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Synthesis and evaluation of moxifloxacin derivatives for effects on proliferation and apoptosis of NCI-H1299 cells
Tetrahedron Letters ( IF 1.5 ) Pub Date : 2020-03-27 , DOI: 10.1016/j.tetlet.2020.151873
Fangmiao Yu , Zhuangwei Zhang , Wei Li , Hengqun Tian , Jun Xu , Yongzhong Bao

Eight novel moxifloxacin (MXF) derivatives 4a-h were synthesized by functional modification of the N-5-Aza ring. Their growth inhibitory activities on human non-small lung cancer cell NCI-H1299 and A549 were evaluated by the MTT colorimetric assay. Based on the half inhibitory concentration (IC50) values, we determined that compounds 4b was the most efficacious derivative (IC50 = 2.56 ± 0.07 μM for NCI-H1299 and IC50 = 13.69 ± 0.70 μM for A549, respectively) that inhibited the proliferation of NCI-H1299 cells. Of these, Compound 4b (1 – cyclopropyl – 6 – fluoro – 8 – methoxy – 4 – oxo – 7 – ((4aS,7aS) – 1 – (2 – oxo – 2 – (p – tolylamino) ethyl) hexahydro – 1H – pyrrolo [3,4-b] pyridine – 6(2H)-yl) – 1,4 – dihydroquinoline – 3-carboxylic acid) showed good potency against the growth of NCI-H1299 cells and also selectivity on HUVEC cells (IC50 > 500 μM). The dose-response relationship of the characteristic morphological changes of NCI-H1299 cells induced by Compound 4b was confirmed by AO/EB fluorescent staining. Furthermore, Compound 4b triggered apoptosis of NCI-H1299 in a concentration-dependent manner and arrested cells in the G0/G1 phase. These data indicate that the N-(p-tolyl)propanamide functionalized N-5-Aza ring of moxifloxacin may be a promising lead compound and candidate for the development of new agents against non-small-cell lung cancer.



中文翻译:

莫西沙星衍生物的合成及其对NCI-H1299细胞增殖和凋亡的影响

通过对N-5-Aza环进行功能修饰,合成了八种新颖的莫西沙星(MXF)衍生物4a-h。通过MTT比色测定评估它们对人非小肺癌细胞NCI-H1299和A549的生长抑制活性。基于所述半抑制浓度(IC 50)值,我们确定化合物4b中是最有效的衍生物(IC 50  = 2.56±0.07μM为NCI-H1299和IC 50 即抑制= 13.69±0.70分别μM为A549,) NCI-H1299细胞的增殖。其中,化合物4b(1 –环丙基– 6 –氟– 8 –甲氧基– 4 –氧代– 7 –(((4aS,7aS)– 1 –(2 –氧代– 2 –(p –甲苯基)乙基))六氢– 1H –吡咯[3, 4-b]吡啶– 6(2H)-基)– 1,4 –二氢喹啉– 3-羧酸)对NCI-H1299细胞的生长表现出良好的效能,对HUVEC细胞具有选择性(IC 50  > 500μM)。通过AO / EB荧光染色证实了化合物4b诱导的NCI-H1299细胞特征性形态变化的剂量反应关系。此外,化合物4b以浓度依赖性方式触发NCI-H1299的凋亡,并使细胞停滞在G0 / G1期。这些数据表明,莫西沙星的N-(对甲苯基)丙酰胺官能化的N-5-Aza环可能是有前途的先导化合物,并且是抗非小细胞肺癌新药开发的候选药物。

更新日期:2020-03-27
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