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Synthesis and Antitumor Activity of Novel Quinazoline Derivatives Containing Acrylamide

Luye Zhang ,  Yang Zhang ,  Zhengjie Wang ,  Tao Wang ,  Erdong Li ,  Limin Liu ,  Xiujuan Liu ,  Jiaxin Zheng ,  Yu Ke ,  Lihong Shan ,  Hongmin Liu ,  Qiurong Zhang

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Citation:  Zhang Luye, Zhang Yang, Wang Zhengjie, Wang Tao, Li Erdong, Liu Limin, Liu Xiujuan, Zheng Jiaxin, Ke Yu, Shan Lihong, Liu Hongmin, Zhang Qiurong. Synthesis and Antitumor Activity of Novel Quinazoline Derivatives Containing Acrylamide[J]. Chinese Journal of Organic Chemistry, 2020, 40(9): 2804-2810. doi: 10.6023/cjoc202005081 shu

含丙烯酰胺结构的喹唑啉衍生物的合成及抗肿瘤活性研究

  • a.

    郑州大学药学院 郑州 45000

  • b.

    新药创制与药物安全性评价河南省协同创新中心 郑州 450001

  • c.

    省部共建食管癌防治国家重点实验室 郑州 450052

  • d.

    教育部药物制备关键技术重点实验室 郑州 450001

    • 通讯作者: 单丽红, shlh@zzu.edu.cn
    刘宏民, liuhm@zzu.edu.cn
    张秋荣, zqr409@yeah.net
  • 基金项目:

    国家自然科学基金 U1904163

    国家自然科学基金(No.U1904163)、省部共建食管癌防治国家重点实验室开放基金(No.K2020000X)资助项目

    省部共建食管癌防治国家重点实验室开放基金 K2020000X

摘要: 为了寻找高效低毒的抗肿瘤药物，设计并合成了一系列新型的含N-（3-丙烯酰胺苯基）乙酰胺结构的喹唑啉类衍生物，并采用噻唑蓝（MTT）法测定了目标化合物对H1975（人肺腺癌细胞系），PC-3（人前列腺癌细胞系），MGC-803（人胃癌细胞系）三种肿瘤细胞的抗增殖活性.结果显示大部分化合物具有较好的抗肿瘤活性，其中N-（3-（2-（（（4-（（4-氯苯基）氨基）-7-甲氧基喹唑啉-6-基）氧基）乙酰氨基）苯基）丙烯酰胺（13j）对H1975，MGC-803两种细胞显示出最好的抗增殖活性，IC50值分别为（6.77±0.65）和（4.06±0.34）μmol/L，其活性均优于阳性对照品吉非替尼，为抗肿瘤药物的研究提供了线索.

English

  • 1.   Introduction

    Currently, the cancer is the second major cause of human death after cardiovascular disease.[1] Statistics show that approximately 13.15 million people will die from cancer until 2035.[2] Chemotherapy is a very important method in clinic. However, Many anti-tumor drugs are prone to drug resistance.[3] Therefore, finding efficient and low toxicity anti-tumor drugs is of great significance for the treatment of tumors.

    Quinazoline derivatives are important nitrogen-contain- ing heterocycles[4] with a variety of pharmacological properties, such as antimalarial, [5-6] antibacterial, [7-8] anti-inflammatory, [9-10] anticonvulsant, [11-12] antihyperten- sive, [13] anti-diabetic, [14] cholinesterase inhibition[15-16] and antitumor.[17-18] With the remarkable progress made in recent years, researchers have found that 4-aminoquinazoline plays an important role in inhibiting epidermal growth factor receptor tyrosine kinase. Some of the drugs with 4-aminoquinazolineare are effective for the treatment of non-small cell lung cancers (NSCLCs), such as erlotinib, gefitinib, lapatinib, and afatinib (Figure 1).[19]

    Figure 1

    Figure 1.  Structures of some 4-aminoquinazoline derivatives containing benzothiazole
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    Acrylamide substituted derivatives play an important role in pharmaceutical chemistry. For example, the third generation epidermal growth factor receptor (EGFR) inhibitors all have the acrylamide moiety (Figure 1).[20]

    Therefore, a series of quinazoline derivatives containing N-(3-aminophenyl)acrylamide were synthesized by using the combination principles and the antiproliferative activity of target compounds in vitro was evaluated by methyl thiazolyl tetrazolium (MTT) assay.

