Anticancer properties of an important drug lead podophyllotoxin can be efficiently mimicked by diverse heterocyclic scaffolds accessible via one-step synthesis

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dc.contributor.authorMagedov I.V.
dc.contributor.authorFrolova L.
dc.contributor.authorManpadi M.
dc.contributor.authorBhoga U.D.
dc.contributor.authorTang H.
dc.contributor.authorEvdokimov N.M.
dc.contributor.authorGeorge O.
dc.contributor.authorHadje Georgiou K.
dc.contributor.authorRenner S.
dc.contributor.authorGetlik M.
dc.contributor.authorKinnibrugh T.L.
dc.contributor.authorFernandes M.A.
dc.contributor.authorVan Slambrouck S.
dc.contributor.authorSteelant W.F.A.
dc.contributor.authorShuster C.B.
dc.contributor.authorRogelj S.
dc.contributor.authorVan Otterlo W.A.L.
dc.contributor.authorKornienko A.
dc.date.accessioned2011-10-13T16:58:19Z
dc.date.available2011-10-13T16:58:19Z
dc.date.issued2011
dc.description.abstractStructural simplification of an antimitotic natural product podophyllotoxin with mimetic heterocyclic scaffolds constructed using multicomponent reactions led to the identification of compounds exhibiting low nanomolar antiproliferative and apoptosis-inducing properties. The most potent compounds were found in the dihydropyridopyrazole, dihydropyridonaphthalene, dihydropyridoindole, and dihydropyridopyrimidine scaffold series. Biochemical mechanistic studies performed with dihydropyridopyrazole compounds showed that these heterocycles inhibit in vitro tubulin polymerization and disrupt the formation of mitotic spindles in dividing cells at low nanomolar concentrations, in a manner similar to podophyllotoxin itself. Separation of a racemic dihydropyridonaphthalene into individual enantiomers demonstrated that only the optical antipode matching the absolute configuration of podophyllotoxin possessed potent anticancer activity. Computer modeling, performed using the podophyllotoxin binding site on β-tubulin, provided a theoretical understanding of these successful experimental findings. © 2011 American Chemical Society.
dc.description.versionArticle
dc.identifier.citationJournal of Medicinal Chemistry
dc.identifier.citation54
dc.identifier.citation12
dc.identifier.citationhttp://www.scopus.com/inward/record.url?eid=2-s2.0-79959480967&partnerID=40&md5=d9614c808abbad0880eaba5fd373337e
dc.identifier.issn222623
dc.identifier.other10.1021/jm200410r
dc.identifier.urihttp://hdl.handle.net/10019.1/16683
dc.subject2 hydroxy 7 (3,4,5 trimethoxyphenyl) 7,11 dihydrobenzo[h]furo[3,4 b]quinolin 8(10h) one
dc.subject4 (2 hydroxy 3 methoxyphenyl) 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one
dc.subject4 (3 bromo 4,5 dimethoxyphenyl) 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one
dc.subject4 (3 bromophenyl) 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one
dc.subject4 (3,4,5 trimethoxyphenyl) 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one
dc.subject4 (3,5 dibromo 2 hydroxyphenyl) 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one
dc.subject4 (3,5 dibromophenyl) 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one
dc.subject4 (3,5 dibromophenyl) 3 methyl 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one
dc.subject4 (4 bromo 2 thienyl) 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one
dc.subject4 (5 bromo 2 hydroxy 3 methoxyphenyl) 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one
dc.subject4 (5 bromo 2 hydroxy 3 methoxyphenyl) 3 methyl 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one
dc.subject4 (5 bromo 2 hydroxyphenyl) 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one
dc.subject4 (5 bromo 2 hydroxyphenyl) 3 methyl 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one
dc.subject4 (5 bromo 3 pyridinyl) 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one
dc.subject4 (5 bromo 3 pyridinyl) 3 methyl 1,4,7,8 tetrahydro 5h furo[3,4 b]pyrazolo[4,3 e]pyridin 5 one
dc.subject7 (3 bromo 4,5 dimethoxyphenyl) 7,11 dihydrobenzo[h]furo[3,4 b]quinolin 8(10h) one
dc.subject7 (3,4,5 trimethoxyphenyl) 7,11 dihydrobenzo[h]furo[3,4 b]quinolin 8(10h) one
dc.subject7 (3,5 dibromo 2 hydroxyphenyl) 7,11 dihydrobenzo[h]furo[3,4 b]quinolin 8(10h) one
dc.subject7 (3,5 dibromophenyl) 7,11 dihydrobenzo[h]furo[3,4 b]quinolin 8(10h) one
dc.subject7 (4 bromo 2 thienyl) 7,11 dihydrobenzo[h]furo[3,4 b] quinolin 8(10h) one
dc.subject7 (5 bromo 2 hydroxy 3 methoxyphenyl) 7,11 dihydrobenzo[h]furo[3,4 b]quinolin 8(10h) one
dc.subject7 (5 bromo 2 hydroxyphenyl) 7,11 dihydrobenzo[h]furo[3,4 b]quinolin 8(10h) one
dc.subject7 (5 bromo 3 pyridinyl) 7,11 dihydrobenzo[h]furo[3,4 b]quinolin 8(10h) one
dc.subjectantineoplastic agent
dc.subjectbeta tubulin
dc.subjectdihydropyridopyrazole derivative
dc.subjectheterocyclic compound
dc.subjectpodophyllotoxin
dc.subjecttubulin
dc.subjectunclassified drug
dc.subjectunindexed drug
dc.subjectantineoplastic activity
dc.subjectapoptosis
dc.subjectarticle
dc.subjectcell proliferation
dc.subjectdrug binding site
dc.subjectdrug synthesis
dc.subjecthuman
dc.subjecthuman cell
dc.subjectin vitro study
dc.subjectmolecular docking
dc.subjectmolecular model
dc.subjectpolymerization
dc.subjectAntineoplastic Agents
dc.subjectApoptosis
dc.subjectBinding Sites
dc.subjectComputer Simulation
dc.subjectHela Cells
dc.subjectHeterocyclic Compounds
dc.subjectHumans
dc.subjectIndoles
dc.subjectModels, Molecular
dc.subjectMolecular Mimicry
dc.subjectNaphthalenes
dc.subjectPodophyllotoxin
dc.subjectPyrazoles
dc.subjectPyridines
dc.subjectSmall Molecule Libraries
dc.subjectStereoisomerism
dc.subjectTubulin Modulators
dc.titleAnticancer properties of an important drug lead podophyllotoxin can be efficiently mimicked by diverse heterocyclic scaffolds accessible via one-step synthesis
dc.typeArticle
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