WO2022198777A1 - 一种三氮唑类化合物在制备抗肿瘤药物中的应用 - Google Patents
一种三氮唑类化合物在制备抗肿瘤药物中的应用 Download PDFInfo
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- -1 triazole compound Chemical class 0.000 title claims abstract description 17
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 13
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 210000004881 tumor cell Anatomy 0.000 claims abstract description 9
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 8
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 8
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- 229940079593 drug Drugs 0.000 claims description 10
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
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- 208000020816 lung neoplasm Diseases 0.000 claims description 6
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- 206010017758 gastric cancer Diseases 0.000 claims description 5
- 201000011549 stomach cancer Diseases 0.000 claims description 5
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- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 229940077388 benzenesulfonate Drugs 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 2
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- 239000010452 phosphate Substances 0.000 claims description 2
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 1
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- XYIUOUXWVHHVSO-UHFFFAOYSA-N 2-(triazol-1-yl)benzamide Chemical compound NC(=O)C1=CC=CC=C1N1N=NC=C1 XYIUOUXWVHHVSO-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
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- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the invention belongs to the field of antitumor drugs, in particular to the application of a triazole compound in the preparation of antitumor drugs.
- small molecule compounds have a wide range of potential applications as medicinal drugs and diagnostics. Especially in clinical anti-cancer, anti-tumor, etc., a large number of small molecule compounds have been successfully developed, sold and widely used in the prevention and treatment of various diseases. It has been widely used in many fields such as chemistry, medicine, biology and materials science.
- Small chemical molecules can pass through the cell membrane and affect the expression and function of intracellular targets, and have a wide range of applications; in addition, small chemical molecules have good oral bioavailability after chemical modification. Better compliance; regardless of price or dosage form, the research on chemical small molecule drugs is more mature than biological drugs, and in contrast, it has good potential and market competitiveness. Therefore, it is of great significance to find new structural types of antitumor drugs.
- the purpose of the present invention is to provide the application of a triazole compound in the preparation of antitumor drugs, and the small molecule compound has good inhibitory activity on multiple primary and transformed tumor cells.
- the triazole compound is N-(5-benzothiazole-2-thiomethyl)-4 hydrogen-1,2,4 triazole-3-benzamide, and has the structure shown in formula I:
- the pharmaceutically acceptable salts are hydrochloride, phosphate, sulfate, acetate, maleate, citrate, benzenesulfonate, toluenesulfonate, rich One or more of malate and tartrate.
- the tumor includes, but is not limited to, colon cancer, stomach cancer, or lung cancer.
- the present invention also provides the application of a triazole compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for inhibiting tumor cells.
- the tumor cells are colon cancer cells SW480, drug-resistant colon cancer cells SW620, gastric cancer cells SGC7901 or lung cancer cells A549.
- the invention provides the application of a triazole compound or a pharmaceutically acceptable salt thereof in the preparation of an antitumor drug.
- the present invention discovers for the first time that the triazole compound N-(5-benzothiazole-2-thiomethyl)-4hydro-1,2,4triazole-3-benzamide has antitumor activity, and has antitumor activity against many
- the primary and transformed tumor cells have a good inhibitory effect and can be used as anti-tumor drugs.
- Figure 1 shows the inhibitory activity of test compounds on colon cancer cell SW480 in vitro
- Figure 2 shows the inhibitory activity of test compounds on drug-resistant colon cancer cells SW620 in vitro.
- N-(5-benzothiazole-2-thiomethyl)-4 hydrogen-1,2,4 triazole-3-benzamide compound is prepared according to the following process:
- N-(5-benzothiazole-2-thiomethyl)-4 hydrogen-1,2,4 triazole-3-benzamide compound used in the present invention is according to the document Shestakov, A.S.; Gusakova, N.V.; Verezhnikov, V.N.; Shikhaliev, Kh.S. Synthesis of triazolamines from cyanamides and hydrazides Izvestiya Vysshikh Uchebnykh Zavedenii, Khimiya i Khimicheskaya Tekhnologiya (2005), 48 (6), 126-129 The method is obtained.
- the selected tumor cells include colon cancer cells SW480, drug-resistant colon cancer cells SW620, gastric cancer cells SGC7901, and lung cancer cells A549.
- Cells in the logarithmic growth phase were taken, digested and counted, and the cell state was adjusted before plating.
