A series of novel 7-substituted 10,11-methylenedioxy-camptothecin (FL118) derivatives were designed, synthesized, and biologically evaluated. All the FL118 analogues showed significant cytotoxic activities in vitro with IC₅₀ values in the nanomolar range and were more potent than topotecan. The most active compound 9c exhibited more significant anti-tumor activity against small-cell lung cancer (NCI–H446, H69, drug-resistant H69AR cells, drug-resistant NCI–H446/Irinotecan cells and drug-resistant NCI–H446/EP cells) in vitro. Additionally, 9c could also induce the expression of apoptosis proteins such as caspase-3, caspase-9, and PARP in small-cell lung cancer. Further studies showed that 9c induced apoptosis by inhibiting the expression of Mcl-1, Bcl-2, XIAP and survivin in small-cell lung cancer. In vivo 9c also showed better anti-tumor efficacy, with the tumor growth inhibition rates were 40.4% (0.75 mg/kg), 73.7% (1.5 mg/kg), and 95.5% (3 mg/kg). It is noteworthy that 9c also demonstrated potent inhibition of drug-resistant tumor growth in NCI–H446/Irinotecan and NCI–H446/EP xenograft models, the tumor growth inhibition rates were 93.42% and 84.46%, respectively. Taken together, these findings indicated that compound 9c displays outstanding antitumor activity and drug-resistance in small-cell lung cancer both in vivo and in vitro, which could be worth further research as a novel anti-tumor drug against small-cell lung cancer.

设计、合成和生物学评估了一系列新型 7 取代 10,11-亚甲二氧基喜树碱 (FL118) 衍生物。所有 FL118 类似物在体外都显示出显着的细胞毒活性，IC ₅₀值在纳摩尔范围内，并且比拓扑替康更有效。活性最强的化合物9c对小细胞肺癌（NCI-H446、H69、耐药 H69AR 细胞、耐药 NCI-H446/伊立替康细胞和耐药 NCI-H446/EP 细胞）表现出更显着的抗肿瘤活性)体外。此外，9c还可以诱导小细胞肺癌中caspase-3、caspase-9和PARP等凋亡蛋白的表达。进一步的研究表明，9c通过抑制小细胞肺癌中 Mcl-1、Bcl-2、XIAP 和 survivin 的表达诱导细胞凋亡。体内 9c也表现出较好的抗肿瘤功效，肿瘤生长抑制率分别为40.4%（0.75 mg/kg）、73.7%（1.5 mg/kg）和95.5%（3 mg/kg）。值得注意的是，9c在 NCI-H446/伊立替康和 NCI-H446/EP 异种移植模型中也表现出对耐药肿瘤生长的有效抑制作用，肿瘤生长抑制率分别为 93.42% 和 84.46%。综上所述，这些发现表明化合物9c在体内和体外对小细胞肺癌中均表现出出色的抗肿瘤活性和耐药性。，作为一种抗小细胞肺癌的新型抗肿瘤药物，值得进一步研究。