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2020 , Vol. 40 >Issue 4: 959 - 968

DOI: https://doi.org/10.6023/cjoc201909017

研究论文

哒嗪并[6,1-b]喹唑啉酮类化合物的合成及其生物活性

  • 王淑琴 ,
  • 黄婉云 ,
  • 张小蓉 ,
  • 张晓婷 ,
  • 潘成学
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  • a 桂林医学院药学院 广西桂林 541004;
    b 广西师范大学化学与药学学院 药用资源化学与药物分子工程国家重点实验室 广西桂林 541004

收稿日期: 2019-09-10

  修回日期: 2019-11-27

  网络出版日期: 2020-05-06

基金资助

国家自然科学基金（No.21362007）资助项目.

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Synthesis and Bioactive Evaluation of Pyridazino-[6,1-b]quinazolinones Derivatives

  • Wang Shuqin ,
  • Huang Wanyun ,
  • Zhang Xiaorong ,
  • Zhang Xiaoting ,
  • Pan Chengxue
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  • a College of Pharmacy, Guilin Medical University, Guilin 541004;
    b State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin, Guangxi 541004

Received date: 2019-09-10

  Revised date: 2019-11-27

  Online published: 2020-05-06

Supported by

Project supported by the National Natural Science Foundation of China (No. 21362007).

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摘要

通过将两个优势结构单元的组合设计了一个含氮杂环新骨架哒嗪并[6，1-b]喹唑啉酮，并发展了一条以2-氨基苯甲酸酯等为原料，以分子内酰腙跟酯基的分子内缩合反应为关键步骤，经4步反应来合成哒嗪并[6，1-b]喹唑啉酮衍生物的路线.14个目标化合物4a~4n被合成，其结构经1H NMR，13C NMR和HRMS表征和确认.采用噻唑蓝（MTT）法测试了目标化合物对人肿瘤细胞SK-OV-3，CNE-2，MGC-803，NCI-H460和人正常肝细胞LO2的体外细胞毒活性，发现2个化合物具有很强的抗肿瘤活性，其中2-（4-溴苯基）-4-羟基-10H-哒嗪并[6，1-b]喹唑啉-10-酮（4b）对人鼻咽癌细胞CNE-2和2-（3-氯苯基）-4-羟基-10H-哒嗪并[6，1-b]喹唑啉-10-酮（4d）对人肺癌细胞NCI-H460的IC50值分别为2.31和0.85 μmol/L，远强于阳性对照药顺铂，与抗肿瘤天然药物喜树碱相当.用紫外光谱法、荧光滴定法进一步研究了化合物与DNA的相互作用，证实化合物可通过嵌入DNA的方式与DNA相互作用.活性强而且毒性低的化合物4d还可以剂量依赖性关系将人肺癌细胞NCI-H460的细胞周期阻滞在G1期，并显著诱导细胞发生凋亡，而毒性高的化合物4b则可诱导细胞的双链DNA发生断裂.

关键词： 喹唑啉酮; 哒嗪衍生物; 抗肿瘤活性; 与DNA相互作用

本文引用格式

王淑琴 , 黄婉云 , 张小蓉 , 张晓婷 , 潘成学 . 哒嗪并[6,1-b]喹唑啉酮类化合物的合成及其生物活性[J]. 有机化学, 2020 , 40(4) : 959 -968 . DOI: 10.6023/cjoc201909017

Abstract

Novel nitrogen-containing heterocyclic scaffold pyridazino[6,1-b]quinazolinones were designed by the combination of two privileged structure units. Then a scheme for the synthesis of pyridazino[6,1-b]quinazolinone derivatives in 4 steps starting from methyl 2-aminobenzoate was developed in which the intramolecular condensation of acylhydrazone with ester was a key step transformation. 14 pyridazino[6,1-b]quinazolinone derivatives were synthesized and their structures were characterized and comfirmed by 1H NMR, 13C NMR and HRMS. Their in vitro cytotoxic activities against a panel of human tumor cell lines (SK-OV-3, CNE-2, MGC-803, NCI-H460) and nomal liver cell LO2 were evaluated via methyl thiazolyl tetrazolium (MTT) assay. The result indicated that 2-(4-bromophenyl)-4-hydroxy-10H-pyridazino[6,1-b]quinazolin-10-one (4b) and 2-(3-chlorophenyl)-4-hydroxy-10H-pyridazino[6,1-b]quinazolin-10-one (4d) exhibted very potent cytotoxic activity. The IC50value of 4b against CNE-2 and 4d against NCI-H460 cell line lowed to 0.85 and 2.31 μmol/L, respectively, far potent than the positive control cisplatin and almost equivalent to the natrual anticancer medicine camptothecin. Ultraviolet spectrometry and fluorescence titration assay were carried out to evaluate the ability of the compound to interact with DNA. The result indicated that they were able to intercalate in to DNA. Compound 4d, which demonstrated potent antitumor activity while less cytotoxicity against the normal liver cell LO2, could arrest cell cycle at G1 phase and significantly induce apoptosis on NCI-H460 cell in a dose-dependent manner, while 4b which exhibit potent cytotoxicity against LO2, could result in significant DNA double strand break when treated with the cell.

