Novel 1-benzyl-2-indolinone indole hybrids as tyrosine kinase inhibitors: Design, synthesis, and biological activity evaluation

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dc.authorid0000-0003-0516-6010
dc.authorid0000-0001-5625-0189
dc.authorid0000-0002-7093-4744
dc.authorid0000-0002-5891-7167
dc.authorid0000-0002-9805-2663
dc.authorid0000-0003-4454-4651
dc.authorid0000-0002-8515-8338
dc.authorid0000-0001-8875-3522
dc.authorid0000-0002-1112-5162
dc.authorid0000-0001-7878-9994
dc.contributor.authorCihan Üstündağ, Gökçe
dc.contributor.authorCinek, Tuğçe
dc.contributor.authorSancar, Serap
dc.contributor.authorYıldırım, Merve
dc.contributor.authorGenç Akar, Öyküm
dc.contributor.authorÖzen Eroğlu, Güneş
dc.contributor.authorErol Bozkurt, Ayşe
dc.contributor.authorÖztay, Füsun
dc.contributor.authorSoylu Eter, Özge
dc.contributor.authorBolkent, Şehnaz
dc.contributor.authorKuruca, Serap
dc.contributor.authorKaralı, Nilgün
dc.date.accessioned2026-02-07T07:44:40Z
dc.date.available2026-02-07T07:44:40Z
dc.date.issued2026
dc.departmentFakülteler, Eczacılık Fakültesi, Eczacılık Meslek Bilimleri Bölümü, Farmasötik Kimya Ana Bilim Dalı
dc.description.abstractIn the present study, new 1-benzyl-2-indolinone indole hybrids (4a-s) were synthesized and their cytotoxic ef fects were determined against human breast (MCF-7 and MDA-MB 231), lung (A549), kidney (CAKI-1 and A498), colon (HT-29 and HCT-116), and pancreas (MIA PaCa-2) cancer cells by MTT assay. Some of the tested com pounds showed significantly better inhibitory effects and safety profiles than sunitinib malate against A498 and MIA PaCa-2 cells. Compound 4s showed a selective and significant cytotoxic effect on MIA PaCa-2 cells (IC50 = 0.15 μM; SI > 666.7). Compound 4b displayed significant cytotoxic effects on both A498 (IC50 = 0.87 μM; SI > 58.3) and MIA PaCa-2 (IC50 = 0.13 μM; SI = 390.0) cells. Compound 4b in A498 cells and compounds 4a-c, 4h, and 4s in MIA PaCa-2 cells significantly decreased general tyrosine kinase activity and induced apoptosis, accompanied by reduced ERK signalings. The inhibitory activities of compounds 4a–c, 4h, and 4s against SRC, PDGFR-β, and c-MET kinases were assessed in MIA PaCa-2 cells. Compounds 4a, 4b, 4h, and 4s inhibited PDGFR β, with 4h and 4s additionally targeting c-MET, while 4a, 4b, and 4h also demonstrated SRC inhibition. In this study, lead compounds 4b and 4s were identified as selective cytotoxic agents against human pancreatic car cinoma cells through induction of apoptosis and inhibition of SRC/PDGFR-β/c-MET signaling. Notably, com pounds 4b and 4s demonstrated a significantly better safety profile than sunitinib malate against noncancerous cells, underscoring their broader therapeutic potential. To understand their potential binding modes, molecular modeling studies were performed at the ATP-binding domains of SRC, PDGFR, and c-MET kinases.
dc.identifier.citationCihan Üstündağ, G., Cinek, T., Sancar, S., Yıldırım, M., Genç Akar, Ö., Özen Eroğlu, G., Erol Bozkurt, A., Öztay, F., Soylu Eter, Ö., Bolkent, Ş., Kuruca, S., & Karalı, N. (2026). Novel 1-benzyl-2-indolinone indole hybrids as tyrosine kinase inhibitors: Design, synthesis, and biological activity evaluation. European Journal of Medicinal Chemistry, 304, pp. 1-24. https://doi.org/10.1016/j.ejmech.2025.118509
dc.identifier.doi10.1016/j.ejmech.2025.118509
dc.identifier.endpage24
dc.identifier.issn0223-5234
dc.identifier.issn1768-3254
dc.identifier.pmidPMID: 41443081
dc.identifier.scopus2-s2.0-105025429201
dc.identifier.scopusqualityQ1
dc.identifier.startpage1
dc.identifier.urihttps://doi.org/10.1016/j.ejmech.2025.118509
dc.identifier.urihttps://hdl.handle.net/20.500.13055/1289
dc.identifier.volume304
dc.identifier.wosWOS:001651940200001
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.subject2-Indolinone
dc.subjectIndole
dc.subjectCytotoxicity
dc.subjectTyrosine Kinase
dc.subjectSRC
dc.subjectPDGFR
dc.subjectc-MET
dc.subjectApoptosis
dc.subjectAKT/ERK
dc.titleNovel 1-benzyl-2-indolinone indole hybrids as tyrosine kinase inhibitors: Design, synthesis, and biological activity evaluation
dc.typeArticle
dspace.entity.typePublication

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