Inhibitory activities against topoisomerase I and II by isoaurostatin derivatives and their structure-activity relationships

Keitarou Suzuki, Tadashi Okawara, Tatuya Higashijima, Kazumi Yokomizo, Tohru Mizushima, Masami Otsuka

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Isoaurostatin A (IAS-A) isolated from Thermomonospora alba showed weak inhibition against topoisomerase (topo) I (IC50 = 307 μM). To get more strong inhibition, derivatives of IAS-A were prepared and their structure-activity relationships against topo I and II were investigated. The addition of hydroxyl group on aromatic rings increased the activities, 3-(3,4,5-trihydroxybenzylidene)-5-hydroxy-3H-benzofuran-2-one (IAS-9) showed strong inhibition (IC50 = 3 μM) against topo I. And also, the increasing of hydroxyl group increased growth inhibition against a variety of cancer cells, and IAS-9 showed most potent inhibition. Unlike camptothecin and etoposide, IAS-9 neither stabilized DNA-topo cleavable complex nor intercalated into DNA, and it inhibited topo I and II noncompetitively. The inhibitory activities also increased by opening of lactone ring in the molecule of IAS-9.

Original languageEnglish
Pages (from-to)2065-2068
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume15
Issue number8
DOIs
Publication statusPublished - 2005 Apr 15

Keywords

  • Anticancer
  • Isoaurostatin
  • Structure-activity relationship
  • Topoisomerase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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