Novel 1-benzyl-oxindole indole hybrids targeting PDGFR-β, SRC, and c-MET signaling and inducing caspase-3-dependent apoptosis in pancreatic cancer cells

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dc.authorid0000-0001-5625-0189
dc.authorid0000-0003-0516-6010
dc.authorid0000-0002-9805-2663
dc.authorid0000-0002-7093-4744
dc.authorid0000-0003-3681-9336
dc.authorid0009-0000-1565-6203
dc.authorid0000-0002-8515-8338
dc.authorid0000-0002-1112-5162
dc.contributor.authorCinek, Tuğçe
dc.contributor.authorYıldırım, Merve
dc.contributor.authorCihan-Üstündağ, Gökçe
dc.contributor.authorGenç Akar, Öyküm
dc.contributor.authorSancar, Serap
dc.contributor.authorErol-Bozkurt, Ayşe
dc.contributor.authorÖzen-Eroğlu, Güneş
dc.contributor.authorKüçüker, Begüm
dc.contributor.authorÖztay, Füsun
dc.contributor.authorKuruca, Serap
dc.contributor.authorBolkent, Şehnaz
dc.contributor.authorKaralı, Nilgün
dc.date.accessioned2026-11-11T13:31:07Z
dc.date.available2026-11-11T13:31:07Z
dc.date.issued2026
dc.departmentFakülteler, Eczacılık Fakültesi, Eczacılık Meslek Bilimleri Bölümü, Farmasötik Kimya Ana Bilim Dalı
dc.description.abstractAs part of our ongoing efforts to develop N-benzylated oxindole derivatives as multi-target anticancer agents, novel N-benzyl oxindole indoles (4a–z) were designed, synthesized and structurally characterized. Their cytotoxic activities were evaluated against HCT-116, HT-29, A549, MIA PaCa-2, A498, CAKI-1, MDA-MB-231, and MCF-7 cancer cells, as well as Beas2b noncancerous cells. Most compounds exhibited significantly stronger cytotoxicity and selectivity than the reference drug sunitinib malate. Mechanistic studies were performed on compounds 4a, 4b, 4d, 4g, 4i, 4q, and 4y, which displayed submicromolar cytotoxic effects (IC50 = 0.27- 0.97 μM) and high selectivity indices (SI = 91.3->370.4). Among these, compounds 4a, 4b, and, 4i, which exhibited stronger cytotoxic effects than sunitinib malate, significantly induced apoptosis and markedly suppressed general tyrosine kinase (TK) activity. Compounds 4a (IC50 = 0.27 μM, SI = 167.8) and 4b (IC50 = 0.48 μM; SI = 91.2) markedly reduced PDGFR-β and SRC signaling, and inhibited ERK signaling more potently than sunitinib malate (IC50 = 4.03 μM, SI = 3.2) in MIA PaCa-2 cells. Notably, compound 4a also exhibited stronger reduction c-MET signaling than sunitinib malate, whereas compound 4b was less effective against this target. Overall, compound 4a displayed the most potent multi-target inhibitory profile and was identified as lead candidate. Molecular docking studies further supported its stable binding within the ATPbinding pockets of PDGFR-β, SRC, and c-MET kinases, consistent with its observed inhibitory activity. Further mechanistic studies demonstrated that compound 4a induces caspase-3-mediated apoptosis through a Bax/Bcl-2- independent pathway, accompanied by increased levels of cytochrome c and p53. Collectively, these findings identify compound 4a as a potent, selective, and multi-target lead candidate for further development against pancreatic cancer.
dc.identifier.citationCinek, T., Yıldırım, M., Cihan-Üstündağ, G., Genç Akar, Ö., Sancar, S., Erol-Bozkurt, A., Özen-Eroğlu, G., Küçüker, B., Öztay, F., Kuruca, S., Bolkent, Ş., & Karalı, N. (2026). Novel 1-benzyl-oxindole indole hybrids targeting PDGFR-β, SRC, and c-MET signaling and inducing caspase-3-dependent apoptosis in pancreatic cancer cells. European Journal of Medicinal Chemistry, 320, pp. 1-22. https://doi.org/10.1016/j.ejmech.2026.119328
dc.identifier.doi10.1016/j.ejmech.2026.119328
dc.identifier.endpage22
dc.identifier.issn1768-3254
dc.identifier.issn0223-5234
dc.identifier.pmidPMID: 42810192
dc.identifier.scopus2-s2.0-105051846969
dc.identifier.scopusqualityQ1
dc.identifier.startpage1
dc.identifier.urihttps://doi.org/10.1016/j.ejmech.2026.119328
dc.identifier.urihttps://hdl.handle.net/20.500.13055/1708
dc.identifier.volume320
dc.identifier.wosWOS:001894399200001
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.indekslendigikaynak.otherSCI-E - Science Citation Index Expanded
dc.institutionauthorCinek, Tuğçe
dc.institutionauthorid0000-0001-5625-0189
dc.language.isoen
dc.publisherElsevier
dc.relation.ispartofEuropean Journal of Medicinal Chemistry
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.subjectOxindole
dc.subjectTyrosine Kinase
dc.subjectPDGFR
dc.subjectc-MET
dc.subjectSRC
dc.subjectApoptosis
dc.titleNovel 1-benzyl-oxindole indole hybrids targeting PDGFR-β, SRC, and c-MET signaling and inducing caspase-3-dependent apoptosis in pancreatic cancer cells
dc.typeArticle
dspace.entity.typePublication

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