    1.   Results and discussion

    1.1   Chemistry

    The synthetic strategy to prepare the target compounds is depicted in Scheme 1. Firstly, 6-hydroxy-7-methoxyquina- zolin-4(3H)-one and pyridine were dissolved in acetic anhydride at 80 ℃ for 4 h to obtained compound 9. Next, phosphorus oxychloride was added to compound 9 and the temperature was slowly raised to 80 ℃ and kept the reaction for 2 h to obtained compound 10. Then compounds 11a~11v were acquired from the reaction of compound 10 with substituted aniline in isopropanol at 80 ℃ for 1 h. NH3•H2O was added to compounds 11a~11q in CH3OH at 75 ℃ for 2 h to obtained compounds 12a~12q. Finally, compounds 12a~12q and commercially available N-(3-(2-chloroacetamido)phenyl)acrylamide were added to N, N'-di- methylformamide (DMF) and the temperature was raised to 90 ℃ for 2 h to get the target compounds 13a~13q. The structures of target compounds were confirmed by 1H NMR, 13C NMR and HRMS.

    Scheme 1

    Scheme 1.  Synthesis of compounds 13a~13q

    Reagents and conditions: (i) (CH3CO)2O, pyridine, 80 ℃, 4 h; (ii) POCl3, 80 ℃, 2 h; (iii) substituted aniline, isopropanol, 80 ℃, 1 h; (iv) NH3•H2O, CH3OH, 75 ℃, 2 h; (V) N-(3-(2-chloroacetamido)-phenyl)acrylamide, DMF, 90 ℃, 2 h

    下载: 全尺寸图片 幻灯片

    1.2   Anti-tumor activity

    In order to explore the antiproliferative activity of the target compounds, compounds 13a~13q were evaluated against three human cancer cell lines including H1975 (human lung cancer cell line), PC-3 (human prostate cancer cell line), MGC-803 (human gastric carcinoma cell line) by using MTT assay. Gefitinib was employed as the positive control. The results are shown in Table 1.

    Table 1

    Table 1.  Antiproliferative activity of target compounds 13a~13q against three cancer cell lines
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    Compound R IC50a/(μmol•L-1)
    H1975 PC-3 MGC-803
    13a 2-F > 50 23.11±0.54 32.54±0.92
    13b 2-Cl > 50 9.79±0.61 30.73±1.21
    13c 2-Br > 50 8.42±0.70 16.85±0.54
    13d 3-F 29.75±0.56 28.24±0.86 18.63±1.18
    13e 3-Cl > 50 > 50 24.28±0.89
    13f 3-Br > 50 30.81±0.58 > 50
    13g 3-NO2 > 50 > 50 49.03±0.72
    13h 3-OCH3 8.94±1.02 14.53±0.64 10.84±0.71
    13i 4-F > 50 > 50 20.79±1.19
    13j 4-Cl 6.77±0.65 9.89±0.75 4.06±0.34
    13k 4-Br 15.89±1.24 23.28±0.87 42.00±1.03
    13l 4-CH3 16.41±1.14 13.4±0.98 9.98±1.36
    13m 4-OCH3 13.2±0.79 41.92±0.74 40.14±1.45
    13n 2, 4-Cl2 > 50 28.42±0.97 49.61±0.78
    13o 3, 4-Cl2 > 50 29.69±1.04 14.81±1.15
    13p 3-Cl-4-F > 50 34.80±0.53 12.84±1.08
    13q 3, 4, 5-(OCH3)3 > 50 33.62±0.81 41.30±0.55
    Gefitinibb — 9.20±0.76 8.92±0. 41 8.19±0.67
    a Antiproliferative was assayed by exposure for 72 h to substances and expressed as concentration required to inhibit tumor cells proliferation by 50% (IC50).b Used as a positive control.

    In order to explore the structure-activity relationship, different substituents were introduced to quinazoline scaf-fold. As shown in Table 1, the majority of the compounds exhibited moderate antiproliferative activity against three human cancer cell lines. Among all the target compounds, compound 13j showed the best cytotoxicity against the tested cell lines (H1975, MGC-803) with IC50 values of (6.77±0.65) and (4.06±0.34) μmol/L, which was better than gefitinib.

    From the biological data of compounds 13a, 13b, 13c, it is known that the contribution to enhance antitumor ac- tivity was F < Cl < Br, when the halogen atoms at 2-position of benzene. From the biological data of compound 13g, it is concluded that compounds with nitro at R of benzene exhibited low cytotoxicity. From the biological data of compounds 13h and 13m, the results revealed that the methoxy at 3-position of benzene had better cytotoxic activity for cancer cells than that at 4-position. From the biological data of compounds 13l and 13m, the results revealed that the methyl at 4-position of benzene had better cytotoxic activity against the tested cell lines (PC-3, MGC-803) than the methoxy at 4-position.

    2.   Conclusion

    In conclusion, a series of novel quinazoline derivatives containing acrylamide were synthesized and evaluated for their cytotoxic activity against H1975, PC-3 and MGC-803 cancer cells using MTT assay.

    Among all the tested compounds, compound 13j showed the most potent anti-proliferative activity against the tested cells. This work provided clues to discover antitumor agent based on the quinazoline scaffold.

