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

doi:10.6023/cjoc201909017

Chinese Journal of Organic Chemistry ›› 2020, Vol. 40 ›› Issue (4): 959-968.DOI: 10.6023/cjoc201909017 Previous Articles Next Articles

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^a, 黄婉云^a, 张小蓉^a, 张晓婷^a, 潘成学^b

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 发布日期:2020-05-06
通讯作者: 黄婉云 E-mail:hwygxnu@163.com
基金资助:
国家自然科学基金（No.21362007）资助项目.

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

Wang Shuqin^a, Huang Wanyun^a, Zhang Xiaorong^a, Zhang Xiaoting^a, Pan Chengxue^b

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:2019-09-10 Revised:2019-11-27 Published:2020-05-06
Supported by:
Project supported by the National Natural Science Foundation of China (No. 21362007).

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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

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Wang Shuqin, Huang Wanyun, Zhang Xiaorong, Zhang Xiaoting, Pan Chengxue. Synthesis and Bioactive Evaluation of Pyridazino-[6,1-b]quinazolinones Derivatives[J]. Chinese Journal of Organic Chemistry, 2020, 40(4): 959-968.

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哒嗪并[6,1-b]喹唑啉酮类化合物的合成及其生物活性

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

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