Abstract：
New chromene derivatives were synthesized based on 4-(3,4-dimethoxy)-4H-chromene scaffold. All target compounds exhibited cytotoxic activity against HepG2 cells (IC50 = 2.40-141.22 μM). Chromens 5 and 9 showed superior cytotoxicity over staurosporine (IC50 = 18.27 μM) and vinblastine (IC50 = 5.20 μM). c-Src kinase inhibition assay of compounds 5 and 9 displayed the dominant c-Src inhibitory activity of 5 (IC50 = 0.184 μM) over 9 (IC50 = 0.288 μM). The safety of the most potent compound 5 against normal WI-38 cells was confirmed via its IC50 of 115.75 μM comparable with 5-FU (IC50 = 16.28 μM). Moreover, the promising chromene 5 displayed potent cytotoxicity against resistant HepG2 cells with IC50 of 26.03 μM comparable with 5-FU (IC50 = 42.68 μM). The most active chromene 5 arrested the HepG2 cell cycle at the S phase and induced a 29-fold increase in the total number of apoptotic cells indicating pre-G1 apoptosis. The ability of compound 5 to induce apoptosis was supported via elevation of caspase-3, caspase-7, caspase-9 and proapoptotic Bax protein levels in addition to downregulation of the antiapoptotic Bcl2 protein. Molecular docking studies of compound 5 showed good binding interaction pattern inside c-Src kinase enzyme active site.
摘要：
基于4-(3,4-二甲氧基)-4H-苯并吡喃支架合成了新的苯并吡喃衍生物。所有靶化合物对HepG2细胞均表现出细胞毒活性(IC50=2.40-141.22μM)。第5号和第9号显现出优于星形孢菌素(IC50=18.27μM)和长春碱(IC50=5.20μM)的细胞毒性。化合物5和9的c-Src激酶抑制测定显示5(IC50=0.184μM)相对于9(IC50=0.288μM)的主要c-Src抑制活性。通过与5-FU相当的115.75μM的IC50(IC50=16.28μM)证实了最有效的化合物5对正常WI-38细胞的安全性。此外，有希望的色烯5对耐药HepG2细胞显示出有效的细胞毒性，IC50为26.03μM，与5-FU相当（IC50=42.68μM）。最活跃的色烯5将HepG2细胞周期阻滞在S期，并诱导凋亡细胞总数增加29倍，表明G1前凋亡。除了下调抗凋亡Bcl2蛋白外,化合物5诱导凋亡的能力还通过提高半胱天冬酶-3、半胱天冬酶-7、半胱天冬酶-9和促凋亡Bax蛋白水平得到支持。化合物5的分子对接研究显示在c-Src激酶活性位点内良好的结合相互作用模式。