Key words： quinazolinones; pyridazine; antitumor; interaction with DNA

参考文献

[1] Hu, Y.; Zhao, T.; Zhang, N.; Zhang, Y.; Cheng, L. Curr. Drug Metab. 2019, 20, 209.
[2] Regalado, E. L.; Haidar Ahmad, I. A.; Bennett, R.; D'Atri, V.; Makarov, A. A.; Humphrey, G. R.; Mangion, I.; Guillarme, D. Acc. Chem. Res. 2019, 52, 1990.
[3] Surabhi; Singh, B. K. J. Drug Delivery Ther. 2018, 8, 504.
[4] Flick, A. C.; Leverett, C. A.; Ding, H. X.; McInturff, E.; Fink, S. J.; Helal, C. J.; O'Donnell, C. J. J. Med. Chem. 2019, 62(16), 7340.
[5] Kim, J.; Kim, H.; Park, S. B. J. Am. Chem. Soc. 2014, 136, 14629.
[6] Kalaria, P. N.; Karad, S. C.; Raval, D. K. Eur. J. Med. Chem. 2018, 158, 917.
[7] Meyers, J.; Chessum, N. E. A.; Ali, S.; Mok, N. Y.; Wilding, B.; Pasqua, A. E.; Rowlands, M.; Tucker, M. J.; Evans, L. E.; Rye, C. S.; O'Fee, L.; Le Bihan, Y.-V.; Burke, R.; Carter, M.; Workman, P.; Blagg, J.; Brown, N.; van Montfort, R. L. M.; Jones, K.; Cheeseman, M. D. ACS Med. Chem. Lett. 2018, 9, 1199.
[8] Duarte, C. D.; Barreiro, E. J.; Fraga, C. A. M. Mini-Rev. Med. Chem. 2007, 7, 1108.
[9] Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfieldt, J. J. Med. Chem. 1988, 31, 2235.
[10] Patchett, A. A.; Nargund, R. P. Annu. Rep. Med. Chem. 2000, 35, 289.
[11] Alagarsamy, V.; Chitra, K.; Saravanan, G.; Solomon, V. R.; Sulthana, M. T.; Narendhar, B. Eur. J. Med. Chem. 2018, 151, 628.
[12] Hameed, A.; Ali, S. A.; Arshia; Ishtiaq, M.; Khan, K. M.; Al-Rashida, M.; Uroos, M. Expert Opin. Ther. Pat. 2018, 28, 281.
[13] He, D.; Wang, M.; Zhao, S.; Shu, Y.; Zeng, H.; Xiao, C.; Lu, C.; Liu, Y. Fitoterapia 2017, 119, 136.
[14] Cao, Q. C.; Wang, H.; Reddy, T. V. K.; Lavanya, G.; Cai, G. X.; Zhou, C. H. Sci. Sin. Chim. 2017, 47, 844(in Chinese). (曹泉诚, 王辉, Reddy, T. V. K.; Lavanya, G.; 蔡桂鑫, 周成合,中国科学:化学, 2017, 47, 844.)
[15] Du, H.; Fan, Z. J.; Yang, L.; Bao, X. P. Chin. J. Org. Chem. 2018, 38, 531(in Chinese). (杜欢, 范治江, 杨岚, 鲍小平, 有机化学, 2018, 38, 531.)
[16] Luo, X.; Zhou, X.; Lin, X.; Qin, X.; Zhang, T.; Wang, J.; Tu, Z.; Yang, B.; Liao, S.; Tian, Y.; Pang, X.; Kaliyaperumal, K.; Li, J. L.; Tao, H.; Liu, Y. Nat. Prod. Res. 2017, 31, 1958.
[17] Zhang, H.; Liu, R.; Yang, J.; Li, H.; Zhou, F. Chem. Nat. Compd. 2017, 53, 802.
[18] Motegi, M.; Nugroho, A. E.; Hirasawa, Y.; Arai, T.; Hadi, A. H. A.; Morita, H. Tetrahedron Lett. 2012, 53, 1227.
[19] Jaballah, M.; Serya, R.; Abouzid, K. Drug Res. 2017, 67, 138.
[20] Asif, M. Curr. Med. Chem. 2012, 19, 2984.
[21] Lamberth, C. J. Heterocycl. Chem. 2017, 54, 2974.
[22] Shemchuk, L. A.; Chernykh, V. P.; Arzumanov, P. S. Russ. J. Org. Chem. 2007, 43, 719.
[23] Tian, T.; Xiao, H.; Weng, X. C.; Wang, S. R.; Zhou, X. Sci. Sin. Chim. 2012, 42, 1700(in Chinese). (田沺, 肖珩, 翁小成, 王少儒, 周翔, 中国科学:化学, 2012, 42, 1700.)
[24] Liu, J.; Luo, G. A.; Wang, Y. M.; Sun, H. W. Acta Pharm. Sin. 2001, 36, 74(in Chinese). (刘军, 罗国安, 王义明, 孙汉文, 药学学报, 2001, 36, 74.)
[25] Wang, Z. B.; Liu, Q. Q.; Zhang, W.; Pan, C. X.; Su, G. F. Chin. J. Org. Chem. 2019, 39, 1962(in Chinese). (王增博, 田成, 刘晴晴, 张玮, 潘成学, 苏桂发, 有机化学, 2019, 39, 1962.)
[26] Yu, Y. K.; Zhu, X. Q.; Yang, J. J. Toxicol. 2006, 20, 408(in Chinese). (余艳柯, 朱心强, 杨军, 毒理学杂志, 2006, 20, 408.)
[27] Zhang, L.; Liu, L.; Zheng, C. Y.; Wang, Y.; Wang, J.; Yao, Q. Z. Chin. J. Org. Chem. 2017, 37, 1523(in Chinese). (张磊, 刘来, 郑诚月, 王杨, 王京, 姚其正, 有机化学, 2017, 37, 1523.)
[28] Li, Y. K.; Liu, P.; Zhang, L. J.; Zhu, J. H.; Wan, C. P.; Mao, Z. W. Chin. J. Org. Chem. 2018, 38, 949(in Chinese). (黎勇坤, 刘蓓, 张丽君, 朱加洪, 万春平, 毛泽伟, 有机化学, 2018, 38, 949.)
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