions were prepared and seeded in 96 well plates at 160. mu.L per well, and 20. mu. mol/L1-phenyl-6- (3, 5-dinitrophenyl) -pyrazolo [3,4-d was added][1,3]Oxazin-4 (1H) -one, ko143 (2.5. mu. mol/L) was used as a positive control. After 1h incubation, a series of different concentrations (100, 200, 400, 800, 1600, 3200nM) of mitoxantrone were added. After 68 hours of incubation, 20. mu.L of 0.5% MTT was added and incubated for an additional 4 hours. The supernatant was removed and 150 μ L DMSO was added to each well to dissolve the MTT crystals. Absorbance was measured at 540nm with a microplate reader, and IC was calculated by Bliss method50Value (IC)50The value is the concentration of the compound corresponding to 50% inhibition of the viability of the cells) and the reversal factor of drug resistance RF (mitoxantrone on sensitive tumor cells IC) is calculated50value/Compound in combination with mitoxantrone on drug resistant cell IC50)。
Drug resistance reversal activity of the compounds of Table 1
Figure BDA0002801145890000061
Figure BDA0002801145890000071
The results are shown in table 1, with the known ABCG2 inhibitor Ko143 as a positive control group. The sensitivity of the drug-resistant cell strain treated by 1-phenyl-6- (3, 5-dinitrophenyl) -pyrazolo [3,4-d ] [1,3] oxazine-4 (1H) -ketone to mitoxantrone is remarkably improved, the drug resistance reversal fold RF value is 6.10, the reversal activity is close to positive control Ko143, and the drug resistance of the ABCG2 over-expression drug-resistant cell S1-MI-80 can be effectively reversed.
It should be noted that the above-mentioned embodiments are only preferred embodiments of the present invention, and the present invention is not limited thereto, and although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications and equivalents can be made in the technical solutions described in the foregoing embodiments, or equivalents thereof. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention. Although the present invention has been described with reference to the specific embodiments, it should be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.

Claims (6)

1. 1-苯基-6-(3,5-二硝基苯基)-吡唑并[3,4-d][1,3]恶嗪-4(1H)-酮在制备肿瘤耐药逆转剂中的应用，所述肿瘤耐药的药物为米托蒽醌；所述肿瘤为结肠癌。1. 1-Phenyl-6-(3,5-dinitrophenyl)-pyrazolo[3,4-d][1,3]oxazin-4(1H)-one in the preparation of tumor drug resistance For use in a reversal agent, the drug resistant to the tumor is mitoxantrone; and the tumor is colon cancer. 2.一种药物组合物，其特征在于，所述药物组合物包括化合物A及药用载体，还包括米托蒽醌；2. a pharmaceutical composition, is characterized in that, described pharmaceutical composition comprises compound A and pharmaceutically acceptable carrier, also comprises mitoxantrone; 其中，所述化合物A为1-苯基-6-(3,5-二硝基苯基)-吡唑并[3,4-d][1,3]恶嗪-4(1H)-酮。Wherein, the compound A is 1-phenyl-6-(3,5-dinitrophenyl)-pyrazolo[3,4-d][1,3]oxazin-4(1H)-one . 3.如权利要求2所述药物组合物，其特征在于，3. pharmaceutical composition as claimed in claim 2, is characterized in that, 所述药物组合物包括口服剂型、胃肠外给药剂型、外用剂型和直肠给药剂型。The pharmaceutical compositions include oral dosage forms, parenteral dosage forms, topical dosage forms and rectal dosage forms. 4.如权利要求2所述药物组合物，其特征在于，所述药物组合物可以是口服的片剂、胶囊、丸剂、粉剂、溶液和悬浮液，用于胃肠外注射的无菌溶液、悬浮液或乳液，用于外用的软膏或乳膏，或者用于直肠给药的栓剂。4. pharmaceutical composition as claimed in claim 2 is characterized in that, described pharmaceutical composition can be oral tablet, capsule, pill, powder, solution and suspension, sterile solution for parenteral injection, Suspension or emulsion, ointment or cream for external use, or suppository for rectal administration. 5.如权利要求2-4任一项所述药物组合物在制备抗肿瘤药剂中的应用，所述肿瘤为结肠癌。5. The application of the pharmaceutical composition according to any one of claims 2-4 in the preparation of an anti-tumor agent, wherein the tumor is colon cancer. 6.如权利要求5所述药物组合物在制备抗肿瘤药剂中的应用，其特征在于，所述抗肿瘤药剂包括用于治疗肿瘤的药物。6 . The application of the pharmaceutical composition according to claim 5 in the preparation of anti-tumor medicaments, wherein the anti-tumor medicaments comprise drugs for treating tumors. 7 .
CN202011350126.3A 2020-11-26 2020-11-26 Application of 3, 5-dinitrophenyl-pyrazolo [3,4-d ] [1,3] oxazine as tumor drug resistance reversal agent Expired - Fee Related CN112402425B (en)

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