- the cells were seeded at a density of 3000 cells/well in a 96-well plate and placed in an incubator overnight. (Note: The outer circle is filled with PBS.) After 18 to 24 hours, the drug administration operation is carried out. Aspirate the cell culture medium and add a culture medium containing a certain concentration of the drug.
- the experiment set blank group (solvent control group) and experimental group.
- the drug concentrations in the experimental group were 1 ⁇ M, 5 ⁇ M, 20 ⁇ M, 50 ⁇ M, 100 ⁇ M, and 200 ⁇ M.
- Three sub-wells were set in each group of experiments, the positive control was pentafluorouracil, and the method was the same as that of the test compound.
- test compound N-(5-benzothiazole-2-thiomethyl)-4hydro-1,2,4triazole-3-benzamide has antitumor activity, and it has antitumor activity against many strains of progenitors. It has a good inhibitory effect on the development and transformation of tumor cells, and can be used as an anti-tumor drug.
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- Chemical Kinetics & Catalysis (AREA)
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Abstract
一种三氮唑类化合物或其可药用的盐在制备抗肿瘤药物中的应用。三氮唑类化合物N-(5-苯并噻唑-2-硫甲基)-4氢-1,2,4三氮唑-3-苯甲酰胺具备抗肿瘤活性，对多株原发及转型肿瘤细胞具有很好的抑制作用，可以用作制备抗肿瘤的药物。
Description
本申请要求于2021年03月22日提交中国专利局、申请号为202110301156.3、发明名称为“一种三氮唑类化合物在制备抗肿瘤药物中的应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
本发明属于抗肿瘤药物领域，尤其涉及一种三氮唑类化合物在制备抗肿瘤药物中的应用。
恶性肿瘤是全球排名第二的致死性疾病，而肺癌、***癌、结直肠癌和乳腺癌位列榜首，近十几年来癌症的发病率和死亡率均呈持续上升态势。其常规治疗手段有多种如手术、化疗、放疗等。但传统治疗手段大多无法达到治愈效果，特别是中晚期恶性肿瘤患者，死亡率高居不下。小分子靶向抗肿瘤药物因具有高疗效，低毒副作用及高度特异性优点，逐渐成为国内外创新药物研发的热点项目。与传统药物不同的是，小分子药物能与人体靶点特异性结合，能有效针对原发性肿瘤发挥抑制作用，其具有低毒性，高生物利用度，广泛的生物活性、良好生物相容性和疗效。许多突出成果表明，小分子类化合物具有广泛的潜在应用作为药用药物和诊断剂。尤其是临床抗癌，抗肿瘤等，大量小分子化合物已经被成功开发，销售和广泛应用于预防和治疗各种疾病。在化学、医学、生物学和材料科学等众多领域得到了广泛应用。
化学小分子能够穿过细胞膜，影响细胞内靶点的表达和功能，其应用范围非常广泛；此外，化学小分子经过化学修饰后具有良好的口服生物利用度，服用化学小分子对患者来说，具有更好的依从性；不管是售价还是剂型的给药方式，化学小分子药物的研究都比生物药物更为成熟，相比之下，它具有良好的潜力和市场竞争力。因此寻找新结构类型的抗肿瘤药物具有重要的意义。
发明内容
本发明的目的在于提供一种三氮唑类化合物在制备抗肿瘤药物中的应用，该小分子化合物对多株原发及转型肿瘤细胞具有很好的抑制活性。
所述三氮唑类化合物为N-(5-苯并噻唑-2-硫甲基)-4氢-1,2,4三氮唑-3-苯甲酰胺，具有式I所示结构：
在本发明中，所述可药用的盐为盐酸盐、磷酸盐、硫酸盐、醋酸盐、马来酸盐、枸橼酸盐、苯磺酸盐、甲基苯磺酸盐、富马酸盐和酒石酸盐中的一种或几种。
所述肿瘤为包括但不限于结肠癌、胃癌或肺癌。
本发明还提供了一种三氮唑类化合物或其可药用的盐在制备抑制肿瘤细胞药物方面的应用。
