Abstract

A new set of 4,6,7,8-tetrahydroquinolin-5(1H)-ones were designed as cytotoxic agents against breast cancer cell line (MCF-7) and synthesised under ultrasonic irradiation using chitosan decorated copper nanoparticles (CS/CuNPs) catalyst. The new compounds 4b, 4j, 4k, and 4e exhibited the most potent cytotoxic activity of IC₅₀ values (0.002 − 0.004 µM) comparing to Staurosporine of IC₅₀; 0.005 μM. The latter derivatives exhibited a promising safety profile against the normal human WI38 cells of IC₅₀ range 0.0149 − 0.048 µM. Furthermore, the most promising cytotoxic compounds 4b, 4j were evaluated as multi-targeting agents against the RTK protein kinases; EGFR, HER-2, PDGFR-β, and VEGFR-2. Compound 4j showed promising inhibitory activity against HER-2 and PDGFR-β of IC₅₀ values 0.17 × 10⁻³, 0.07 × 10⁻³ µM in comparison with the reference drug sorafenib of IC₅₀; 0.28 × 10⁻³, 0.13 × 10⁻³ µM, respectively. In addition, 4j induced apoptotic effect and cell cycle arrest at G2/M phase preventing the mitotic cycle in MCF-7 cells.

摘要

一组新的 4,6,7,8-四氢喹啉-5(1H)-ones 被设计为抗乳腺癌细胞系 (MCF-7) 的细胞毒剂，并在超声波照射下使用壳聚糖修饰的铜纳米粒子 (CS/CuNPs) 合成催化剂。新化合物4b中，4J，4K，和4E显示出IC的最有效的细胞毒活性₅₀值（0.002 - 0.004μM）比较IC的星形孢菌素₅₀ ; 0.005 微米。后一种衍生物对 IC ₅₀范围为 0.0149 - 0.048 µM的正常人 WI38 细胞表现出有希望的安全性。此外，最有希望的细胞毒性化合物4b、4j被评估为针对 RTK 蛋白激酶的多靶向药物；EGFR、HER-2、PDGFR-β 和 VEGFR-2。化合物4J显示有希望的抑制活性对IC的HER-2和PDGFR-β ₅₀值0.17×10 ^-3，0.07×10 ^-3  μM与IC的参考药物索拉非尼的比较₅₀ ; 分别为0.28 × 10 ^-3、0.13 × 10 ^-3  µM。此外，4j在 G2/M 期诱导细胞凋亡效应和细胞周期停滞，从而阻止 MCF-7 细胞的有丝分裂周期。