技术领域Technical Field
本发明涉及喹喔啉衍生物的合成及抗肿瘤应用技术领域，具体为一种喹喔啉类化合物及其制备方法与应用。The present invention relates to the technical field of synthesis and anti-tumor application of quinoxaline derivatives, and specifically to a quinoxaline compound and a preparation method and application thereof.
背景技术Background technique
现有2,3-二芳基的合成方法主要是邻苯二胺与1,2-二羰基化合物的缩合环化，合成分子结构中的R2和R3结构类型较少，左侧苯环上的取代基一般是对称的，合成的化合物取代类型比较单调，为此，我们提出一种喹喔啉类化合物及其制备方法与应用。The existing synthesis method of 2,3-diaryl is mainly the condensation cyclization of o-phenylenediamine and 1,2-dicarbonyl compounds. There are fewer R2 and R3 structural types in the synthetic molecular structure, the substituents on the left benzene ring are generally symmetrical, and the substitution type of the synthesized compound is relatively monotonous. Therefore, we propose a quinoxaline compound and its preparation method and application.
发明内容Summary of the invention
因此，本发明的目的是提供一种喹喔啉类化合物及其制备方法与应用，将邻苯二胺与取代吲哚及碘代试剂通过多步转化反应合成了一系列喹喔啉衍生物，合成过程简单且易于控制，目标产物结构类型多样，能够实现在喹喔啉结构母核的2-位、3-位、5-位、6-位和7-位引入多样性的取代基，为合成含喹喔啉结构的药物分子奠定基础。Therefore, the purpose of the present invention is to provide a quinoxaline compound and a preparation method and application thereof, wherein a series of quinoxaline derivatives are synthesized by multi-step conversion reactions of o-phenylenediamine, substituted indole and an iodine reagent, the synthesis process is simple and easy to control, the target product has various structural types, and a variety of substituents can be introduced at the 2-position, 3-position, 5-position, 6-position and 7-position of the quinoxaline structure mother nucleus, laying a foundation for the synthesis of drug molecules containing quinoxaline structures.
为解决上述技术问题，根据本发明的一个方面，本发明提供了如下技术方案：To solve the above technical problems, according to one aspect of the present invention, the present invention provides the following technical solutions:
一种喹喔啉类化合物及其制备方法与应用，包括：A quinoxaline compound and a preparation method and application thereof, comprising:
S1：取代吲哚1与α位2,2,6,6-四甲基哌啶氧化物取代的1,3-二羰基化合物2在酸性溶剂中通过串联反应制得喹喔啉类化合物3；S1: Substituted indole 1 and α-substituted 2,2,6,6-tetramethylpiperidinoxide substituted 1,3-dicarbonyl compound 2 were reacted in an acidic solvent to prepare quinoxaline compound 3;
S2：反应过程的反应方程式为：S2: The reaction equation of the reaction process is:
，其中，R1为烷基、烷氧基、卤素、多氟烷基、硝基；R2为苯基、烷基取代的苯基、卤素取代的苯基、噻吩基、吡啶基、环丙基；硝基或腈基，R3为烷基、烷氧基、卤素、三氟甲基。, wherein R1 is alkyl, alkoxy, halogen, polyfluoroalkyl, or nitro; R2 is phenyl, alkyl-substituted phenyl, halogen-substituted phenyl, thienyl, pyridyl, cyclopropyl; nitro or nitrile; and R3 is alkyl, alkoxy, halogen, or trifluoromethyl.
作为本发明所述的一种喹喔啉类化合物及其制备方法与应用的一种优选方案，其中，取代吲哚1与碘代试剂与邻苯二胺类化合物的摩尔比为 1:1-1.1:1。As a preferred embodiment of the quinoxaline compound and its preparation method and application described in the present invention, the molar ratio of the substituted indole 1 to the iodine reagent to the o-phenylenediamine compound is 1:1-1.1:1.
