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Novel xanthone-polyamine conjugates as catalytic inhibitors of human topoisomerase IIα.

Authors
  • Minniti, Elirosa1
  • Byl, Jo Ann W2
  • Riccardi, Laura3
  • Sissi, Claudia4
  • Rosini, Michela5
  • De Vivo, Marco6
  • Minarini, Anna7
  • Osheroff, Neil8
  • 1 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy; Laboratory of Molecular Modeling and Drug Discovery, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy. , (Italy)
  • 2 Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA.
  • 3 Laboratory of Molecular Modeling and Drug Discovery, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy. , (Italy)
  • 4 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy. , (Italy)
  • 5 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy. , (Italy)
  • 6 Laboratory of Molecular Modeling and Drug Discovery, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy; IAS-5/INM-9 Computational Biomedicine, Forschungszentrum Jülich, Wilhelm-Johnen-Straβe, 52428 Jülich, Germany. , (Germany)
  • 7 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy. Electronic address: [email protected] , (Italy)
  • 8 Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA; Department of Medicine (Hematology/Oncology), Vanderbilt University School of Medicine, Nashville, TN 37232-6307, USA; VA Tennessee Valley Healthcare System, Nashville, TN 37212, USA. Electronic address: [email protected]
Type
Published Article
Journal
Bioorganic & medicinal chemistry letters
Publication Date
Oct 15, 2017
Volume
27
Issue
20
Pages
4687–4693
Identifiers
DOI: 10.1016/j.bmcl.2017.09.011
PMID: 28919339
Source
Medline
Keywords
License
Unknown

Abstract

It has been proposed that xanthone derivatives with anticancer potential act as topoisomerase II inhibitors because they interfere with the ability of the enzyme to bind its ATP cofactor. In order to further characterize xanthone mechanism and generate compounds with potential as anticancer drugs, we synthesized a series of derivatives in which position 3 was substituted with different polyamine chains. As determined by DNA relaxation and decatenation assays, the resulting compounds are potent topoisomerase IIα inhibitors. Although xanthone derivatives inhibit topoisomerase IIα-catalyzed ATP hydrolysis, mechanistic studies indicate that they do not act at the ATPase site. Rather, they appear to function by blocking the ability of DNA to stimulate ATP hydrolysis. On the basis of activity, competition, and modeling studies, we propose that xanthones interact with the DNA cleavage/ligation active site of topoisomerase IIα and inhibit the catalytic activity of the enzyme by interfering with the DNA strand passage step.

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