    3.   Experimental section

    3.1   Instruments and reagents

    Melting points were determined on an X-5 micro-melting apparatus and are uncorrected. 1H NMR and 13C NMR spectra were recorded on a Bruker 400 MHz and 101 MHz spectrometer, respectively. High resolution mass spectra (HRMS) were recorded on a Waters Micro-mass Q-T of Micro-mass spectrometer by electrospray ionization (ESI). Reagents and solvents were purchased from commercial sources and were used without further purification. Column chromatography was carried out on 200~300 mesh silica gel (Qingdao Haiyang Chemical, China). Reactions were monitored by thin-layer chromatography (TLC) on 0.25 mm silicagel plates (GF254) and visualized under UV light.

    7-Methoxy-4-oxo-3, 4-dihydroquinazolin-6-ylacetate (9), 4-chloro-7-methoxyquinazolin-6-yl acetate (10), compounds 11a, 11d, 11e, 11f, 11g, 11i, 11l, 11m, 11o, 11p, 11q, and compounds 12a, 12d, 12e, 12f, 12g, 12i, 12l, 12m, 12o, 12p, 12q were synthesized according to the published literature.[21] Compounds 11b, 11c, 11j, 11k, and compounds 12b, 12c, 12j, 12k were synthesized according to the published literature.[22] Compounds 11n, 11h, and compounds 12n, 12h were synthesized according to the published literature.[23] The characterization data of all these compounds were consistent with the literature.

    3.2   General procedure for synthesis of target compounds 13a~13q

    N-(3-(2-Chloroacetamido)phenyl)acrylamide (0.35 mmol) was dissolved in 4 mL of N, N-dimethylformamide at room temperature. Then, compounds 12a~12q (0.39 mmol) were added dropwise to the above system. The reaction was carried out at 90 ℃ for 2 h. After the reaction was completed (TLC detection reaction), it was cooled to room temperature. An appropriate amount of water was added into the system and white solids were obtained. The precipitate was collected by filtration. Next, crude compound was subjected to column chromatography (petroleum ether/ethyl acetate, V:V=3:1). Concentrated eluent to give solid compounds 13a~13q.

    N-(3-(2-((4-((2-Fluorophenyl)amino)-7-methoxyquina- zolin-6-yl)oxy)acetamido)phenyl)acrylamide (13a): White solid, yield 78.2%. m.p. 258~259 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 10.19 (s, 1H), 10.14 (s, 1H), 9.50 (s, 1H), 8.38 (s, 1H), 8.10 (s, 1H), 7.94 (s, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.37 (d, J=8.2 Hz, 1H), 7.31 (dt, J=11.9, 4.8 Hz, 3H), 7.26 (s, 2H), 6.46 (dd, J=17.0, 10.1 Hz, 1H), 6.27 (dd, J=17.0, 2.1 Hz, 1H), 5.75 (dd, J=10.0, 2.1 Hz, 1H), 4.90 (s, 2H), 4.00 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ: 165.9 (d, J=276.7 Hz), 158.1, 157.3, 155.6, 154.4, 153.4, 147.5, 147.2, 139.6, 138.7, 131.8, 129.0, 128.4, 127.1, 126.9, 126.5, 124.4 (d, J=3.0 Hz), 116.0 (d, J=20.2. Hz), 114.7, 110.6, 108.4, 107.4, 103.9, 68.2, 55.9. HRMS (ESI) calcd for C26H23FN5O4 [M+H]+: 488.1734, found 488.1733.

    N-(3-(2-((4-((2-Chlorophenyl)amino)-7-methoxyquina- zolin-6-yl)oxy)acetamido)phenyl)acrylamide (13b): White solid, yield 77.1%. m.p. 236~237 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 10.18 (s, 1H), 10.13 (s, 1H), 9.50 (s, 1H), 8.34 (s, 1H), 8.09 (s, 1H), 7.94 (s, 1H), 7.60~7.55 (m, 2H), 7.42 (d, J=8.1 Hz, 2H), 7.36 (d, J=8.3 Hz, 1H), 7.33 (d, J=7.7 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H), 7.26 (s, 1H), 6.45 (dd, J=17.0, 10.1 Hz, 1H), 6.26 (dd, J=17.0, 2.2 Hz, 1H), 5.75 (dd, J=10.1, 2.2 Hz, 1H), 4.89 (s, 2H), 3.99 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ: 165.8, 163.1, 157.5, 154.4, 153.4, 147.5, 147.2, 139.4, 138.7, 136.1, 131.8, 130.8, 129.7, 129.0, 127.6, 127.5, 126.8, 114.7, 114.7, 110.6, 108.3, 107.4, 103.9, 68.2, 55.9. HRMS (ESI) calcd for C26H23ClN5O4 [M+H]+ 504.1439, found 504.1440.