作为本发明所述的一种喹喔啉类化合物及其制备方法与应用的一种优选方案，其中，碘代试剂为碘单质、二碘海因、N-碘代丁二酰亚胺。As a preferred embodiment of the quinoxaline compound and its preparation method and application described in the present invention, the iodination reagent is elemental iodine, diiodide hydantoin, or N-iodosuccinimide.
作为本发明所述的一种喹喔啉类化合物及其制备方法与应用的一种优选方案，其中，所述S1步骤中，反应温度为20-100℃。As a preferred embodiment of the quinoxaline compound and its preparation method and application described in the present invention, in the step S1, the reaction temperature is 20-100°C.
作为本发明所述的一种喹喔啉类化合物及其制备方法与应用的一种优选方案，其中，所述S1步骤中制得的喹喔啉类化合物共有43种。As a preferred embodiment of the quinoxaline compounds and the preparation method and application thereof described in the present invention, there are 43 quinoxaline compounds prepared in step S1.
作为本发明所述的一种喹喔啉类化合物及其制备方法与应用的一种优选方案，其中，43种喹喔啉类化合物中，化合物3-1的制备方法为：将0.2mmol 2-苯基吲哚和0.2mmolNIS溶于20mL二甲基亚砜中，室温搅拌反应2小时，然后在反应混合物中加入0.2mmol邻苯二胺室温搅拌6小时，反应完全后反应液加水20mL,用乙酸乙酯萃取反应液3次，合并有机相，旋转蒸发除去乙酸乙酯，柱色谱，洗脱剂：石油醚：乙酸乙酯＝10:1，分离得到喹喔啉衍生物3-1， 83％。As a preferred embodiment of a quinoxaline compound and its preparation method and application described in the present invention, among the 43 quinoxaline compounds, the preparation method of compound 3-1 is as follows: 0.2mmol 2-phenylindole and 0.2mmol NIS are dissolved in 20mL dimethyl sulfoxide, stirred at room temperature for 2 hours, then 0.2mmol o-phenylenediamine is added to the reaction mixture and stirred at room temperature for 6 hours. After the reaction is complete, 20mL of water is added to the reaction solution, and the reaction solution is extracted with ethyl acetate for 3 times. The organic phases are combined, and the ethyl acetate is removed by rotary evaporation. Column chromatography, eluent: petroleum ether: ethyl acetate = 10:1, separates and obtains quinoxaline derivative 3-1, 83%.
与现有技术相比，本发明具有的有益效果是：将邻苯二胺与取代吲哚及碘代试剂通过多步转化反应合成了一系列喹喔啉衍生物，合成过程简单且易于控制，目标产物结构类型多样，能够实现在喹喔啉结构母核的2-位、3-位、 5-位、6-位和7-位引入多样性的取代基，为合成含喹喔啉结构的药物分子奠定基础，在具体使用时，取代吲哚1与α位2,2,6,6-四甲基哌啶氧化物取代的1,3-二羰基化合物2在酸性溶剂中通过串联反应制得喹喔啉类化合物3，制得的喹喔啉类化合物共有43种，依次为，化合物3-1、化合物3-2、化合物3-3、化合物3-4、化合物3-6、化合物3-7、化合物3-8、化合物3-9、化合物3-10、化合物3-11、化合物3-12、化合物3-13、化合物3-14、化合物 3-15、化合物3-16、化合物3-17、化合物3-18、化合物3-19、化合物3-20、化合物3-21、化合物3-22、化合物3-23、化合物3-24、化合物3-25、化合物3-26、化合物3-27、化合物3-28、化合物3-29、化合物3-30、化合物3-31、化合物3-32、化合物3-33、化合物3-34、化合物3-35、化合物3-36、化合物3-37、化合物3-38、化合物3-39、化合物3-40、化合物3-41、化合物3-42、化合物3-43，其中，化合物3-1的制备方法为：将0.2mmol 2-苯基吲哚和 0.2mmol NIS溶于20mL二甲基亚砜中，室温搅拌反应2小时，然后在反应混合物中加入0.2mmol邻苯二胺室温搅拌6小时，反应完全后反应液加水20mL, 用乙酸乙酯萃取反应液3次，合并有机相，旋转蒸发除去乙酸乙酯，柱色谱，洗脱剂：石油醚：乙酸乙酯＝10:1，分离得到喹喔啉衍生物3-1，83％，其它种类化合物与化合物3-1制备方法相同，对制备后的喹喔啉类化合物进应用试验检测，收集对数期细胞，接种到96孔细胞培养板上，并加入不同浓度待测药物溶液。在经过72小时的培养后，加入10％的三氯乙酸，在4℃下培养1 小时，用自来水冲洗5次并风干，存活下来的细胞在室温下被0.4％(w/v)磺酰罗丹明B染色20min，用1％的乙酸冲洗5次，用10mM的Tris溶液进行了溶液的溶解，在酶联免疫检测仪540nm处测量各孔的吸光值，并根据抑制率(％)＝(无药细胞对照孔A值平均值-用药孔A值平均值)/无药细胞对照孔 A值平均值×100％计算得出，化合物3-6、3-7、3-17、3-21、3-22、3-34、 3-38具有显著的癌细胞抑制活性，化合物3-7、3-17对人肺癌细胞半数抑制浓度分别为1.2和2.4μM。