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Pyridazino[1,6-b]quinazolinones as new anticancer scaffold: Synthesis, DNA intercalation, topoisomerase I inhibition and antitumor evaluation in vitro and in vivo.
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2020-04-04 , DOI: 10.1016/j.bioorg.2020.103814 Wan-Yun Huang 1 , Xiao-Rong Zhang 1 , Liang Lyu 2 , Shu-Qin Wang 1 , Xiao-Ting Zhang 1
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2020-04-04 , DOI: 10.1016/j.bioorg.2020.103814 Wan-Yun Huang 1 , Xiao-Rong Zhang 1 , Liang Lyu 2 , Shu-Qin Wang 1 , Xiao-Ting Zhang 1
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A new anticancer N-containing heterocyclic scaffold was designed and 30 pyridazino[1,6-b]quinazolinone derivatives were synthesized and characterized. Antiproliferation evaluation in vitro against four human cancer cell lines including SK-OV-3(ovarian cell), CNE-2(nasopharyngeal cell), MGC-803(gastric cell) and NCI-H460(lung cell) indicated that most of them exhibited potent anticancer activity and the IC50 value of the most potent compound lowered to sub-μM. DNA interaction assay indicated that compounds 4e, 4g, 6o, 6p, 8o can intercalate into DNA. Compounds 6 and 8 also demonstrated potent topoisomerase I (topo I) activity. Annexin V- FITC/propidium iodide dual staining assay and cell cycle analysis indicated that 2-(4-bromophenyl)-4-((3-(diethylamino)propyl)amino) -10H-pyridazino [1,6-b]quinazolin- 10-one (8p) could induce arrest cell cycle at G2 phase and apoptosis in MGC-803 cells in a dose-dependent manner. The in vivo antitumor efficiency of compound 8p was also evaluated on MGC-803 xenograft nude mice, and the relative tumor growth inhibition was up to 55.9% at a dose of 20 mg/kg per two days. The results suggested that pyridazino[1,6-b]-quinazolinones might serve as a promising novel scaffold for the development of new antitumor agents.
中文翻译：
吡唑并[1,6-b]喹唑啉酮类作为新型抗癌支架：在体内和体外合成，DNA嵌入，拓扑异构酶I抑制和抗肿瘤评估。
设计了一种新型的含氮抗癌杂环骨架，合成并表征了30种哒嗪并[1,6-b]喹唑啉酮衍生物。对SK-OV-3（卵巢细胞），CNE-2（鼻咽细胞），MGC-803（胃细胞）和NCI-H460（肺细胞）四种人类癌细胞系的体外抗增殖评价表明，它们大多数表现出有效的抗癌活性，最有效的化合物的IC50值降至亚微米以下。DNA相互作用测定表明化合物4e，4g，6o，6p，8o可以插入DNA中。化合物6和8还表现出有效的拓扑异构酶I（拓扑I）活性。Annexin V- FITC /碘化丙啶双重染色法和细胞周期分析表明，2-（4-溴苯基）-4-（（3-（二（乙基乙氨基）丙基）氨基）-10H-吡啶并[1，6-b] quinazolin-10-one（8p）可以剂量依赖性诱导G2期阻滞细胞周期和MGC-803细胞凋亡。还在MGC-803异种移植裸鼠上评估了化合物8p的体内抗肿瘤效率，并且在每两天20 mg / kg的剂量下，相对肿瘤生长抑制率高达55.9％。结果表明，哒嗪并[1,6-b]-喹唑啉酮类可能作为开发新型抗肿瘤药物的有希望的新型支架。
更新日期：2020-04-20
中文翻译：
吡唑并[1,6-b]喹唑啉酮类作为新型抗癌支架：在体内和体外合成，DNA嵌入，拓扑异构酶I抑制和抗肿瘤评估。
设计了一种新型的含氮抗癌杂环骨架，合成并表征了30种哒嗪并[1,6-b]喹唑啉酮衍生物。对SK-OV-3（卵巢细胞），CNE-2（鼻咽细胞），MGC-803（胃细胞）和NCI-H460（肺细胞）四种人类癌细胞系的体外抗增殖评价表明，它们大多数表现出有效的抗癌活性，最有效的化合物的IC50值降至亚微米以下。DNA相互作用测定表明化合物4e，4g，6o，6p，8o可以插入DNA中。化合物6和8还表现出有效的拓扑异构酶I（拓扑I）活性。Annexin V- FITC /碘化丙啶双重染色法和细胞周期分析表明，2-（4-溴苯基）-4-（（3-（二（乙基乙氨基）丙基）氨基）-10H-吡啶并[1，6-b] quinazolin-10-one（8p）可以剂量依赖性诱导G2期阻滞细胞周期和MGC-803细胞凋亡。还在MGC-803异种移植裸鼠上评估了化合物8p的体内抗肿瘤效率，并且在每两天20 mg / kg的剂量下，相对肿瘤生长抑制率高达55.9％。结果表明，哒嗪并[1,6-b]-喹唑啉酮类可能作为开发新型抗肿瘤药物的有希望的新型支架。
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