Wang Wenchao, Wang Ruojiong, An Lianhao, Li Lei, Xiong Haonan, Li Dan, Dong Fangze, Lei Junrong, Wang Mengke, Yang Zhikun, Wang Hong, Ling Xiang, Fountzilas Christos, Li Fengzhi, Li Qingyong
Urology & Nephrology Center, Department of Urology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.
College of Pharmaceutical Sciences, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Zhejiang University of Technology, Hangzhou, 310014, China.
Eur J Med Chem. 2025 Feb 5;283:117143. doi: 10.1016/j.ejmech.2024.117143. Epub 2024 Dec 4.
Addition of fluorine atoms into chemical compounds is a validated strategy to enhance their physical, chemical and biological properties. In this study, FL118, a novel camptothecin-related small molecule known for its unique mechanism of action and superior antitumor efficacy, was utilized as a foundational drug platform. By replacing the hydrogen atom at position 7 of FL118 with a fluoroaryl group, a diverse array of FL118 derivatives were synthesized. Our investigations revealed that the majority of these newly synthesized compounds exhibited improved cytotoxicity compared to FL118, with some demonstrating enhanced in vivo antitumor efficacy. Among these derivatives, compound 7h stood out and was subjected to detailed analysis. Compound 7h demonstrated a remarkable ability to inhibit colorectal cancer (CRC) cell colony formation and cell migration, while also promoting reactive oxygen species (ROS) production and CRC cell apoptosis. Notably, our studies unveiled that the presence of DDX5 could modulate Topoisomerase I (Top1) activity, a process effectively reversed by a low concentration of 7h, but not SN38. Moreover, only 7h was able to decrease DDX5 expression, SN38 was not. Molecular docking studies further supported the binding of 7h to DDX5. Interestingly, although both 7h and SN38 exhibited similar inhibitory effects on Top1 activity, only 7h, and not SN38, could inhibit DDX5. These findings not only pave the way for deeper mechanistic explorations of FL118 and its derivatives in cancer research but also position the identified compound 7h as a promising candidate for further development.
将氟原子引入化合物是一种经过验证的增强其物理、化学和生物学性质的策略。在本研究中，FL118是一种新型喜树碱相关小分子，以其独特的作用机制和卓越的抗肿瘤疗效而闻名，被用作基础药物平台。通过用氟芳基取代FL118第7位的氢原子，合成了一系列多样的FL118衍生物。我们的研究表明，与FL118相比，这些新合成的化合物大多数表现出改善的细胞毒性，有些在体内抗肿瘤疗效方面有所增强。在这些衍生物中，化合物7h脱颖而出并进行了详细分析。化合物7h表现出显著抑制结肠直肠癌（CRC）细胞集落形成和细胞迁移的能力，同时还促进活性氧（ROS）生成和CRC细胞凋亡。值得注意的是，我们的研究发现DDX5的存在可以调节拓扑异构酶I（Top1）的活性，低浓度的7h可以有效逆转这一过程，但SN38不能。此外，只有7h能够降低DDX5的表达，而SN38不能。分子对接研究进一步支持了7h与DDX5的结合。有趣的是，尽管7h和SN38对Top1活性表现出相似的抑制作用，但只有7h能够抑制DDX5，而SN38不能。这些发现不仅为在癌症研究中对FL118及其衍生物进行更深入的机制探索铺平了道路，也将鉴定出的化合物7h定位为有前景的进一步开发候选物。