Compared with the prior art, the present invention has the following beneficial effects: a series of quinoxaline derivatives are synthesized by multi-step conversion reactions of o-phenylenediamine, substituted indole and iodine reagent, the synthesis process is simple and easy to control, the target product has various structural types, and it is possible to introduce diverse substituents at the 2-position, 3-position, 5-position, 6-position and 7-position of the quinoxaline structure mother nucleus, laying a foundation for the synthesis of drug molecules containing quinoxaline structure. When used specifically, substituted indole 1 and 1,3-dicarbonyl compound 2 substituted by α-position 2,2,6,6-tetramethylpiperidinyl oxide are reacted in series in an acidic solvent to obtain quinoxaline compound 3. A total of 43 quinoxaline compounds are obtained, which are, in order, compound 3-1, compound 3-2, compound 3-3, compound 3-4, compound 3-6, compound 3-7, compound 3-8, compound 3-9, compound 3-10, compound 3-11, compound 3-12, compound 3-13, compound 3-14, compound Compound 3-15, compound 3-16, compound 3-17, compound 3-18, compound 3-19, compound 3-20, compound 3-21, compound 3-22, compound 3-23, compound 3-24, compound 3-25, compound 3-26, compound 3-27, compound 3-28, compound 3-29, compound 3-30, compound 3-31, compound 3-32, compound 3-33, compound 3-34, compound 3-35, compound 3-36, compound 3-37, compound 3-38, compound 3-39, compound 3-40, compound 3-41, compound 3-42, compound 3-43, wherein the preparation method of compound 3-1 is as follows: 0.2mmol 2-phenylindole and 0.2mmol NIS are dissolved in 20mL dimethyl sulfoxide, stirred at room temperature for 2 hours, then 0.2mmol o-phenylenediamine is added to the reaction mixture and stirred at room temperature for 6 hours, after the reaction is complete, 20mL of water is added to the reaction solution, The reaction solution was extracted with ethyl acetate three times, the organic phases were combined, and the ethyl acetate was removed by rotary evaporation. Column chromatography, eluent: petroleum ether: ethyl acetate = 10:1, separated and obtained quinoxaline derivative 3-1, 83%. The preparation method of other types of compounds was the same as that of compound 3-1. The prepared quinoxaline compounds were tested by application experiments. Logarithmic phase cells were collected, inoculated into 96-well cell culture plates, and different concentrations of the drug solutions to be tested were added. After 72 hours of culture, 10% trichloroacetic acid was added, and the cells were cultured at 4°C for 1 hour, rinsed 5 times with tap water and air-dried. The surviving cells were stained with 0.4% (w/v) sulforhodamine B at room temperature for 20 minutes, rinsed 5 times with 1% acetic acid, and dissolved with 10mM Tris solution. The absorbance of each well was measured at 540nm on an enzyme-linked immunosorbent assay instrument, and the inhibition rate (%) = (average A value of drug-free cell control wells-average A value of drug-treated wells) / average A value of drug-free cell control wells × 100% was calculated to show that compounds 3-6, 3-7, 3-17, 3-21, 3-22, 3-34, and 3-38 had significant cancer cell inhibitory activity, and the half-maximal inhibitory concentrations of compounds 3-7 and 3-17 on human lung cancer cells were 1.2 and 2.4μM, respectively.
