title: Design, synthesis, biological evaluation and QSAR studies of novel bisepipodophyllotoxins as cytotoxic agents.
abstract: Two moieties of epipodophyllotoxin have been linked at C4-position to provide novel bisepipodophyllotoxin analogues. These have been evaluated for their anticancer potential and DNA-topoisomerase II poisoning activity. Most of these analogues have exhibited promising in vitro anticancer activity against different human tumour cell lines and interestingly 4(')-O-methylated analogues have shown increased cytotoxic activity. Similarly, the DNA-topo II poisoning activity tested for these compounds has not only exhibited the DNA cleavage potential comparable to etoposide, but for some compounds this cleavage potential is superior to etoposide. Further, an interesting structure-activity relationship of these epipodophyllotoxin dimers have been generated on the basis of GI(50) values. The equations indicated that GI(50) activity is strongly dependent on structural and thermodynamic properties. These QSAR results are discussed in conjunction with conformational analysis from molecular modelling studies. QSAR models developed in these studies will be helpful in the future to design novel potent bispodophyllotoxin analogues by minor structural modifications.
authors.affiliation: Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India. ahmedkamal@iict.res.in
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
authors.forename: E
authors.initials: E
authors.lastname: Laxman
authors.forename: G B Ramesh
authors.initials: GB
authors.lastname: Khanna
authors.forename: P S M M
authors.initials: PS
authors.lastname: Reddy
authors.forename: Tasneem
authors.initials: T
authors.lastname: Rehana
authors.forename: M
authors.initials: M
authors.lastname: Arifuddin
authors.forename: K
authors.initials: K
authors.lastname: Neelima
authors.forename: Anand K
authors.initials: AK
authors.lastname: Kondapi
authors.forename: Sunanda G
authors.initials: SG
authors.lastname: Dastidar
mesh_terms: D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008968:Molecular Conformation; D011034:Podophyllotoxin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
chemical_list: D059005:Topoisomerase II Inhibitors; D011034:Podophyllotoxin