title: Synthesis of novel 10-hydroxycamptothecin derivatives utilizing topotecan hydrochloride as ortho-quinonemethide precursor.
abstract: A series of 9-(alkylthiomethyl)-10-hydroxycamptothecins and pyrano-fused camptothecin derivatives were synthesized via the reaction of topotecan hydrochloride with various thiols and alkyl vinyl ethers respectively. In the reactions, topotecan hydrochloride was utilized as ortho-quinonemethide (o-QM) precursor. The configuration of 19 was determined by (1)H NMR and NOESY spectra as syn-isomers, suggesting that the cycloaddition of topotecan with alkyl vinyl ethers could undergo a hetero Diels-Alder reaction. All the synthesized compounds were screened on cancer cell lines HepG2, KB, HCT-8 and SGC7901. Some compounds were selected to assess their inhibitory activity against Topo I via Topo I mediated DNA cleavage assays. The results showed that among those tested 9-(alkylthiomethyl)-10-hydroxycamptothecins, the compounds with bulkier hydrophobic side chains at 9-position have better bioactivities. As well as all pyrano-fused camptothecins possess antiproliferative activity against the tested cancer cell lines. Docking studies suggested that there are more interactions between the novel analogues and the binding site of Topo I.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Hanyi
authors.initials: H
authors.lastname: Tan
authors.affiliation: PET Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.
authors.forename: Guolin
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Guangrong
authors.initials: G
authors.lastname: Meng
authors.affiliation: PET Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.
authors.forename: Zhenfeng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: PET Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.
authors.forename: Mengjie
authors.initials: M
authors.lastname: Dong
authors.affiliation: Department of Biosynthesis, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Biosynthesis, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: dianwenju@gmail.com.
authors.forename: Dianwen
authors.initials: D
authors.lastname: Ju
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: zhangqian511@shmu.edu.cn.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D061565:Cycloaddition Reaction; D056945:Hep G2 Cells; D006801:Humans; D007624:KB Cells; D062105:Molecular Docking Simulation; D011809:Quinones / Q000737:chemistry; D019772:Topotecan / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D011809:Quinones; D019772:Topotecan; C028098:10-hydroxycamptothecin; D002166:Camptothecin
keywords: 10-Hydroxycamptothecin derivatives; Antiproliferation; Configuration determination; Cycloaddition; Nucleophilic addition; ortho-Quinonemethide intermediate