具体实施方式Detailed ways
为使本发明的上述目的、特征和优点能够更加明显易懂，下面对本发明的具体实施方式做详细的说明。In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific embodiments of the present invention are described in detail below.
在下面的描述中阐述了很多具体细节以便于充分理解本发明，但是本发明还可以采用其他不同于在此描述的其它方式来实施，本领域技术人员可以在不违背本发明内涵的情况下做类似推广，因此本发明不受下面公开的具体实施方式的限制。In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein, and those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.
为使本发明的目的、技术方案和优点更加清楚，下面对本发明的实施方式作进一步地详细描述。In order to make the objectives, technical solutions and advantages of the present invention more clear, the embodiments of the present invention are described in further detail below.
本发明提供一种喹喔啉类化合物及其制备方法与应用，将邻苯二胺与取代吲哚及碘代试剂通过多步转化反应合成了一系列喹喔啉衍生物，合成过程简单且易于控制，目标产物结构类型多样，能够实现在喹喔啉结构母核的2- 位、3-位、5-位、6-位和7-位引入多样性的取代基，为合成含喹喔啉结构的药物分子奠定基础。The invention provides a quinoxaline compound and a preparation method and application thereof. A series of quinoxaline derivatives are synthesized by multi-step conversion reaction of o-phenylenediamine, substituted indole and iodine reagent. The synthesis process is simple and easy to control, the target product has various structural types, and it is possible to introduce diverse substituents at the 2-position, 3-position, 5-position, 6-position and 7-position of the quinoxaline structure mother nucleus, laying a foundation for synthesizing drug molecules containing quinoxaline structures.
一种喹喔啉类化合物及其制备方法与应用，包括：A quinoxaline compound and a preparation method and application thereof, comprising:
S1：取代吲哚1与α位2,2,6,6-四甲基哌啶氧化物取代的1,3-二羰基化合物2在酸性溶剂中通过串联反应制得喹喔啉类化合物3，制得的喹喔啉类化合物共有43种，具体分子式如下：S1: Substituted indole 1 and α-position 2,2,6,6-tetramethylpiperidinoxide substituted 1,3-dicarbonyl compound 2 were reacted in an acidic solvent to obtain quinoxaline compound 3. A total of 43 quinoxaline compounds were obtained, and the specific molecular formulas are as follows:
S2：反应过程的反应方程式为：S2: The reaction equation of the reaction process is:
，其中，R1为烷基、烷氧基、卤素、多氟烷基、硝基；R2为苯基、烷基取代的苯基、卤素取代的苯基、噻吩基、吡啶基、环丙基；硝基或腈基，R3为烷基、烷氧基、卤素、三氟甲基。, wherein R1 is alkyl, alkoxy, halogen, polyfluoroalkyl, or nitro; R2 is phenyl, alkyl-substituted phenyl, halogen-substituted phenyl, thienyl, pyridyl, cyclopropyl; nitro or nitrile; and R3 is alkyl, alkoxy, halogen, or trifluoromethyl.
