title: Antitumor agents. Part 235: Novel 4'-ester etoposide analogues as potent DNA topoisomerase II inhibitors with improved therapeutic potential.
abstract: Eight 4'-ester epipodophyllotoxin derivatives (9-16) were designed and synthesized with the aim to overcome drug-resistance and improve water-solubility simultaneously. These compounds were superior to etoposide (1) in causing cellular protein-linked DNA breaks and inhibiting KB and 1-resistant KB-7d cell replication. Compounds 9 and 10 showed significant inhibitory activity against DNA topoisomerase II in vitro. Compound 10 also exhibited an in vitro DNA cleavage pattern similar to that of GL-331 (5). A hypothetical model on the action mode of 1-analogues is proposed based on the results.
authors.affiliation: Natural Products Laboratory, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA.
authors.forename: Zhiyan
authors.initials: Z
authors.lastname: Xiao
authors.forename: John R
authors.initials: JR
authors.lastname: Vance
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Bastow
authors.forename: Arnold
authors.initials: A
authors.lastname: Brossi
authors.forename: Hui-Kang
authors.initials: HK
authors.lastname: Wang
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D005047:Etoposide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D059005:Topoisomerase II Inhibitors
chemical_list: C495619:4'-ester etoposide; D000970:Antineoplastic Agents; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D004250:DNA Topoisomerases, Type II