    N-(3-(2-((4-((2-Bromophenyl)amino)-7-methoxyquina- zolin-6-yl)oxy)acetamido)phenyl)acrylamide (13c): White solid, yield 73.8%. m.p. 236~237 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 10.18 (s, 1H), 10.13 (s, 1H), 9.48 (s, 1H), 8.33 (s, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.57 (d, J=7.9 Hz, 1H), 7.44 (dd, J=15.4, 7.8 Hz, 2H), 7.36 (d, J=8.3 Hz, 1H), 7.26 (d, J=7.7 Hz, 3H), 6.45 (dd, J=17.0, 10.1 Hz, 1H), 6.30~6.21 (m, 1H), 5.75 (dd, J=10.1, 2.2 Hz, 1H), 4.89 (s, 2H), 3.99 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ: 165.8, 163.1, 157.5, 154.4, 153.4, 147.4, 139.4, 138.7, 137.5, 132.8, 131.8, 123.0, 129.0, 128.2, 127.9, 126.8, 121.9, 114.7, 114.7, 110.6, 108.3, 107.4, 103.8, 68.1, 55.9. HRMS (ESI) calcd for C26H23Br- N5O4 [M+H]+ 548.0933, found 548.0932.

    N-(3-(2-((4-((3-Fluorophenyl)amino)-7-methoxyquina- zolin-6-yl)oxy)acetamido)phenyl)acrylamide (13d): White solid, yield 76.8%. m.p. 183~184 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 10.19 (s, 1H), 10.13 (s, 1H), 9.58 (s, 1H), 8.56 (s, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.90 (dt, J=11.9, 2.4 Hz, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.43 (dt, J=7.2, 3.4 Hz, 2H), 7.38 (d, J=7.7 Hz, 1H), 7.29 (t, J=4.1 Hz, 2H), 6.93 (td, J=8.5, 2.4 Hz, 1H), 6.46 (dd, J=17.0, 10.1 Hz, 1H), 6.27 (dd, J=17.0, 2.2 Hz, 1H), 5.76 (dd, J=10.1, 2.2 Hz, 1H), 4.91 (s, 2H), 4.01 (s, 3H); 13C NMR (101 MHz, DMSO-d6) 165.8, 163.1 (d, J=237.3 Hz), 156.2, 154.5, 153.0, 147.5, 147.4, 141.2, 139.4, 138.6, 131.8, 129.9 (d, J=10.1 Hz), 129.0, 126.8, 117.5, 114.7, 110.6, 109.6, 109.4, 108.8, 108.5, 107.6, 104.2, 68.6, 56.0. HRMS (ESI) calcd for C26H23FN5O4 [M+H]+ 488.1734, found 488.1735.

    N-(3-(2-((4-((3-Chlorophenyl)amino)-7-methoxyquina- zolin-6-yl)oxy)acetamido)phenyl)acrylamide (13e): White solid, yield 72.9%. m.p. 270~271 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 10.19 (s, 1H), 10.13 (s, 1H), 9.55 (s, 1H), 8.56 (s, 1H), 8.11 (s, 1H), 8.04 (t, J=2.0 Hz, 1H), 7.97 (s, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.43 (d, J=8.2 Hz, 2H), 7.38 (d, J=9.5 Hz, 1H), 7.29 (s, 2H), 7.18~7.13 (m, 1H), 6.46 (dd, J=17.0, 10.1 Hz, 1H), 6.27 (dd, J=17.0, 2.1 Hz, 1H), 5.76 (dd, J=10.1, 2.1 Hz, 1H), 4.91 (s, 2H), 4.01 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ: 165.8, 163.1, 156.1, 154.5, 153.0, 147.5, 147.4, 141.0, 139.4, 138.6, 132.7 131.8, 130.0, 129.0, 126.9, 122.8, 121.2, 120.2, 114.8, 110.6, 108.7, 107.6, 104.1, 68.6, 56.0. HRMS (ESI) calcd for C26H23ClN5O4 [M+H]+ 504.1439, found 504.1438.

    N-(3-(2-((4-((3-Bromophenyl)amino)-7-methoxyqui- nazolin-6-yl)oxy)acetamido)phenyl)acrylamide (13f): White solid, yield 71.5%. m.p. 246~247 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 10.20 (s, 1H), 10.12 (s, 1H), 9.54 (s, 1H), 8.56 (d, J=2.6 Hz, 1H), 8.18~8.10 (m, 2H), 7.96 (s, 1H), 7.88~7.83 (m, 1H), 7.44 (d, J=8.1 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.30 (d, J=8.5 Hz, 3H), 6.47 (dd, J=17.0, 10.0 Hz, 1H), 6.28 (dd, J=17.0, 2.3 Hz, 1H), 5.76 (dd, J=10.1, 2.2 Hz, 1H), 4.91 (s, 2H), 4.01 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ: 165.8, 163.1, 156.1, 154.5, 153.0, 147.5, 147.5, 141.1, 139.4, 138.6, 131.8, 130.3, 129.0, 126.9, 125.7, 124.0, 121.2, 120.6, 114.8, 110.6, 108.7, 107.6, 104.1, 68.6, 56.0. HRMS (ESI) calcd for C26H23BrN5O4 [M+H]+ 548.0933, found 548.0932.