化合物3-1的制备Preparation of compound 3-1
将0.2mmol 2-苯基吲哚和0.2mmol NIS溶于20mL二甲基亚砜中，室温搅拌反应2小时，然后在反应混合物中加入0.2mmol邻苯二胺室温搅拌6小时，反应完全后反应液加水20mL,用乙酸乙酯萃取反应液3次，合并有机相，旋转蒸发除去乙酸乙酯，柱色谱(洗脱剂：石油醚：乙酸乙酯＝10:1)分离得到喹喔啉衍生物3-1(83％)。0.2 mmol 2-phenylindole and 0.2 mmol NIS were dissolved in 20 mL dimethyl sulfoxide, stirred at room temperature for 2 hours, then 0.2 mmol o-phenylenediamine was added to the reaction mixture and stirred at room temperature for 6 hours. After the reaction was complete, 20 mL of water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate 3 times. The organic phases were combined, and the ethyl acetate was removed by rotary evaporation. The quinoxaline derivative 3-1 (83%) was separated by column chromatography (eluent: petroleum ether: ethyl acetate = 10:1).
1H NMR(400MHz,CDCl3)δ8.24–8.15(m,1H),8.15–8.06(m, 1H),7.84–7.72(m,2H),7.65–7.52(m,2H),7.42–7.29(m,3H), 7.20–7.08(m,1H),6.91–6.78(m,2H),6.55(t,J＝7.5Hz,1H), 4.62(s,2H)；1H NMR (400MHz,CDCl3)δ8.24–8.15(m,1H),8.15–8.06(m, 1H),7.84–7.72(m,2H),7.65–7.52(m,2H),7.42–7.29(m,3H), 7.20–7.08(m,1H),6.91–6.78(m,2H),6.55(t,J＝7.5Hz,1H), 4.62(s,2H);
化合物3-2的制备Preparation of compound 3-2
除了3,4-二甲基邻苯二胺代替邻苯二胺外，以与制备化合物3-1相同的方法制备化合物3-2。Compound 3-2 was prepared in the same manner as compound 3-1, except that 3,4-dimethyl-o-phenylenediamine was used instead of o-phenylenediamine.
1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.85(s,1H),7.58–7.51(m,2H),7.34–7.27(m,3H),7.10(td,J＝8.1,1.5Hz,1H),6.84(dd,J＝7.7,1.4Hz,1H),6.79(d,J＝7.6Hz,1H),6.54(td,J＝7.6, 1.0Hz,1H),4.57(s,2H),2.52(s,3H),2.51(s,3H)。1H NMR (400 MHz, CDCl3) δ7.92 (s, 1H), 7.85 (s, 1H), 7.58–7.51 (m, 2H), 7.34–7.27 (m, 3H), 7.10 (td, J=8.1, 1.5 Hz, 1H), 6.84 (dd, J=7.7, 1.4 Hz, 1H), 6.79 (d, J=7.6 Hz, 1H), 6.54 (td, J=7.6, 1.0 Hz, 1H), 4.57 (s, 2H), 2.52 (s, 3H), 2.51 (s, 3H).
化合物3-3、化合物3-4、化合物3-6、化合物3-7、化合物3-8、化合物 3-9、化合物3-10、化合物3-11、化合物3-12、化合物3-13、化合物3-14、化合物3-15、化合物3-16、化合物3-17、化合物3-18、化合物3-19、化合物3-20、化合物3-21、化合物3-22、化合物3-23、化合物3-24、化合物3-25、化合物3-26、化合物3-27、化合物3-28、化合物3-29、化合物3-30、化合物3-31、化合物3-32、化合物3-33、化合物3-34、化合物3-35、化合物3-36、化合物3-37、化合物3-38、化合物3-39、化合物3-40、化合物3-41、化合物3-42、化合物3-43的制备方法与化合物3-1相同。The preparation methods of compound 3-3, compound 3-4, compound 3-6, compound 3-7, compound 3-8, compound 3-9, compound 3-10, compound 3-11, compound 3-12, compound 3-13, compound 3-14, compound 3-15, compound 3-16, compound 3-17, compound 3-18, compound 3-19, compound 3-20, compound 3-21, compound 3-22, compound 3-23, compound 3-24, compound 3-25, compound 3-26, compound 3-27, compound 3-28, compound 3-29, compound 3-30, compound 3-31, compound 3-32, compound 3-33, compound 3-34, compound 3-35, compound 3-36, compound 3-37, compound 3-38, compound 3-39, compound 3-40, compound 3-41, compound 3-42 and compound 3-43 are the same as those of compound 3-1.
