A novel camptothecin analogue, (20S)-10,11-methylenedioxy-camptothecin (FL118), has been proven to show significant antitumor efficacy for a wide variety of solid tumors. However, the further development of FL118 is severely hindered due to its extremely poor water solubility and adverse side effects. Here, two series of novel 20-substituted (20S)-10,11-methylenedioxy-camptothecin coupled with 5-substituted uracils and other heterocyclic rings through glycine were synthesized. All the derivatives showed superior cytotoxic activities in vitro with IC50 values in the nanomolar range. Among them, 12e displayed higher cytotoxic activities in several cancer cell lines with better water solubility than FL118. Our results further showed that, like FL118, 12e inhibited cell proliferation resulting from cell cycle arrest and apoptosis by blocking the anti-apoptotic gene transcription of survivin, Mcl-1, Bcl-2, and XIAP in both A549 cells and NCI-H446 cells. Furthermore, 12e did not show any inhibitory activity on Topo I, which is involved in hematopoietic toxicity. In vivo, 12e showed similar antitumor efficacy to FL118 but lower toxicity. Our findings indicate that 12e is a promising therapeutic agent for cancer treatment, and the core structure of FL118 represents a promising platform to generate novel FL118-based antitumor drugs.

中文翻译：

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新型(20S)-10,11-亚甲二氧基-喜树碱杂环衍生物的设计、合成和体内外抗癌活性

一种新型喜树碱类似物（20S）-10,11-亚甲二氧基喜树碱（FL118）已被证明对多种实体瘤具有显着的抗肿瘤功效。然而，由于FL118的水溶性极差和不良副作用，其进一步发展受到严重阻碍。在这里，合成了两个系列的新型20-取代的(20S)-10,11-亚甲二氧基-喜树碱，通过甘氨酸与5-取代的尿嘧啶和其他杂环偶联。所有衍生物在体外均表现出优异的细胞毒活性，IC50 值在纳摩尔范围内。其中，12e在多种癌细胞系中表现出更高的细胞毒活性，且水溶性比FL118更好。我们的结果进一步表明，与 FL118 一样，12e 通过阻断 A549 细胞和 NCI-H446 细胞中 survivin、Mcl-1、Bcl-2 和 XIAP 的抗凋亡基因转录来抑制细胞周期停滞和凋亡引起的细胞增殖。 。此外，12e 对与造血毒性有关的 Topo I 没有表现出任何抑制活性。在体内，12e表现出与FL118相似的抗肿瘤功效，但毒性较低。我们的研究结果表明，12e 是一种有前途的癌症治疗药物，而 FL118 的核心结构代表了一个有前途的平台，可以产生基于 FL118 的新型抗肿瘤药物。