    N-(3-(2-((7-Methoxy-4-((3-nitrophenyl)amino)quina- zolin-6-yl)oxy)acetamido)phenyl)acrylamide (13g): White solid, yield 67.6%. m.p. 247~248 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 10.19 (s, 1H), 10.16 (s, 1H), 9.96 (s, 1H), 8.66 (s, 1H), 8.29 (d, J=9.0 Hz, 2H), 8.19 (d, J=9.0 Hz, 2H), 8.11 (s, 1H), 8.00 (s, 1H), 7.39 (t, J=8.4 Hz, 2H), 7.34 (s, 1H), 7.28 (t, J=8.1 Hz, 1H), 6.45 (dd, J=17.0, 10.1 Hz, 1H), 6.26 (dd, J=17.0, 2.1 Hz, 1H), 5.76 (dd, J=10.0, 2.0 Hz, 1H), 4.93 (s, 2H), 4.02 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ: 13C NMR (101 MHz, DMSO) δ: 165.7, 163.1, 155.7, 155.2, 154.9, 152.8, 152.7, 147.9, 147.8, 146.2, 141.5, 139.4, 138.6, 131.8, 129.1, 126.9, 124.6, 120.5, 114.8, 114.7, 110.6, 107.6, 104.1, 68.6, 56.1. HRMS (ESI) calcd for C26H23N6O6 [M+H]+ 515.1679, found 515.1677.

    N-(3-(2-((7-Methoxy-4-((3-methoxyphenyl)amino)qu- inazolin-6-yl)oxy)acetamido)phenyl)acrylamide (13h): White solid, yield 72.8%. m.p. 187~188 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 10.19 (s, 1H), 10.13 (s, 1H), 9.44 (s, 1H), 8.50 (d, J=2.6 Hz, 1H), 8.11 (s, 1H), 7.99 (s, 1H), 7.49 (d, J=2.4 Hz, 1H), 7.45~7.35 (m, 3H), 7.32~7.29 (m, 1H), 7.27 (d, J=6.1 Hz, 2H), 6.70 (dd, J=8.3, 2.4 Hz, 1H), 6.46 (dd, J=17.0, 10.1 Hz, 1H), 6.27 (dd, J=17.0, 2.2 Hz, 1H), 5.75 (dd, J=9.9, 2.2 Hz, 1H), 4.91 (s, 2H), 4.00 (s, 3H), 3.78 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ: 165.9, 163.1, 159.4, 156.4, 154.4, 153.2, 147.4, 140.5, 139.4, 138.6, 131.8, 129.1, 129.0, 126.8, 114.8, 114.5, 113.8, 110.6, 108.7, 108.6, 108.1, 107.6, 104.3, 68.6, 56.0, 55.1. HRMS (ESI) calcd for C27H26N5O5 [M+H]+ 500.1934, found 500.1935.

    N-(3-(2-((4-((4-Fluorophenyl)amino)-7-methoxy- quinazolin-6-yl)oxy)acetamido)phenyl)acrylamide (13i): White solid, yield 75.7%. m.p. 251~252 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 10.19 (s, 1H), 10.12 (s, 1H), 9.50 (s, 1H), 8.46 (s, 1H), 8.11 (d, J=2.2 Hz, 1H), 7.96 (s, 1H), 7.81~7.74 (m, 2H), 7.42 (d, J=8.1 Hz, 1H), 7.38 (d, J=8.1 Hz, 1H), 7.31~7.20 (m, 4H), 6.46 (dd, J=17.0, 10.1 Hz, 1H), 6.27 (dd, J=17.0, 2.1 Hz, 1H), 5.76 (dd, J=10.1, 2.1 Hz, 1H), 4.90 (s, 2H), 4.00 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ: 165.9, 163.1 (d, J=363.4 Hz), 157.1, 156.5, 154.4, 153.2, 147.4, 147.3, 139.4, 138.6, 135.6, 131.8, 129.0, 126.8, 124.5 (d, J=8.1 Hz), 115.1 (d, J=22.2Hz), 114.7, 110.6, 108.5, 107.6, 104.2, 68.5, 55.9. HRMS (ESI) calcd for C26H23FN5O4 [M+H]+ 488.1734, found 488.1733.

