Formaldehyde-activated Pixantrone is a monofunctional DNA alkylator that binds selectively to CpG and CpA doublets

Molecular Pharmacology
Benny J EvisonSuzanne M Cutts

Abstract

The topoisomerase II poison mitoxantrone is important in the clinical management of human malignancies. Pixantrone, a novel aza-anthracenedione developed to improve the therapeutic profile of mitoxantrone, can efficiently alkylate DNA after formaldehyde activation. In vitro transcriptional analysis has now established that formaldehyde-activated pixantrone generates covalent adducts selectively at discrete CpG or CpA dinucleotides, suggesting that the activated complex binds to guanine or cytosine (or both) bases. The stability of pixantrone adduct-induced transcriptional blockages varied considerably, reflecting a mixture of distinct pixantrone adduct types that may include relatively labile monoadducts and more stable interstrand cross-links. 6,9-Bis-[[2-(dimethylamino)ethyl]amino]benzo[g]isoquinoline-5,10-dione (BBR 2378), the dimethyl N-substituted analog of pixantrone, could not form adducts, suggesting that pixantrone alkylates DNA through the primary amino functions located in each side chain of the drug. Pixantrone generated DNA adducts only when guanine was present in substrates and exhibited a lack of adduct formation with inosine-containing polynucleotides, confirming that the N2 amino group of guanine is the site fo...Continue Reading

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Citations

Dec 25, 2012·Cancer Chemotherapy and Pharmacology·Robert A ForrestSuzanne M Cutts
Sep 13, 2011·Expert Opinion on Drug Metabolism & Toxicology·Mariam Jamal-Hanjani, Ruth Pettengell
Jun 24, 2010·Expert Opinion on Pharmacotherapy·Deborah Mukherji, Ruth Pettengell
Jul 27, 2011·Mutation Research·Anh DuongLuoping Zhang
May 2, 2015·Organic & Biomolecular Chemistry·Shyam K KondaJ Grant Collins
May 5, 2016·Organic & Biomolecular Chemistry·Shyam K KondaJ Grant Collins
Jun 19, 2018·Expert Review of Hematology·Giorgio MinottiFrancesco Bertoni
Sep 25, 2010·Organic & Biomolecular Chemistry·Najia AdnanJ Grant Collins
Jan 25, 2021·Bioorganic & Medicinal Chemistry Letters·Jelena MedanSuzanne M Cutts
Sep 24, 2010·Journal of Medicinal Chemistry·Oula C MansourSuzanne M Cutts

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