Role of the 20-hydroxyl group in camptothecin binding by the topoisomerase I-DNA binary complex.
Recent findings concerning the structure of the covalent binary complex formed by DNA topisomerase I and its DNA substrate, as well as the nature of interactions with inhibitors that bind reversibly to this binary complex, have led to two proposed models for the binding of the prototype inhibitor camptothecin to the DNA-topisomerase I binary complex. While these models differ in many regards, they both suggest the involvement of the 20-OH group of camptothecin in a donor hydrogen bond with an enzyme side chain functional group. Presently, five analogues of camptothecin that differ only at C-20 have been evaluated for their ability to bind to the topoisomerase I-DNA binary complex and thereby inhibit enzyme function. Both 20-chloro- and 20-bromocamptothecin bound as well to the enzyme-DNA binary complex as 20-aminoCPT despite the absence of a substituent at C-20 capable of contributing a donor hydrogen bond.
Wang
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Department of Chemistry, University of Virginia, Charlottesville 22901, USA.
Zhou
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Hecht
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D001483:Base Sequence; D001665:Binding Sites; D002166:Camptothecin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism* / Q000633:toxicity; D011088:DNA Ligases / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism*; D004795:Enzyme Stability; D006801:Humans; D006868:Hydrolysis; D008969:Molecular Sequence Data; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D012965:Sodium Chloride / Q000737:chemistry; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D059004:Topoisomerase I Inhibitors
D059004:Topoisomerase I Inhibitors; D012965:Sodium Chloride; D004264:DNA Topoisomerases, Type I; D011088:DNA Ligases; D002166:Camptothecin