为寻找新型抗肺癌耐药活性化合物, 本文以5-苯基-2,4-二氢-3H-吡唑-3-酮、丙二腈、靛红为原料, 绿色合成3,4'-吡喃并[2,3-c]吡唑螺吲哚酮衍生物21个; 体外抗肺癌活性研究表明, 该类化合物不仅对A549细胞具有良好的抑制活性, 同时对A549/DDP也具有良好的活性, 特别是化合物HDY-3对耐药株A549/DDP的活性是阳性对照药物顺铂的92倍; 机制研究表明, 化合物HDY-3可以显著地阻滞A549/DDP细胞G1/G0及G2/M期, 诱导细胞凋亡, 抑制细胞迁移; 分子对接、分子动力学模拟及MM-PBSA法计算结合自由能揭示, 化合物HDY-3-ERK1复合物表现出较高的稳定性和较强的结合能力; 化合物HDY-3可能通过抑制ERK1来影响RAS-RAF-MEK1/2-ERK1/2信号通路发挥抗肿瘤活性. 以上结果表明化合物HDY-3可以作为先导化合物进一步开发成为高效的抗肺癌药物.
Aiming to discover novel compounds active against drug-resistant lung cancer, a series of 21 3,4'-pyrano[2,3-c]pyrazole-spirooxindole derivatives were synthesized via an environmentally friendly procedure using 5-phenyl-2,4-dihydro-3H-pyrazol-3-one, malononitrile, and isatin as starting materials. In vitro anti-lung cancer activity evaluation revealed that these compounds exhibited potent inhibitory activity not only against parental A549 cells but also against cisplatin-resistant A549/DDP cells. Particularly, compound HDY-3 exhibited exceptional potency against the A549/DDP cells, with activity 92-fold higher than that of the positive control drug cisplatin. Mechanistic studies indicated that HDY-3 significantly blocked the cell cycle of A549/DDP cells at both the G₀/G₁ and G₂/M phases, induced apoptosis, and suppressed cell migration. Furthermore, molecular docking, molecular dynamics simulations, and MM-PBSA binding free energy calculations revealed that the HDY-3-ERK1 complex exhibited high stability and strong binding affinity. The antitumor activity of HDY-3 is likely mediated through inhibition of ERK1, thereby interfering with the RAS-RAF-MEK1/2-ERK1/2 signaling pathway. Collectively, these results suggest that compound HDY-3 represents a promising lead compound for further development into highly efficacious anti-lung cancer therapeutics.
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