title: Cyclane-aminol 10-hydroxycamptothecin analogs as novel DNA topoisomerase I inhibitors induce apoptosis selectively in tumor cells.
abstract: A novel series of cyclane-aminol 10-hydroxycamptothecin (HCPT) analogs was designed and synthesized through the Mannich reaction using HCPT as the lead compound, such as 10-hydroxyl-9-L-prolinol (+) methylcamptothecin (PRPT), 10-hydroxyl-9-(4'-hydroxy) piperidinylmethylcamptothecin (PPPT), and 10-hydroxy-9-(4'-hydroxyethyl)-piperazinylmethycamptothecin (QPPT). Three kinds of new cyclane-aminols were introduced into the structure of HCPT, which modified strong cytotoxic HCPT into cyclane-aminol HCPT analogs with moderate cytotoxicity and improved selectivity toward DNA topoisomerase I inhibition in tumor cells. Special metabolic pathways for cyclane-aminol HCPT analogs in rats were discovered, which differed from other HCPT analogs. Cyclane-aminol HCPT analogs can capture O2 and cause an increase in intracellular hydrogen peroxide levels with selective induction of apoptosis in tumor cells rather than in normal peripheral blood mononuclear cells. Among them, PPPT has a much better druggability than topotecan (TPT) and has the potential to be developed into an antitumor agent.
authors: aState Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology bSchool of Environmental and Biological Science and Technology, Dalian University of Technology, Dalian cNorman Bethune College of Medicine, Jilin University, Changchun, China.
authors: Shixuan
authors: S
authors: Zhang
authors: Tao
authors: T
authors: Geng
authors: Bo
authors: B
authors: Jiang
authors: Ge
authors: G
authors: Song
authors: Lisha
authors: L
authors: Ha
authors: Chenguang
authors: C
authors: Sun
authors: Yuan
authors: Y
authors: Qian
authors: Qingyu
authors: Q
authors: Fan
authors: Hongmin
authors: H
authors: Guo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D059004:Topoisomerase I Inhibitors; D002166:Camptothecin