Inhibitory activities against topoisomerase I and II by isoaurostatin derivatives and their structure-activity relationships |
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Authors: | Suzuki Keitarou Okawara Tadashi Higashijima Tatuya Yokomizo Kazumi Mizushima Tohru Otsuka Masami |
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Institution: | Department of Pharmaceutical Microbiology, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan. keitarou@gpo.kumamoto-u.ac.jp |
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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. |
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