Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, PR China; Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, PR China.
Eur J Med Chem. 2018 Oct 5;158:201-213. doi: 10.1016/j.ejmech.2018.08.066. Epub 2018 Aug 28.
A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 1,8-naphthyridin-2-one moiety were designed, synthesized and evaluated for their biological activities. The target compounds exhibited moderate to high antiproliferative activity against three cancer cell lines (A549, HepG2 and MCF-7) and several compounds (25, 27, 33, 37, 41, 43, 49 and 53) were evaluated for the activity against c-Met kinase. The most promising compound 33 (IC c-Met = 2.36 nM) showed excellent activity against A549, HepG2 and MCF-7 cell lines with IC values of 0.23 μM, 0.42 μM and 0.21 μM, respectively, which was 1.5-2.1 times of the positive control. Furthermore, compound 33 was evaluated for the activity against Flt3, PDGFR-α, PDGFR-β, c-Kit, Flt4, ALK and EGFR kinase. Structure activity relationship studies indicated that mono-EWGs (such as R = F) at 4-position of moiety C was a key factor in improving the antitumor activity. In addition, further research on compound 33 was mainly including concentration dependence, apoptosis (acridine orange staining), apoptosis result analyzing and molecular docking.
一系列含有 1,8-萘啶-2-酮部分的 6,7-二取代-4-苯氧基喹啉衍生物被设计、合成并评估其生物活性。目标化合物对三种癌细胞系（A549、HepG2 和 MCF-7）表现出中等至高的抗增殖活性，并且几种化合物（25、27、33、37、41、43、49 和 53）被评估对 c-Met 激酶的活性。最有前途的化合物 33（IC c-Met = 2.36 nM）对 A549、HepG2 和 MCF-7 细胞系表现出优异的活性，IC 值分别为 0.23 μM、0.42 μM 和 0.21 μM，分别是阳性对照的 1.5-2.1 倍。此外，化合物 33 还被评估了对 Flt3、PDGFR-α、PDGFR-β、c-Kit、Flt4、ALK 和 EGFR 激酶的活性。构效关系研究表明，C 部分 4 位的单 EWGs（如 R = F）是提高抗肿瘤活性的关键因素。此外，对化合物 33 的进一步研究主要包括浓度依赖性、凋亡（吖啶橙染色）、凋亡结果分析和分子对接。
