E-pharmacophore guided discovery of pyrazolo[1,5-c]quinazolines as dual inhibitors of topoisomerase-I and histone deacetylase

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dc.contributor.authorJoshi G.
dc.contributor.authorKalra S.
dc.contributor.authorYadav U.P.
dc.contributor.authorSharma P.
dc.contributor.authorSingh P.K.
dc.contributor.authorAmrutkar S.
dc.contributor.authorAnsari A.J.
dc.contributor.authorKumar S.
dc.contributor.authorSharon A.
dc.contributor.authorSharma S.
dc.contributor.authorSawant D.M.
dc.contributor.authorBanerjee U.C.
dc.contributor.authorSingh S.
dc.contributor.authorKumar R.
dc.date.accessioned2020-02-18T10:06:33Z
dc.date.accessioned2024-08-13T12:05:03Z
dc.date.available2020-02-18T10:06:33Z
dc.date.available2024-08-13T12:05:03Z
dc.date.issued2020
dc.description.abstractIn the quest to ameliorate the camptothecin (CPT) downsides, we expedite to search for stable non-CPT analogues among 11 motifs of pyrazoloquinazolines reported. E-pharmacophore drug design approach helped filtering out pyrazolo[1,5-c]quinazolines as Topoisomerase I (TopoI) 'interfacial' inhibitors. Three compounds, 3c, 3e, and 3l were shown to be potent non-intercalating inhibitors of TopoI specifically and showed cancer cell-specific cytotoxicity in lung, breast and colon cancer cell lines. The compounds induced cell cycle arrest at S-phase, mitochondrial cell death pathway and modulated oxidative stress in cancer cells. Furthermore, a preliminary study was conducted to explore the feasibility of these compounds to be developed as dual TopoI-HDAC1 (histone deacetylase 1) inhibitors (4a) to combat resistance. Compound 4a was found to possess dual inhibitory capabilities in-vitro. Cytotoxic potential of 4a was found to be significantly higher than parent compound in 2D as well as 3D cancer cell models. Probable binding modes of 4a with TopoI and HDAC1 active sites were examined by molecular modelling.en_US
dc.identifier.doi10.1016/j.bioorg.2019.103409
dc.identifier.issn452068
dc.identifier.urihttp://10.2.3.109/handle/32116/2618
dc.identifier.urlhttps://www.sciencedirect.com/science/article/pii/S0045206819313203
dc.language.isoenen_US
dc.publisherAcademic Press Inc.en_US
dc.subject3D Cultureen_US
dc.subjectDual inhibitorsen_US
dc.subjectE-pharmacophoreen_US
dc.subjectHistone deacetylasesen_US
dc.subjectPyrazolo[1,5-c]quinazolinesen_US
dc.subjectTopoisomerase inhibitorsen_US
dc.titleE-pharmacophore guided discovery of pyrazolo[1,5-c]quinazolines as dual inhibitors of topoisomerase-I and histone deacetylaseen_US
dc.title.journalBioorganic Chemistryen_US
dc.typeArticleen_US
dc.type.accesstypeOpen Accessen_US

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