所述肿瘤细胞为结肠癌细胞SW480、耐药结肠癌细胞SW620、胃癌细胞SGC7901或肺癌细胞A549。
本发明提供了一种三氮唑类化合物或其可药用的盐在制备抗肿瘤药物中的应用。本发明首次发现了三氮唑类化合物N-(5-苯并噻唑-2-硫甲基)-4氢-1,2,4三氮唑-3-苯甲酰胺具备抗肿瘤活性，对多株原发及转型肿瘤细胞具有很好的抑制作用，可以用作制备抗肿瘤的药物。
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据提供的附图获得其他的附图。
图1为受试化合物体外对结肠癌细胞SW480抑制活性；
图2为受试化合物体外对耐药结肠癌细胞SW620抑制活性。
在本发明中，所述N-(5-苯并噻唑-2-硫甲基)-4氢-1,2,4三氮唑-3-苯甲酰胺化合物按照以下流程制备：
具体的，本发明所使用的N-(5-苯并噻唑-2-硫甲基)-4氢-1,2,4三氮唑-3-苯甲酰胺化合物按照文献Shestakov,A.S.；Gusakova,N.V.；Verezhnikov,V.N.；Shikhaliev,Kh.S.Synthesis of triazolamines from cyanamides and hydrazides Izvestiya Vysshikh Uchebnykh Zavedenii,Khimiya i Khimicheskaya Tekhnologiya(2005),48(6),126-129中的方法制备得到。
1.化合物的抗肿瘤活性测定
选用的肿瘤细胞有结肠癌细胞SW480，耐药结肠癌细胞SW620，胃癌细胞SGC7901，肺癌细胞A549，取处于对数生长期细胞，消化计数，将细胞状态调整好后，进行铺板操作。按3000/孔细胞密度接种于96孔板，在培养箱中放置过夜。(注：外圈PBS填满。)18～24h后，进行给药操作。吸走细胞培养基，加入含有一定浓度的药物的培养液。实验设置空白组(溶剂对照组)、实验组。实验组的药物浓度依次为1μM、5μM、20μM、50μM、100μM、200μM。每组实验均设置3个副孔，阳性对照为五氟尿嘧啶，方法与受试化合物相同。
给药72h后，每孔加入10μL MTT溶液，置于细胞培养箱继续孵育2h。用酶标仪检测每孔在492nm波长处的光吸收值。
根据吸光值计算每孔细胞的存活率，从而算出药物的IC50值。结果如表1所示。
表1 受试化合物的体外抗肿瘤活性筛选
由表1可知，受试化合物N-(5-苯并噻唑-2-硫甲基)-4氢-1,2,4三氮唑-3-苯甲酰胺具备抗肿瘤活性，对多株原发及转型肿瘤细胞具有很好的抑制作用，可以用作制备抗肿瘤的药物。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (5)
- 三氮唑类化合物或其可药用的盐在制备抗肿瘤药物中的应用；所述三氮唑类化合物具有式I所示结构：
- 根据权利要求1所述的应用，其特征在于，所述可药用的盐为盐酸盐、磷酸盐、硫酸盐、醋酸盐、马来酸盐、枸橼酸盐、苯磺酸盐、甲基苯磺酸盐、富马酸盐和酒石酸盐中的一种或几种。
- 根据权利要求1所述的应用，其特征在于，所述肿瘤包括结肠癌、胃癌或肺癌。
- 根据权利要求1所述的应用，其特征在于，所述抗肿瘤为抑制肿瘤细胞的增殖。
- 根据权利要求4所述的应用，其特征在于，所述肿瘤细胞为结肠癌细胞SW480、耐药结肠癌细胞SW620、胃癌细胞SGC7901或肺癌细胞A549。
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| CN109456312A (zh) * | 2018-10-29 | 2019-03-12 | 郑州大学 | 1,2,3-三氮唑类微管蛋白聚合抑制剂其合成方法和应用 |
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| WO2005097758A1 (en) * | 2004-03-26 | 2005-10-20 | Amphora Discovery Corporation | Certain triazole-based compounds, compositions, and uses thereof |
| CN102725281A (zh) * | 2009-06-05 | 2012-10-10 | 奥斯陆大学医院公司 | 作为wtn通路抑制剂的氮杂茂类衍生物 |
| CN106380465A (zh) * | 2016-09-05 | 2017-02-08 | 郑州大学 | 含1，2，3‑三氮唑结构单元的2，4‑二取代喹唑啉类化合物及其制备方法和用途 |
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| CN109456312A (zh) * | 2018-10-29 | 2019-03-12 | 郑州大学 | 1,2,3-三氮唑类微管蛋白聚合抑制剂其合成方法和应用 |
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