2. Academic Validation
  3. Design, synthesis and investigation of biological activity and mechanism of fluoroaryl-substituted derivatives at the FL118 position 7

Design, synthesis and investigation of biological activity and mechanism of fluoroaryl-substituted derivatives at the FL118 position 7

  • Eur J Med Chem. 2025 Feb 5:283:117143. doi: 10.1016/j.ejmech.2024.117143.
Wenchao Wang 1,  Ruojiong Wang 2,  Lianhao An 2,  Lei Li 2,  Haonan Xiong 2,  Dan Li 2,  Fangze Dong 2,  Junrong Lei 2,  Mengke Wang 2,  Zhikun Yang 2,  Hong Wang 2,  Xiang Ling 3,  Christos Fountzilas 4,  Fengzhi Li 5,  Qingyong Li 6
Affiliations

Affiliations

  • 1 Urology & Nephrology Center, Department of Urology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.
  • 2 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.
  • 3 Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA; Canget BioTekpharma LLC, Buffalo, NY, 14203, USA.
  • 4 Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.
  • 5 Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA. Electronic address: fengzhi.li@roswellpark.org.
  • 6 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. Electronic address: liqy@zjut.edu.cn.
PMID: 39647420 DOI: 10.1016/j.ejmech.2024.117143
Abstract

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.

Keywords

Antitumor; DDX5; FL118 derivatives; Fluorine; Topoisomerase I.

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