试验测试实施例：Experimental test example:
测试原理：磺酰罗丹明比色法，主要用来检测细胞增殖情况。SRB是一种粉红色阴离子染料，易溶于水，在酸性条件下可特异性地与细胞内组成蛋白质的碱性氨基酸结合；在540nm波长下产生吸收峰，吸光值与细胞量成线性正相关，故可用作细胞数的定量检测。Test principle: Sulforhodamine colorimetry is mainly used to detect cell proliferation. SRB is a pink anionic dye that is easily soluble in water and can specifically bind to the basic amino acids that make up proteins in cells under acidic conditions; it produces an absorption peak at a wavelength of 540nm, and the absorbance value is linearly positively correlated with the cell amount, so it can be used for quantitative detection of cell number.
试验方法：experiment method:
样品配制：取受试样品用DMSO溶解化合物，超声溶解，浓度100mM/L，所得药物溶液可在-20℃条件下储存；Sample preparation: Take the test sample and dissolve the compound in DMSO, dissolve it by ultrasonic, the concentration is 100mM/L, and the obtained drug solution can be stored at -20℃;
收集对数期细胞，接种到96孔细胞培养板上，并加入不同浓度待测药物溶液。在经过72小时的培养后，加入10％的三氯乙酸，在4℃下培养1小时，用自来水冲洗5次并风干，存活下来的细胞在室温下被0.4％(w/v)磺酰罗丹明B染色20min，用1％的乙酸冲洗5次，用10mM的Tris溶液进行了溶液的溶解，在酶联免疫检测仪540nm处测量各孔的吸光值。The logarithmic phase cells were collected, inoculated into 96-well cell culture plates, and different concentrations of the drug solution to be tested were added. After 72 hours of culture, 10% trichloroacetic acid was added, cultured at 4°C for 1 hour, rinsed 5 times with tap water and air-dried, and the surviving cells were stained with 0.4% (w/v) sulforhodamine B at room temperature for 20 minutes, rinsed 5 times with 1% acetic acid, and dissolved with 10mM Tris solution, and the absorbance of each well was measured at 540nm in an enzyme-linked immunosorbent assay.
试验数据计算方法：Test data calculation method:
抑制率(％)＝(无药细胞对照孔A值平均值-用药孔A值平均值)/无药细胞对照孔A值平均值×100％.Inhibition rate (%) = (average value of A value of drug-free cell control wells - average value of A value of drug-treated wells) / average value of A value of drug-free cell control wells × 100%.
根据实验结果，按点斜法原理算出与正规法相当接近的全部IC50的有关数据。Based on the experimental results, the point-slope method was used to calculate all IC50 data that were quite close to the regular method.
基本公式：Basic formula:
1.IC50:IC50＝Log-1[Xm-i×(∑p–0.5)+i/4×(1-Pm-Pn)]1.IC50: IC50 = Log-1 [Xm-i × (∑p–0.5) + i/4 × (1-Pm-Pn)]
2.含0％及100％死亡率的LD50：2. LD50 with 0% and 100% mortality:
IC50＝Log-1[Xm-i×(∑p–0.5)]IC50＝Log-1[Xm-i×(∑p–0.5)]
式中Xm为最高死亡率Pm组的剂量对数值，i为组距，Pm为最高死亡率， Pn为最低死亡率，n为各组内动物数。Where Xm is the logarithmic value of the dose of the group with the highest mortality rate Pm, i is the group interval, Pm is the highest mortality rate, Pn is the lowest mortality rate, and n is the number of animals in each group.
