title: Inhibitory activities against topoisomerase I and II by isoaurostatin derivatives and their structure-activity relationships.
abstract: Isoaurostatin A (IAS-A) isolated from Thermomonospora alba showed weak inhibition against topoisomerase (topo) I (IC(50)=307microM). 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 (IC(50)=3microM) 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.
authors.affiliation: Department of Pharmaceutical Microbiology, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan. keitarou@gpo.kumamoto-u.ac.jp <keitarou@gpo.kumamoto-u.ac.jp>
authors.forename: Keitarou
authors.initials: K
authors.lastname: Suzuki
authors.forename: Tadashi
authors.initials: T
authors.lastname: Okawara
authors.forename: Tatuya
authors.initials: T
authors.lastname: Higashijima
authors.forename: Kazumi
authors.initials: K
authors.lastname: Yokomizo
authors.forename: Tohru
authors.initials: T
authors.lastname: Mizushima
authors.forename: Masami
authors.initials: M
authors.lastname: Otsuka
mesh_terms: D001572:Benzofurans / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004264:DNA Topoisomerases, Type I / Q000502:physiology; D004250:DNA Topoisomerases, Type II / Q000502:physiology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
chemical_list: D001572:Benzofurans; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; C433579:isoaurostatin; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II