    N-(3-(2-((4-((4-Chlorophenyl)amino)-7-methoxyqui- nazolin-6-yl)oxy)acetamido)phenyl)acrylamide (13j): White solid, yield 74.9%. m.p. 259~260 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 10.69 (s, 1H), 10.51 (s, 1H), 10.22 (s, 1H), 8.52 (s, 1H), 8.25 (s, 1H), 8.17 (d, J=8.6 Hz, 2H), 7.47 (d, J=8.5 Hz, 2H), 7.37 (t, J=7.9 Hz, 2H), 7.32 (d, J=7.8 Hz, 1H), 6.85 (d, J=2.3 Hz, 1H), 6.57 (d, J=2.3 Hz, 1H), 6.48 (dd, J=17.0, 10.1 Hz, 1H), 6.30 (dd, J=17.0, 2.2 Hz, 1H), 5.79 (dd, J=10.1, 2.2 Hz, 1H), 5.07 (s, 2H), 3.91 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ: 165.7, 163.2, 162.7, 156.7, 155.1, 155.0, 153.5, 139.5, 138.5, 138.3, 131.9, 129.2 128.4, 126.8, 126.8, 123.0, 114.8, 110.5, 101.3, 100.7, 99.4, 67.9, 55.7. HRMS (ESI) calcd for C26H23ClN5O4 [M+H]+ 504.1439, found 504.1440.

    N-(3-(2-((4-((4-Bromophenyl)amino)-7-methoxyquina- zolin-6-yl)oxy)acetamido)phenyl)acrylamide (13k) White solid, yield 71.9%. m.p. 178~179 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 10.19 (s, 1H), 10.13 (s, 1H), 9.53 (s, 1H), 8.51 (s, 1H), 8.10 (s, 1H), 7.96 (s, 1H), 7.81 (d, J=8.8 Hz, 2H), 7.57 (d, J=8.7 Hz, 2H), 7.39 (dd, J=15.4, 8.1 Hz, 2H), 7.27 (s, 2H), 6.45 (dd, J=17.0, 10.1 Hz, 1H), 6.26 (dd, J=16.9, 2.2 Hz, 1H), 5.75 (dd, J=9.8, 2.2 Hz, 1H), 4.90 (s, 2H), 4.00 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ: 165.8, 163.1, 156.2, 154.5, 153.0, 147.5, 147.4, 139.4, 138.8, 138.6, 131.8, 131.2, 129.1, 126.9, 124.0, 114.9, 114.8, 110.6, 108.7, 107.6, 104.2, 68.5, 56.0. HRMS (ESI) calcd for C26H23BrN5O4 [M+H]+ 548.0933, found 548.0933.

    N-(3-(2-((7-Methoxy-4-(p-tolylamino)quinazolin-6- yl)oxy)acetamido)phenyl)acrylamide (13l): White solid, yield 75.3%. m.p. 157~158 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 10.19 (s, 1H), 10.12 (s, 1H), 9.40 (s, 1H), 8.45 (s, 1H), 8.11 (s, 1H), 7.97 (s, 1H), 7.64 (d, J=8.1 Hz, 2H), 7.42 (d, J=8.1 Hz, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.30~7.23 (m, 2H), 7.19 (d, J=8.1 Hz, 2H), 6.46 (dd, J=17.0, 10.1 Hz, 1H), 6.27 (dd, J=17.0, 2.1 Hz, 1H), 5.76 (dd, J=10.0, 2.1 Hz, 1H), 4.89 (s, 2H), 3.99 (s, 3H), 2.31 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ: 165.9, 163.1, 156.5, 154.2, 153.3, 147.3, 147.2, 139.4, 138.6, 136.6, 132.5, 131.8, 129.0, 128.8, 126.9, 122.6, 114.8, 110.6, 108.6, 107.5, 104.2, 68.5, 55.9, 20.5. HRMS (ESI) calcd for C27H26N5O4 [M+H]+ 484.1985, found 484.1986.

    N-(3-(2-((7-Methoxy-4-((4-methoxyphenyl)amino)qui- nazolin-6-yl)oxy)acetamido)phenyl)acrylamide (13m): White solid, yield 70.8%. m.p. 150~151 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 10.19 (s, 1H), 10.11 (s, 1H), 9.39 (s, 1H), 8.41 (s, 1H), 8.11 (s, 1H), 7.95 (s, 1H), 7.61 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.1 Hz, 1H), 7.37 (d, J=8.2 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.23 (s, 1H), 6.97 (d, J=8.6 Hz, 2H), 6.46 (dd, J=17.0, 10.1 Hz, 1H), 6.27 (dd, J=17.0, 2.2 Hz, 1H), 5.75 (dd, J=10.1, 2.0 Hz, 1H), 4.89 (s, 2H), 3.99 (s, 3H), 3.77 (d, J=2.2 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ: 165.9, 163.1, 156.7, 155.7, 154.2, 153.38, 147.2, 147.1, 139.4, 138.6, 132.0, 131.8, 129.0, 126.9, 124.5, 114.8, 113.6, 110.6, 108.5, 107.5, 104.2, 68.4, 55.9, 55.2. HRMS (ESI) calcd for C27H26N5O5 [M+H]+ 500.1934, found 500.1933.