活性结果如下表：The activity results are shown in the following table:
从以上抗肿瘤活性结果可以看到，本发明的化合物3-6、3-7、3-17、3-21、 3-22、3-34、3-38具有显著的癌细胞抑制活性，化合物3-7、3-17对人肺癌细胞半数抑制浓度分别为1.2和2.4μM。From the above anti-tumor activity results, it can be seen that compounds 3-6, 3-7, 3-17, 3-21, 3-22, 3-34 and 3-38 of the present invention have significant cancer cell inhibition activity, and the half-inhibitory concentrations of compounds 3-7 and 3-17 on human lung cancer cells are 1.2 and 2.4 μM, respectively.
本实施方式的一种喹喔啉类化合物及其制备方法与应用，具体使用时，取代吲哚1与α位2,2,6,6-四甲基哌啶氧化物取代的1,3-二羰基化合物2在酸性溶剂中通过串联反应制得喹喔啉类化合物3，制得的喹喔啉类化合物共有 43种，依次为，化合物3-1、化合物3-2、化合物3-3、化合物3-4、化合物 3-6、化合物3-7、化合物3-8、化合物3-9、化合物3-10、化合物3-11、化合物3-12、化合物3-13、化合物3-14、化合物3-15、化合物3-16、化合物 3-17、化合物3-18、化合物3-19、化合物3-20、化合物3-21、化合物3-22、化合物3-23、化合物3-24、化合物3-25、化合物3-26、化合物3-27、化合物3-28、化合物3-29、化合物3-30、化合物3-31、化合物3-32、化合物3-33、化合物3-34、化合物3-35、化合物3-36、化合物3-37、化合物3-38、化合物3-39、化合物3-40、化合物3-41、化合物3-42、化合物3-43，其中，化合物3-1的制备方法为：将0.2mmol 2-苯基吲哚和0.2mmol NIS溶于20mL二甲基亚砜中，室温搅拌反应2小时，然后在反应混合物中加入0.2mmol邻苯二胺室温搅拌6小时，反应完全后反应液加水20mL,用乙酸乙酯萃取反应液3 次，合并有机相，旋转蒸发除去乙酸乙酯，柱色谱，洗脱剂：石油醚：乙酸乙酯＝10:1，分离得到喹喔啉衍生物3-1，83％，其它种类化合物与化合物3-1 制备方法相同，对制备后的喹喔啉类化合物进应用试验检测，收集对数期细胞，接种到96孔细胞培养板上，并加入不同浓度待测药物溶液。在经过72 小时的培养后，加入10％的三氯乙酸，在4℃下培养1小时，用自来水冲洗5 次并风干，存活下来的细胞在室温下被0.4％(w/v)磺酰罗丹明B染色20min，用1％的乙酸冲洗5次，用10mM的Tris溶液进行了溶液的溶解，在酶联免疫检测仪540nm处测量各孔的吸光值，并根据抑制率(％)＝(无药细胞对照孔 A值平均值-用药孔A值平均值)/无药细胞对照孔A值平均值×100％计算得出，化合物3-6、3-7、3-17、3-21、3-22、3-34、3-38具有显著的癌细胞抑制活性，化合物3-7、3-17对人肺癌细胞半数抑制浓度分别为1.2和2.4μM。A quinoxaline compound and its preparation method and application in this embodiment, when used specifically, substituted indole 1 and α-position 2,2,6,6-tetramethylpiperidinyl oxide substituted 1,3-dicarbonyl compound 2 are reacted in an acidic solvent to obtain quinoxaline compound 3 by tandem reaction. There are 43 quinoxaline compounds obtained, which are compound 3-1, compound 3-2, compound 3-3, compound 3-4, compound 3-6, compound 3-7, compound 3-8, compound 3-9, compound 3-10, compound 3-11, compound 3-12, compound 3-13, compound 3-14, compound 3-15, compound 3-16, compound Compound 3-17, compound 3-18, compound 3-19, compound 3-20, compound 3-21, compound 3-22, compound 3-23, compound 3-24, compound 3-25, compound 3-26, compound 3-27, compound 3-28, compound 3-29, compound 3-30, compound 3-31, compound 3-32, compound 3-33, compound 3-34, compound 3-35, compound 3-36, compound 3-37, compound 3-38, compound 3-39, compound 3-40, compound 3-41, compound 3-42, compound 3-43, wherein the preparation method of compound 3-1 is as follows: 0.2mmol 2-phenylindole and 0.2mmol NIS are dissolved in 20mL dimethyl sulfoxide, stirred at room temperature for 2 hours, then 0.2mmol o-phenylenediamine is added to the reaction mixture and stirred at room temperature for 6 hours, after the reaction is complete, 20mL of water is added to the reaction solution, and the reaction solution is extracted with ethyl acetate. The organic phases were combined and the ethyl acetate was removed