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Synthesis and antitumor activity of novel substituted uracil-1'(N)-acetic acid ester derivatives of 20(S)-camptothecins.
Eur J Med Chem. 2017 Jan 05; 125:1235-1246.EJ

Abstract

A series of novel substituted uracil-1'(N)-acetic acid esters (6-20) of camptothecins (CPTs) were synthesized by the acylation method. These new compounds were evaluated for in vitro antitumor activity against tumor cell lines, A549, Bel7402, BGC-823, HCT-8 and A2780. In vitro results showed that most of the derivatives exhibited comparable or superior cytotoxicity compare to CPT (1) and topotecan (TPT, 2), with 12 and 13 possessing the best efficacy. Four compounds, 9, 12, 13 and 16, were selected to be evaluated for in vivo antitumor activity against H22, BGC-823 and Bel-7402 in mice. In vivo testing results indicated that 12 and 13 had antitumor activity against mouse liver carcinoma H22 close to Paclitaxel and cyclophosphamide. 12 had similar antitumor activity against human gastric carcinoma BGC-823 in nude mice compared to irinotecan (3) and possessed better antitumor activity against human hepatocarcinoma Bel-7402 in nude mice than 2. It is also discovered that 12 showed a similar mechanism but better inhibitory activity on topoisomerase I (Topo I) compared to 2. These findings indicate that 20(S)-O-fluorouracil-1'(N)-acetic acid ester derivative of CPTs, 12, could be developed as an antitumor drug candidate for clinical trial.

Authors+Show Affiliations

College of Pharmacy and State Key Laboratory of Medicinal Chemical Biology, State Key Laboratory of Elemento-Organic Chemistry and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China.College of Pharmacy and State Key Laboratory of Medicinal Chemical Biology, State Key Laboratory of Elemento-Organic Chemistry and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China.Xu Zhou College of Industrial Technology, Xuzhou 221000, PR China.College of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot, Inner Mongolia, 010021, PR China.College of Pharmacy and State Key Laboratory of Medicinal Chemical Biology, State Key Laboratory of Elemento-Organic Chemistry and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China.College of Pharmacy and State Key Laboratory of Medicinal Chemical Biology, State Key Laboratory of Elemento-Organic Chemistry and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China.State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China.State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China.Beijing Land Medical Technology Co., Ltd, Beijing 101111, PR China.Beijing Land Medical Technology Co., Ltd, Beijing 101111, PR China.State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China. Electronic address: jitf@imm.ac.cn.State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China. Electronic address: xdp@imm.ac.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27871039

Citation

Li, Di-Zao, et al. "Synthesis and Antitumor Activity of Novel Substituted uracil-1'(N)-acetic Acid Ester Derivatives of 20(S)-camptothecins." European Journal of Medicinal Chemistry, vol. 125, 2017, pp. 1235-1246.
Li DZ, Zhang QZ, Wang CY, et al. Synthesis and antitumor activity of novel substituted uracil-1'(N)-acetic acid ester derivatives of 20(S)-camptothecins. Eur J Med Chem. 2017;125:1235-1246.
Li, D. Z., Zhang, Q. Z., Wang, C. Y., Zhang, Y. L., Li, X. Y., Huang, J. T., Liu, H. Y., Fu, Z. D., Song, H. X., Lin, J. P., Ji, T. F., & Pan, X. D. (2017). Synthesis and antitumor activity of novel substituted uracil-1'(N)-acetic acid ester derivatives of 20(S)-camptothecins. European Journal of Medicinal Chemistry, 125, 1235-1246. https://doi.org/10.1016/j.ejmech.2016.11.013
Li DZ, et al. Synthesis and Antitumor Activity of Novel Substituted uracil-1'(N)-acetic Acid Ester Derivatives of 20(S)-camptothecins. Eur J Med Chem. 2017 Jan 5;125:1235-1246. PubMed PMID: 27871039.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis and antitumor activity of novel substituted uracil-1'(N)-acetic acid ester derivatives of 20(S)-camptothecins. AU - Li,Di-Zao, AU - Zhang,Qiang-Zhe, AU - Wang,Cun-Ying, AU - Zhang,Yan-Ling, AU - Li,Xing-Yu, AU - Huang,Ji-Tao, AU - Liu,Hong-Yan, AU - Fu,Zhao-Di, AU - Song,Hua-Xian, AU - Lin,Jin-Ping, AU - Ji,Teng-Fei, AU - Pan,Xian-Dao, Y1 - 2016/11/08/ PY - 2016/08/01/received PY - 2016/10/30/revised PY - 2016/11/06/accepted PY - 2016/11/22/pubmed PY - 2017/2/18/medline PY - 2016/11/22/entrez KW - Antitumor activity KW - Camptothecin KW - Substituted uracil-1′(N)-acetic acid KW - Synthesis KW - The mechanism of antitumor activity SP - 1235 EP - 1246 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 125 N2 - A series of novel substituted uracil-1'(N)-acetic acid esters (6-20) of camptothecins (CPTs) were synthesized by the acylation method. These new compounds were evaluated for in vitro antitumor activity against tumor cell lines, A549, Bel7402, BGC-823, HCT-8 and A2780. In vitro results showed that most of the derivatives exhibited comparable or superior cytotoxicity compare to CPT (1) and topotecan (TPT, 2), with 12 and 13 possessing the best efficacy. Four compounds, 9, 12, 13 and 16, were selected to be evaluated for in vivo antitumor activity against H22, BGC-823 and Bel-7402 in mice. In vivo testing results indicated that 12 and 13 had antitumor activity against mouse liver carcinoma H22 close to Paclitaxel and cyclophosphamide. 12 had similar antitumor activity against human gastric carcinoma BGC-823 in nude mice compared to irinotecan (3) and possessed better antitumor activity against human hepatocarcinoma Bel-7402 in nude mice than 2. It is also discovered that 12 showed a similar mechanism but better inhibitory activity on topoisomerase I (Topo I) compared to 2. These findings indicate that 20(S)-O-fluorouracil-1'(N)-acetic acid ester derivative of CPTs, 12, could be developed as an antitumor drug candidate for clinical trial. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/27871039/Synthesis_and_antitumor_activity_of_novel_substituted_uracil_1'_N__acetic_acid_ester_derivatives_of_20_S__camptothecins_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(16)30951-5 DB - PRIME DP - Unbound Medicine ER -