title: Synthesis and antitumor activity of novel substituted uracil-1'(N)-acetic acid ester derivatives of 20(S)-camptothecins.
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 H22close 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.affiliation: 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.
authors.forename: Di-Zao
authors.initials: DZ
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Qiang-Zhe
authors.initials: QZ
authors.lastname: Zhang
authors.affiliation: Xu Zhou College of Industrial Technology, Xuzhou 221000, PR China.
authors.forename: Cun-Ying
authors.initials: CY
authors.lastname: Wang
authors.affiliation: College of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot, Inner Mongolia, 010021, PR China.
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Xing-Yu
authors.initials: XY
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Ji-Tao
authors.initials: JT
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Zhao-Di
authors.initials: ZD
authors.lastname: Fu
authors.affiliation: Beijing Land Medical Technology Co., Ltd, Beijing 101111, PR China.
authors.forename: Hua-Xian
authors.initials: HX
authors.lastname: Song
authors.affiliation: Beijing Land Medical Technology Co., Ltd, Beijing 101111, PR China.
authors.forename: Jin-Ping
authors.initials: JP
authors.lastname: Lin
authors.affiliation: 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.
authors.forename: Teng-Fei
authors.initials: TF
authors.lastname: Ji
authors.affiliation: 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.
authors.forename: Xian-Dao
authors.initials: XD
authors.lastname: Pan
mesh_terms: D000085:Acetates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D006801:Humans; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000085:Acetates; D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; D014498:Uracil; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin
keywords: Antitumor activity; Camptothecin; Substituted uracil-1′(N)-acetic acid; Synthesis; The mechanism of antitumor activity