Exploring DNA Topoisomerase I Ligand Space in Search of Novel Anticancer Agents 英文参考文献.docVIP

ExploringDNATopoisomeraseILigandSpaceinSearch ofNovelAnticancerAgents MalgorzataN.Drwal1,KeliAgama2,LaurenceP.G.Wakelin1,YvesPommier2,RenateGriffith1* 1DepartmentofPharmacology,SchoolofMedicalSciences,UniversityofNewSouthWales,Sydney,Australia,2LaboratoryofMolecularPharmacology,CenterforCancer Research,NationalCancerInstitute,Bethesda,Maryland,UnitedStatesofAmerica Abstract DNAtopoisomeraseI(Top1)isover-expressedintumourcellsandisanimportanttargetincancerchemotherapy.Itrelaxes DNA torsional strain generated during DNA processing by introducing transient single-strand breaks and allowing the brokenstrandtorotatearoundtheintermediateTop1–DNAcovalentcomplex.Thiscomplexcanbetrappedbyagroupof anticanceragentsinteractingwiththeDNAbasesandtheenzymeatthecleavagesite,preventingfurthertopoisomerase activity.HerewehaveidentifiednovelTop1inhibitorsaspotentialanticanceragentsbyusingacombinationofstructure- and ligand-based molecular modelling methods. Pharmacophore models have been developed based on the molecular characteristicsofderivativesofthealkaloidcamptothecin(CPT),whichrepresentpotentantitumouragentsandthemain groupofTop1inhibitors.ThemodelsgeneratedwereusedforinsilicoscreeningoftheNationalCancerInstitute(NCI,USA) compounddatabase,leadingtotheidentificationofasetofstructurallydiversemolecules.Thestrategyisvalidatedbythe observationthatamongstthesemoleculesareseveralknownTop1inhibitorsandagentscytotoxicagainsthumantumour celllines.ThepotentialoftheuntestedhitstoinhibitTop1activitywasfurtherevaluatedbydockingintothebindingsiteof a Top1 – DNA complex, resulting in a selection of 10 compounds for biological testing. Limited by the compound availability,7compoundshavebeentestedinvitrofortheirTop1inhibitoryactivity,5ofwhichdisplaymildtomoderate Top1 inhibition. A further compound, found by similarity search to the active compounds, also shows mild activity. Although the tested compounds display only low in vitro antitumour activity, our approach has been successful in the id