Discovery of Furopyrimidine-Pyrazole Hybrid Compounds Targeting p53-MDM2 Interaction as Anticancer Agents

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dc.contributor.authorMansour, Mai A.
dc.contributor.authorHassan, Ghaneya S.
dc.contributor.authorJaballah, Maiy Y.
dc.contributor.authorSerya, Rabah A. T.
dc.contributor.authorDege, Necmi
dc.contributor.authorSahin, Onur
dc.contributor.authorSharaky, Marwa
dc.date.accessioned2026-04-25T14:19:44Z
dc.date.available2026-04-25T14:19:44Z
dc.date.issued2025
dc.departmentSinop Üniversitesi
dc.description.abstractInhibiting the p53-MDM2 interaction restores the function of the tumour suppressor protein, p53, and offers a promising avenue for anticancer therapies. Herein, a novel series of pyrazoline-derived compounds was developed and synthesised to serve as potential inhibitors of the p53-MDM2 interaction. Scaffold hopping was adopted via replacing the cis-imidazoline core of Nutlin-2 with a pyrazoline core, and molecular docking confirmed the binding orientation of the designed compounds at the p53-MDM2 interaction site. The antiproliferative activities of these compounds were evaluated against the NCI60 cell lines, where compounds 6c, 6d and 9d displayed the highest inhibitory activities. Subsequently, compound 6d was selected for the five-doses NCI60 cell panel assay to afford a mean GI(50) value of 8.39 mu M. Moreover, 6d significantly reduced MDM2 expression and elevated the expression of p53 in an ELISA-based assay, yielding a biochemical IC50 value of 13.8 mu M against MDM2, which was confirmed by Western blot as well. Cytotoxicity study confirmed the selectivity of 6d towards cancerous cell lines over normal cell lines. Additionally, X-ray crystallography was used to check the stereochemistry of compound 6d. These newly identified MDM2 inhibitors represent promising candidates for the development of novel targeted anticancer agents.
dc.description.sponsorshipTianjin Municipal Science and Technology Bureau [24PTLYHZ00280]
dc.description.sponsorshipThe biological study was partially supported by a grant from the 'Belt and Road' International Joint Laboratory Project of Tianjin Municipal Science and Technology Bureau (24PTLYHZ00280 to D.K.).
dc.identifier.doi10.1002/ardp.70085
dc.identifier.issn0365-6233
dc.identifier.issn1521-4184
dc.identifier.issue9
dc.identifier.orcid0000-0002-3964-0393
dc.identifier.orcid0000-0002-0202-8272
dc.identifier.orcid0000-0003-0660-4721
dc.identifier.pmid40899411
dc.identifier.scopus2-s2.0-105015128970
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://doi.org/10.1002/ardp.70085
dc.identifier.urihttps://hdl.handle.net/11486/8128
dc.identifier.volume358
dc.identifier.wosWOS:001588611800023
dc.identifier.wosqualityQ2
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherWiley-V C H Verlag Gmbh
dc.relation.ispartofArchiv Der Pharmazie
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.snmzKA_WOS_20260420
dc.subjectanticancer activity
dc.subjectMDM2 inhibition
dc.subjectp53-MDM2 interaction
dc.subjectsynthesis
dc.subjectwild-type p53
dc.subjectX-ray diffraction
dc.titleDiscovery of Furopyrimidine-Pyrazole Hybrid Compounds Targeting p53-MDM2 Interaction as Anticancer Agents
dc.typeArticle

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