    N-(3-(2-((4-((2, 4-Dichlorophenyl)amino)-7-methoxy- quinazolin-6-yl)oxy)acetamido)phenyl)acrylamide (13n): white solid, yield 73.7%. m.p. 163~164 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 10.17 (s, 1H), 10.14 (s, 1H), 9.53 (s, 1H), 8.35 (s, 1H), 8.08 (s, 1H), 7.91 (s, 1H), 7.74 (d, J=2.4 Hz, 1H), 7.61 (d, J=8.6 Hz, 1H), 7.49 (dd, J=8.5, 2.4 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.26 (q, J=6.6, 5.0 Hz, 2H), 6.45 (dd, J=17.0, 10.1 Hz, 1H), 6.25 (dd, J=17.0, 2.2 Hz, 1H), 5.75 (dd, J=10.2, 2.2 Hz, 1H), 4.88 (s, 2H), 3.99 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ: 165.8, 163.1, 157.3, 154.47, 153.2, 147.5, 147.3, 139.3, 138.7, 135.3, 131.8, 131.7, 130.7, 129.1, 129.0, 127.7, 126.9, 114.7, 114.6, 110.5, 108.3, 107.4, 103.8, 68.1, 56.0. HRMS (ESI) calcd for C26H22Cl2N5O4 [M+H]+ 538.1049, found 538.1049.

    N-(3-(2-((4-((3, 4-Dichlorophenyl)amino)-7-methoxy- quinazolin-6-yl)oxy)acetamido)phenyl)acrylamide (13o): White solid, yield 75.4%. m.p. 275~276 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 10.19 (s, 1H), 10.12 (s, 1H), 9.60 (s, 1H), 8.58 (d, J=2.3 Hz, 1H), 8.25 (d, J=2.5 Hz, 1H), 8.12 (s, 1H), 7.94 (s, 1H), 7.86 (dd, J=8.9, 2.5 Hz, 1H), 7.63 (d, J=8.9 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.38 (d, J=8.1 Hz, 1H), 7.29 (s, 2H), 6.47 (dd, J=17.0, 10.1 Hz, 1H), 6.27 (dd, J=17.1, 2.2 Hz, 1H), 5.76 (dd, J=10.1, 2.2 Hz, 1H), 4.91 (s, 2H), 4.01 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ: 165.8, 163.1, 155.9, 154.6, 152.9, 147.6, 147.5, 139.7, 139.4, 138.6, 131.8, 130.6, 130.2, 129.0, 126.8, 124.4, 122.7, 121.6, 114.8, 110.6, 108.7, 107.6, 104.1, 68.6, 56.0. HRMS (ESI) calcd for C26H22Cl2N5O4 [M+H]+ 538.1049, found 538.1048.

    N-(3-(2-((4-((3-Chloro-4-fluorophenyl)amino)-7-meth- oxyquinazolin-6-yl)oxy)acetamido)phenyl)acrylami (13p): White solid, yield 73.6%. m.p. 257~258 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 10.18 (s, 1H), 10.11 (s, 1H), 9.56 (s, 1H), 8.54 (s, 1H), 8.12 (dd, J=7.0, 2.5 Hz, 2H), 7.94 (s, 1H), 7.77 (ddd, J=9.2, 4.4, 2.5 Hz, 1H), 7.44 (t, J=9.3 Hz, 2H), 7.38 (d, J=8.1 Hz, 1H), 7.31~7.25 (m, 2H), 6.46 (dd, J=17.0, 10.1 Hz, 1H), 6.27 (dd, J=16.9, 2.1 Hz, 1H), 5.76 (dd, J=10.1, 2.1 Hz, 1H), 4.90 (s, 2H), 4.01 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ: 165.8 (d, J=271.7 Hz), 156.1, 154.5, 153.0, 152.0, 147.5, 147.4, 139.4, 138.6, 136.7, 131.8, 129.0, 126.8, 123.5, 122.3, 118.9, 116.6 (d, J=21.2 Hz), 114.8, 114.7, 110.6, 108.6, 107.6, 104.1, 68.6, 56.0. HRMS (ESI) calcd for C26H22ClFN5O4 [M+H]+ 522.1344, found 522.1342.

