Isodiospyrin as a novel human DNA topoisomerase I inhibitor. 2003

Chun-Yuan Ting, and Chia-Tse Hsu, and Hsiang-Ting Hsu, and Jin-Shan Su, and Tzong-Yueh Chen, and Woan-Yuh Tarn, and Yao-Haur Kuo, and Jacqueline Whang-Peng, and Leroy F Liu, and Jaulang Hwang
Institute of Biochemistry, School of Life Science, National Yang Ming University, Taipei, Taiwan.

Isodiospyrin is a natural product from the plant Diospyros morrisiana, which consists of an asymmetrical 1,2-binaphthoquinone chromophore. Isodiospyrin exhibits cytotoxic activity to tumor cell lines but very little is known about its cellular target and mechanism of action. Unlike the prototypic human topoisomerase I (htopo I) poison camptothecin, isodiospyrin does not induce htopo I-DNA covalent complexes. However, isodiospyrin antagonizes camptothecin-induced, htopo I-mediated DNA cleavage. Binding analysis indicated that isodiospyrin binds htopo I but not DNA. These results suggest that isodiospyrin inhibits htopo I by direct binding to htopo I, which limits htopo I access to the DNA substrate. Furthermore, isodiospyrin exhibits strong inhibitory effect on the kinase activity of htopo I toward splicing factor 2/alternate splicing factor in the absence of DNA. Thus, these findings have important implications on naphthoquinone and its derivatives' cellular mode of actions, i.e. these novel DNA topoisomerase I inhibitors can prevent both DNA relaxation and kinase activities of htopo I.

UI MeSH Term Description Entries
D009285 Naphthoquinones Naphthalene rings which contain two ketone moieties in any position. They can be substituted in any position except at the ketone groups. Naphthalenediones,Naphthazarins,Naphthoquinone
D004247 DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA, Double-Stranded,Deoxyribonucleic Acid,ds-DNA,DNA, Double Stranded,Double-Stranded DNA,ds DNA
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000255 Adenosine Triphosphate An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter. ATP,Adenosine Triphosphate, Calcium Salt,Adenosine Triphosphate, Chromium Salt,Adenosine Triphosphate, Magnesium Salt,Adenosine Triphosphate, Manganese Salt,Adenylpyrophosphate,CaATP,CrATP,Manganese Adenosine Triphosphate,MgATP,MnATP,ATP-MgCl2,Adenosine Triphosphate, Chromium Ammonium Salt,Adenosine Triphosphate, Magnesium Chloride,Atriphos,Chromium Adenosine Triphosphate,Cr(H2O)4 ATP,Magnesium Adenosine Triphosphate,Striadyne,ATP MgCl2
D059004 Topoisomerase I Inhibitors Compounds that inhibit the activity of DNA TOPOISOMERASE I. DNA Topoisomerase I Inhibitor,DNA Topoisomerase III Inhibitor,DNA Topoisomerase III Inhibitors,DNA Type 1 Topoisomerase Inhibitor,DNA Type III Topoisomerase Inhibitor,DNA Type III Topoisomerase Inhibitors,Topoisomerase 1 Inhibitor,Topoisomerase 1 Inhibitors,Topoisomerase 3 Inhibitor,Topoisomerase 3 Inhibitors,Topoisomerase I Inhibitor,Topoisomerase III Inhibitor,Topoisomerase III Inhibitors,DNA Topoisomerase I Inhibitors,DNA Type 1 Topoisomerase Inhibitors,1 Inhibitor, Topoisomerase,3 Inhibitor, Topoisomerase,3 Inhibitors, Topoisomerase,I Inhibitor, Topoisomerase,III Inhibitor, Topoisomerase,III Inhibitors, Topoisomerase,Inhibitor, Topoisomerase 1,Inhibitor, Topoisomerase 3,Inhibitor, Topoisomerase I,Inhibitor, Topoisomerase III,Inhibitors, Topoisomerase 1,Inhibitors, Topoisomerase 3,Inhibitors, Topoisomerase I,Inhibitors, Topoisomerase III

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