兰州大学机构库
Improved anti-tumor activity of fluorinated camptothecin derivatives 9-fluorocamptothecin and 7-ethyl-9-fluorocamptothecin on hepatocellular carcinoma by targeting topoisomerase I
Zhang, Mi1,2; Zhu, Li-Zu1,2; Yang, Cheng-Jie1; Yan, Jia-Xuan5; Wang, ZP(王志平)4; Bai, Yin-Peng1,2; Peng, Li-Zeng3; Luo, Hong-Bo6; Zhang, ZJ(张智军)1; Li, Lei2; Xu, Chuan-Rui2; Liu, YQ(刘映前)1
2023-10
Online publication date2023-06
Source PublicationBIOORGANIC CHEMISTRY   Impact Factor & Quartile
ISSN0045-2068 ; 1090-2120
Volume139
page numbers16
AbstractPrimary liver cancer is one of the most common malignant cancers of the digestive system that lacks effective chemotherapeutic drugs in clinical settings. Camptothecin (CPT) and its derivatives have been approved for cancer treatment; however, their application is limited by their systemic toxicity. For lead optimization in new drug discovery stages, fluorination is an effective and robust approach to increase the bioavailability and optimize the pharmacokinetics of candidate compounds, thereby improving their efficacy. To obtain new and highly active CPT derivatives, we designed, synthesized, and evaluated two new fluorinated CPT derivatives, 9-fluorocamptothecin (A1) and 7-ethyl-9-fluorocamptothecin (A2), in this study. In vitro, A1 and A2 exhibited more robust anti-tumor activity than topotecan (TPT) in various cancer cells, particularly hepatocellular carcinoma (HCC) cells. In vivo, A1 and A2 exhibited greater anti-tumor activity than TPT in both AKT/Met induced primary HCC mouse models and implanted HepG2 cell xenografts. Acute toxicity tests revealed that A1 and A2 were not lethal and did not cause significant body weight loss at high doses. Moreover, A1 and A2 exhibited no significant toxicity in the mouse liver, heart, lung, spleen, kidney, and hematopoietic systems at therapeutic doses. Mechanistically, A1 and A2 blocked HCC cell proliferation by inhibiting the enzymatic activity of Topo I, subsequently inducing DNA damage, cell cycle arrest, and apoptosis. In summary, our results indicate that fluorination improves the anti-tumor activity of CPT while decreasing its toxicity and highlight the application potential of fluorination products A1 and A2 in clinical settings.
KeywordAnti -tumor activity Camptothecin Fluorine Synthesis Hepatocellular carcinoma
PublisherACADEMIC PRESS INC ELSEVIER SCIENCE
DOI10.1016/j.bioorg.2023.106652
Indexed BySCIE ; IC
Language英语
WOS Research AreaBiochemistry & Molecular Biology ; Chemistry
WOS SubjectBiochemistry & Molecular Biology ; Chemistry, Organic
WOS IDWOS:001024249200001
Original Document TypeArticle
PMID 37390632
Citation statistics
Cited Times:1[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttps://ir.lzu.edu.cn/handle/262010/568569
Collection兰州大学
药学院
第二临床医学院
Corresponding AuthorLi, Lei; Xu, Chuan-Rui; Liu, Ying-Qian
Affiliation
1.Lanzhou Univ, Sch Pharm, Lanzhou 730000, Peoples R China;
2.Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Pharm, Wuhan 430030, Peoples R China;
3.Jinan AISI Pharmaceut Technol Co Ltd, Jinan 250104, Peoples R China;
4.Lanzhou Univ, Inst Urol, Gansu Nephro Urol Clin Ctr, Dept Urol,Hosp 2,Key Lab Urol Dis Gansu Prov, Lanzhou 730030, Gansu, Peoples R China;
5.Peking Univ, Sch Pharmaceut Sci, Beijing 100191, Peoples R China;
6.Second Hosp Huangshi, Dept Urol, Huangshi 435000, Hubei, Peoples R China
First Author AffilicationSchool of Pharmacy
Corresponding Author AffilicationSchool of Pharmacy
Recommended Citation
GB/T 7714
Zhang, Mi,Zhu, Li-Zu,Yang, Cheng-Jie,et al. Improved anti-tumor activity of fluorinated camptothecin derivatives 9-fluorocamptothecin and 7-ethyl-9-fluorocamptothecin on hepatocellular carcinoma by targeting topoisomerase I[J]. BIOORGANIC CHEMISTRY,2023,139.
APA Zhang, Mi.,Zhu, Li-Zu.,Yang, Cheng-Jie.,Yan, Jia-Xuan.,Wang, Zhi-Ping.,...&Liu, Ying-Qian.(2023).Improved anti-tumor activity of fluorinated camptothecin derivatives 9-fluorocamptothecin and 7-ethyl-9-fluorocamptothecin on hepatocellular carcinoma by targeting topoisomerase I.BIOORGANIC CHEMISTRY,139.
MLA Zhang, Mi,et al."Improved anti-tumor activity of fluorinated camptothecin derivatives 9-fluorocamptothecin and 7-ethyl-9-fluorocamptothecin on hepatocellular carcinoma by targeting topoisomerase I".BIOORGANIC CHEMISTRY 139(2023).
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