    N-(3-(2-((7-Methoxy-4-((3, 4, 5-trimethoxyphenyl)ami- no)quinazolin-6-yl)oxy)acetamido)phenyl)acrylamide (13q): White solid, yield 77.9%. m.p. 234~235 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 10.18 (s, 1H), 10.11 (s, 1H), 9.39 (s, 1H), 8.49 (s, 1H), 8.11 (s, 1H), 7.96 (s, 1H), 7.42 (d, J=8.2 Hz, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.26 (s, 1H), 7.17 (s, 2H), 6.45 (dd, J=17.0, 10.1 Hz, 1H), 6.26 (dd, J=17.1, 2.0 Hz, 1H), 5.75 (dd, J=10.0, 2.0 Hz, 1H), 4.91 (s, 2H), 4.00 (s, 3H), 3.80 (s, 6H), 3.67 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ: 165.9, 163.1, 156.6, 154.3, 153.2, 152.5, 147.3, 147.2, 139.4, 138.6, 135.3, 133.8, 131.8, 129.0, 126.9, 114.8, 110.6, 108.7, 107.6, 104.4, 100.5, 68.6, 60.1, 55.9, 55.9. HRMS (ESI) calcd for C29H30N5O7 [M+H]+ 560.2145, found 560.2145.

    3.2.5   Cell culture and treatment

    Human cancer cells MCF-7, MGC-803 and PC-3, HGC- 27 was purchased from the China Center for Type Culture Collection (CCTCC, China) and maintained in RPMI-1640 (Solarbio, China) and dulbecco's modified eagle medium (DMEM) (Solarbio) complete medium (which supplemented with 10% fetal calf serum (FBS) and 100 U/mL penicillin and 100 g/mL streptomycin antibiotics) at 37 ℃ in a humidified atmosphere of 5% CO2.

    3.2.6   MTT assay

    Cells in the logarithmic growth phase were seeded in 96-well plates at 3000~5000 cells per well. After the cells were cultured for 24 h, different concentrations of compounds 13a~13q were treated for 72 h, respectively. MTT (3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bro- mide, Solarbio) was added to each well at a final concentration of 0.5 mg/mL. After 4 h in a 37 ℃ incubator, the medium was aspirated. 150 μL of dimethyl sulfoxide (DMSO) was then added to each well to dissolve the formazan, and the plate was shaken on a shaker for 10 min. The absorbance was measured by an enzyme-linked immunosorbent assay reader (BioTek, USA) at a wavelength of 490 nm, and the cell survival rate was measured. Viability rate (%)=Abs 490 treated cells/Abs 490 control cells×100%. The concentration-response curve generated by SPSS 16.0 software was used to determine the concentration of compound (IC50) required to inhibit cell growth by 50%. Cell viability curves were generated using GraphPad Prism 7.0 software at various concentrations of all compounds. Results were mean±SD of three independent experiments.

    Supporting Information  The 1H NMR, 13C NMR and HRMS of compounds 13a~13q are available for free download from our website (http://sioc-journal.cn/).


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  • Figure 1  Structures of some 4-aminoquinazoline derivatives containing benzothiazole

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    Scheme 1  Synthesis of compounds 13a~13q

    Reagents and conditions: (i) (CH3CO)2O, pyridine, 80 ℃, 4 h; (ii) POCl3, 80 ℃, 2 h; (iii) substituted aniline, isopropanol, 80 ℃, 1 h; (iv) NH3•H2O, CH3OH, 75 ℃, 2 h; (V) N-(3-(2-chloroacetamido)-phenyl)acrylamide, DMF, 90 ℃, 2 h

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    Table 1.  Antiproliferative activity of target compounds 13a~13q against three cancer cell lines

    Compound R IC50a/(μmol•L-1)
    H1975 PC-3 MGC-803
    13a 2-F > 50 23.11±0.54 32.54±0.92
    13b 2-Cl > 50 9.79±0.61 30.73±1.21
    13c 2-Br > 50 8.42±0.70 16.85±0.54
    13d 3-F 29.75±0.56 28.24±0.86 18.63±1.18
    13e 3-Cl > 50 > 50 24.28±0.89
    13f 3-Br > 50 30.81±0.58 > 50
    13g 3-NO2 > 50 > 50 49.03±0.72
    13h 3-OCH3 8.94±1.02 14.53±0.64 10.84±0.71
    13i 4-F > 50 > 50 20.79±1.19
    13j 4-Cl 6.77±0.65 9.89±0.75 4.06±0.34
    13k 4-Br 15.89±1.24 23.28±0.87 42.00±1.03
    13l 4-CH3 16.41±1.14 13.4±0.98 9.98±1.36
    13m 4-OCH3 13.2±0.79 41.92±0.74 40.14±1.45
    13n 2, 4-Cl2 > 50 28.42±0.97 49.61±0.78
    13o 3, 4-Cl2 > 50 29.69±1.04 14.81±1.15
    13p 3-Cl-4-F > 50 34.80±0.53 12.84±1.08
    13q 3, 4, 5-(OCH3)3 > 50 33.62±0.81 41.30±0.55
    Gefitinibb — 9.20±0.76 8.92±0. 41 8.19±0.67
    a Antiproliferative was assayed by exposure for 72 h to substances and expressed as concentration required to inhibit tumor cells proliferation by 50% (IC50).b Used as a positive control.
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  • 发布日期:  2020-09-01
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