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Design, semisynthesis and potent cytotoxic activity of novel 10-fluorocamptothecin derivatives.
Bioorg Med Chem Lett. 2017 10 15; 27(20):4694-4697.BM

Abstract

Fluorination is a well-known strategy for improving the bioavailability of bioactive molecules in the lead optimization phase of drug discovery projects. In an attempt to improve the antitumor activity of camptothecins (CPTs), novel 10-fluoro-CPT derivatives were designed, synthesized and evaluated for cytotoxicity against five human cancer cell lines (A-549, MDA-MB-231, KB, KB-VIN and MCF-7). All of the derivatives showed more potent in vitro cytotoxic activity than the clinical CPT-derived drug irinotecan against the tumor cell lines tested, and most of them showed comparable or superior potency to topotecan. Remarkably, compounds 16b (IC50, 67.0nM) and 19b (IC50, 99.2nM) displayed the highest cytotoxicity against the multidrug-resistant (MDR) KB-VIN cell line and merit further development as preclinical drug candidates for treating cancer, including MDR phenotype. Our study suggested that incorporation of a fluorine atom into position 10 of CPT is an effective method for discovering new potent CPT derivatives.

Authors+Show Affiliations

School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China.School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China.Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States.Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States.School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China.School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China.School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China. Electronic address: yqliu@lzu.edu.cn.School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China.Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States.School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China.Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States; Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan. Electronic address: khlee@email.unc.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28927790

Citation

Yang, Cheng-Jie, et al. "Design, Semisynthesis and Potent Cytotoxic Activity of Novel 10-fluorocamptothecin Derivatives." Bioorganic & Medicinal Chemistry Letters, vol. 27, no. 20, 2017, pp. 4694-4697.
Yang CJ, Song ZL, Goto M, et al. Design, semisynthesis and potent cytotoxic activity of novel 10-fluorocamptothecin derivatives. Bioorg Med Chem Lett. 2017;27(20):4694-4697.
Yang, C. J., Song, Z. L., Goto, M., Hsu, P. L., Zhang, X. S., Yang, Q. R., Liu, Y. Q., Wang, M. J., Morris-Natschke, S. L., Shang, X. F., & Lee, K. H. (2017). Design, semisynthesis and potent cytotoxic activity of novel 10-fluorocamptothecin derivatives. Bioorganic & Medicinal Chemistry Letters, 27(20), 4694-4697. https://doi.org/10.1016/j.bmcl.2017.09.012
Yang CJ, et al. Design, Semisynthesis and Potent Cytotoxic Activity of Novel 10-fluorocamptothecin Derivatives. Bioorg Med Chem Lett. 2017 10 15;27(20):4694-4697. PubMed PMID: 28927790.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design, semisynthesis and potent cytotoxic activity of novel 10-fluorocamptothecin derivatives. AU - Yang,Cheng-Jie, AU - Song,Zi-Long, AU - Goto,Masuo, AU - Hsu,Pei-Ling, AU - Zhang,Xiao-Shuai, AU - Yang,Qian-Ru, AU - Liu,Ying-Qian, AU - Wang,Mei-Juan, AU - Morris-Natschke,Susan L, AU - Shang,Xiao-Fei, AU - Lee,Kuo-Hsiung, Y1 - 2017/09/08/ PY - 2017/08/08/received PY - 2017/09/01/revised PY - 2017/09/02/accepted PY - 2017/9/21/pubmed PY - 2017/11/4/medline PY - 2017/9/21/entrez KW - Camptothecin KW - Cytotoxic activity KW - Fluorination KW - Synthesis SP - 4694 EP - 4697 JF - Bioorganic & medicinal chemistry letters JO - Bioorg. Med. Chem. Lett. VL - 27 IS - 20 N2 - Fluorination is a well-known strategy for improving the bioavailability of bioactive molecules in the lead optimization phase of drug discovery projects. In an attempt to improve the antitumor activity of camptothecins (CPTs), novel 10-fluoro-CPT derivatives were designed, synthesized and evaluated for cytotoxicity against five human cancer cell lines (A-549, MDA-MB-231, KB, KB-VIN and MCF-7). All of the derivatives showed more potent in vitro cytotoxic activity than the clinical CPT-derived drug irinotecan against the tumor cell lines tested, and most of them showed comparable or superior potency to topotecan. Remarkably, compounds 16b (IC50, 67.0nM) and 19b (IC50, 99.2nM) displayed the highest cytotoxicity against the multidrug-resistant (MDR) KB-VIN cell line and merit further development as preclinical drug candidates for treating cancer, including MDR phenotype. Our study suggested that incorporation of a fluorine atom into position 10 of CPT is an effective method for discovering new potent CPT derivatives. SN - 1464-3405 UR - https://www.unboundmedicine.com/medline/citation/28927790/Design_semisynthesis_and_potent_cytotoxic_activity_of_novel_10_fluorocamptothecin_derivatives_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0960-894X(17)30891-0 DB - PRIME DP - Unbound Medicine ER -