摘要
为发现新的抗肿瘤氟喹诺酮先导化合物,用噻唑并[3,2-b][1,2,4]三唑酮稠杂环作为环丙沙星C-3羧基的等排体,进一步与芳香醛发生Claisen缩合构建成C-3稠杂环α,β-不饱和酮类目标化合物6a^6r,其结构经元素分析、1H NMR、MS确证。采用MTT法评价了目标化合物对人肝癌Hep-3B细胞、人胰腺癌Capan-1细胞及人白血病HL60细胞的体外增值抑制活性。结果表明,18个目标化合物对3种实验癌细胞的抗增殖活性均显著高于母体环丙沙星1的活性,其中对Capan-1细胞的活性最强,尤其是苯环带有吸电子羧基(6k、6m)和磺酰胺基(6q、6r)化合物的活性相当于或优于对照抗肿瘤药物阿霉素的活性。以上的结果表明,氟喹诺酮C-3羧基用稠杂环不饱和酮取代有利于提高其抗肿瘤活性。
To discover novel antitumor fluoroquinolone lead compounds from a rational modification for antibacterial fluoroquinolones, a fused heterocyclic ketone corresponding to thiazolo[2,3-b][1,2,4]triazolone used as a bioisosteric replacement of the C-3 carboxylic acid group of ciprofloxacin 1, and further modification by a Claisen condensation reaction with substituted benzaldehydes formed novel fluoroquinolone C-3 fuse heterocyclic α,β-unsaturated ketones as the title compounds （6a-6r）, separately. The structures of eighteen title compounds were characterized by elemental analysis, 11H NMR and MS, and the in votro anti-proliferative activity against human hepatoma Hep-3B cells, pancreatic Capan-1 cells and leukemia HL60 cells was evaluated by a MTT assay. The preliminary results showed that the title compounds not only had more significant anti-proliferative activity against three tested cancer cell lines than that of the parent ciprofloxacin 1, but also exhibited the highest activity against Capan-1 cells. In particular, compounds carrying an electron-withdrawing carboxyl （6k, 6m） or sulfonamide substituent （6q, 6r） attached to benzene ring were comparable to or better than constraetive drug doxorubicin against Capan-1 cells. As such, it suggests that it is favorable for a fused heterocyclic α,β-unsaturated ketone scaffold instead of the C-3 carboxylic acid group to improve the antitumor activity of fluoroquinolones.
出处
《药学学报》
CAS
CSCD
北大核心
2015年第5期569-573,共5页
Acta Pharmaceutica Sinica
基金
国家自然科学基金资助项目(20872028
21072045)
河南大学科研基金资助项目
关键词
氟喹诺酮
噻唑并三唑酮
不饱和酮
抗增殖活性
fluoroquinolone
thiazolotriazolone
unsaturated ketone
anti-proliferative activity
作者简介
通讯作者Tel／Fax：86—371-23880680．E-mail：hgqxy@sina．com．cn
