Arylstibonic acids: novel inhibitors and activators of human topoisomerase IB.
Human topoisomerase IB (hTopo) forms a covalent phosphotyrosyl linkage with the DNA backbone, and controls genomic DNA topology by relaxing DNA supercoils during the processes of DNA replication, transcription, chromosome condensation and decondensation. The essential role of hTopo in these processes has made it a preeminent anticancer drug target. We have screened a small library of arylstibonic acids for their effects on plasmid supercoil relaxation catalyzed by hTopo. Despite the similar structures of the library compounds, some compounds were found to be effective competitive inhibitors, and others, nonessential activators. Some arylstibonic acids show selectivity in their action against hTopo and the related enzyme from poxvirus (vTopo). Structure-activity relationships and structural modeling suggest that competitive inhibition may result from positioning of the negatively charged stibonic acid and carboxylate groups of the inhibitors into DNA phosphate binding pockets on hTopo. The hTopo activators act by a surprising allosteric mechanism without interfering with DNA binding or binding of the widely used hTopo poison camptothecin. Arylstibonic acid competitive inhibitors may become useful small molecules for elucidating the cellular functions of hTopo.
Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205-2185, USA.
Hyeongnam
H
Kim
John H
JH
Cardellina
Rhone
R
Akee
James J
JJ
Champoux
James T
JT
Stivers
D000143:Acids / Q000737:chemistry* / Q000494:pharmacology*; D002166:Camptothecin / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D011485:Protein Binding; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
D000143:Acids; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D004247:DNA; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D002166:Camptothecin