by rotary evaporation. Column chromatography was performed with the eluent being petroleum ether:ethyl acetate=10:1 to separate the quinoxaline derivative 3-1 with a purity of 83%. The preparation method of other types of compounds was the same as that of compound 3-1. The prepared quinoxaline compounds were subjected to application tests. Logarithmic phase cells were collected and inoculated into 96-well cell culture plates, and different concentrations of the drug solutions to be tested were added. After 72 hours of culture, 10% trichloroacetic acid was added, and the cells were cultured at 4°C for 1 hour, rinsed 5 times with tap water and air-dried. The surviving cells were stained with 0.4% (w/v) sulforhodamine B at room temperature for 20 minutes, rinsed 5 times with 1% acetic acid, and dissolved with 10mM Tris solution. The absorbance of each well was measured at 540nm on an enzyme-linked immunosorbent assay instrument, and the inhibition rate (%) = (average A value of drug-free cell control wells - average A value of drug-treated wells) / average A value of drug-free cell control wells × 100% was calculated to indicate that compounds 3-6, 3-7, 3-17, 3-21, 3-22, 3-34, and 3-38 had significant cancer cell inhibitory activity, and the half-maximal inhibitory concentrations of compounds 3-7 and 3-17 on human lung cancer cells were 1.2 and 2.4μM, respectively.
虽然在上文中已经参考实施方式对本发明进行了描述，然而在不脱离本发明的范围的情况下，可以对其进行各种改进并且可以用等效物替换其中的部件。尤其是，只要不存在结构冲突，本发明所披露的实施方式中的各项特征均可通过任意方式相互结合起来使用，在本说明书中未对这些组合的情况进行穷举性的描述仅仅是出于省略篇幅和节约资源的考虑。因此，本发明并不局限于文中公开的特定实施方式，而是包括落入权利要求的范围内的所有技术方案。Although the present invention has been described above with reference to the embodiments, various modifications may be made thereto and parts thereof may be replaced with equivalents without departing from the scope of the present invention. In particular, as long as there is no structural conflict, the various features in the embodiments disclosed in the present invention may be used in combination with each other in any manner, and the fact that these combinations are not exhaustively described in this specification is only for the sake of omitting space and saving resources. Therefore, the present invention is not limited to the specific embodiments disclosed herein, but includes all technical solutions falling within the scope of the claims.
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| CN202210233387.XACN114573517B (en) | 2022-03-10 | 2022-03-10 | Quinoxaline compound and preparation method and application thereof |
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| CN202210233387.XACN114573517B (en) | 2022-03-10 | 2022-03-10 | Quinoxaline compound and preparation method and application thereof |
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| WO2015161142A1 (en)* | 2014-04-18 | 2015-10-22 | Millennium Pharmaceuticals, Inc. | Quinoxaline compounds and uses thereof |
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