Inhibition of human DNA topoisomerase II alpha by two novel ellipticine derivatives

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Vann K. R., Ergun Y., ZENCİR S., ÖNCÜOĞLU S., Osheroff N., TOPÇU Z.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, cilt.26, sa.7, ss.1809-1812, 2016 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 26 Sayı: 7
  • Basım Tarihi: 2016
  • Doi Numarası: 10.1016/j.bmcl.2016.02.034
  • Dergi Adı: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.1809-1812
  • Anahtar Kelimeler: Ellipticine derivatives, DNA topoisomerase II alpha, Anticancer drugs, Catalytic inhibitor, DNA cleavage, DNA intercalation, ANTICANCER DRUGS, CLEAVAGE, POISONS, STIMULATION, METABOLITES, MECHANISM
  • Dokuz Eylül Üniversitesi Adresli: Evet

Özet

Ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole) is an antineoplastic agent that intercalates into DNA and alters topoisomerase II activity. Unfortunately, this compound displays a number of adverse properties. Therefore, to investigate new ellipticine-based compounds for their potential as topoisomerase II-targeted drugs, we synthesized two novel derivatives, N-methyl-5-demethyl ellipticine (ET1) and 2-methyl-N-methyl-5-demethyl ellipticinium iodide (ET-2). As determined by DNA decatenation and cleavage assays, ET-1 and ET-2 act as catalytic inhibitors of human topoisomerase II alpha and are both more potent than the parent compound. Neither compound impairs the ability of the type II enzyme to bind its DNA substrate. Finally, the potency of ET-1 and ET-2 as catalytic inhibitors of topoisomerase II alpha appears to be related to their ability to intercalate into the double helix. (C) 2016 Elsevier Ltd. All rights reserved.