title: Synthesis and biological evaluation of novel 10-substituted-7-ethyl-10-hydroxycamptothecin (SN-38) prodrugs.
abstract: In an attempt to improve the antitumor activity and reduce the side effects of irinotecan (2), novel prodrugs of SN-38 (3) were prepared by conjugating amino acids or dipeptides to the 10-hydroxyl group of SN-38 via a carbamate linkage. The synthesized compounds completely generated SN-38 in pH 7.4 buffer or in human plasma, while remaining stable under acidic conditions. All prodrug compounds demonstrated much greater in vitro antitumor activities against HeLa cells and SGC-7901 cells than irinotecan. The most active compounds, 5h, 7c, 7d, and 7f, exhibited IC50 values that were 1000 times lower against HeLa cells and 30 times lower against SGC-7901 cells than those of irinotecan, and the inhibitory activities of these prodrugs against acetylcholinesterase (AchE) were significantly reduced, with IC50 values more than 6.8 times greater than that of irinotecan. In addition, compound 5e exhibited the same level of tumor growth inhibitory activity as irinotecan (CPT-11) in a human colon xenograft model in vivo.
authors.affiliation: Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China. michelle_zm2011@163.com.
authors.forename: Mo
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China. liumeixia@163.com.
authors.forename: Meixia
authors.initials: M
authors.lastname: Liu
authors.affiliation: Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China. hexinhua01@163.com.
authors.forename: Xinhua
authors.initials: X
authors.lastname: He
authors.affiliation: Cell Biology Laboratory of Jilin Province Tumor Institute, No 1018 Huguang Road, Changchun 130012, China. yuhong123@163.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.affiliation: Tumor Centre, No.1 Hospital, Jilin University, 71 Xin-Min Street, Changchun 130012, China. wd78@163.com.
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.affiliation: Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China. spray_yao123456@hotmail.com.
authors.forename: Yishan
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China. fsyn1996@163.com.
authors.forename: Shiyong
authors.initials: S
authors.lastname: Fan
authors.affiliation: Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China. gundnir@163.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China. shiwg1988@126.com.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Shi
authors.affiliation: Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China. bohuazhong0501@163.com.
authors.forename: Bohua
authors.initials: B
authors.lastname: Zhong
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D004355:Drug Stability; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000077146:Irinotecan; D008819:Mice, Nude; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D002800:Cholinesterase Inhibitors; D011355:Prodrugs; D000077146:Irinotecan; D002166:Camptothecin