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Yayın New 2-indolinone-indole hybrid compounds carrying a benzoyl moiety as tyrosine kinase inhibitors(Elsevier, 2025) Camcı Eren, Merve; Cinek, Tuğçe; Cihan Üstündağ, Gökçe; Özen Eroğlu, Güneş; Yıldırım, Merve; Genç Akar, Öyküm; Erol Bozkurt, Ayşe; Sancar, Serap; Öztay, Füsun; Soylu Eter, Özge; Bolkent, Şehnaz; Kuruca, SerapIn this study, new 2-indolinone-indole hybrid compounds (4a-s) carrying a benzoyl moiety were synthesized and their cytotoxic effects were examined against pancreatic (MIA-PaCa-2) and colon (HT-29 and HCT-116) cancer cells by MTT assays. Most of the tested compounds exhibited a better inhibitory activity and safety profile than the reference standard sunitinib malate against MIA-PaCa-2 and HCT-116 cancer cells. Compound 4e displayed the greatest cytotoxic effect on HCT-116 cell with an IC50 value of 0.16 µM and a remarkable selectivity profile (SI > 625). Compound 4g exhibited a selective activity against HCT-116 cancer cell (IC50 = 0.34 µM), with no activity against the other cells at the highest concentrations tested. Compound 4b demonstrated a potent inhibitory activity against MIA-PaCa-2 cell (IC50 = 0.54 µM). General tyrosine kinase inhibitor (TKI) activities and apoptotic effects were examined for compounds 4b, 4e and 4g. The tested compounds were observed to significantly reduce general TK activities in HCT-116 cell and induce apoptosis in HCT-116 and MIA-PaCa-2 cells. Lead compound 4e, the most effective general TKI, was determined to have a specific SRC kinase inhibitor effect in HCT-116 cell and the molecular modelling studies were performed to understand the potential binding mode at the ATP-binding domain of SRC kinase.Yayın Novel 1-benzyl-2-indolinone indole hybrids as tyrosine kinase inhibitors: Design, synthesis, and biological activity evaluation(Elsevier, 2026) Cihan Üstündağ, Gökçe; Cinek, Tuğçe; Sancar, Serap; Yıldırım, Merve; Genç Akar, Öyküm; Özen Eroğlu, Güneş; Erol Bozkurt, Ayşe; Öztay, Füsun; Soylu Eter, Özge; Bolkent, Şehnaz; Kuruca, Serap; Karalı, NilgünIn 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.Yayın Novel 1-benzyl-oxindole indole hybrids targeting PDGFR-β, SRC, and c-MET signaling and inducing caspase-3-dependent apoptosis in pancreatic cancer cells(Elsevier, 2026) Cinek, Tuğçe; Yıldırım, Merve; Cihan-Üstündağ, Gökçe; Genç Akar, Öyküm; Sancar, Serap; Erol-Bozkurt, Ayşe; Özen-Eroğlu, Güneş; Küçüker, Begüm; Öztay, Füsun; Kuruca, Serap; Bolkent, Şehnaz; Karalı, NilgünAs 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.Yayın The effect of radiofrequency exposure on the cytotoxic activity of sunitinib and a novel sunitinib-class compound 4, in colorectal cancer cells(MDPI Publishing, 2026) Erol Bozkurt, Ayşe; Süleymanoğlu, Mediha; Cinek, Tuğçe; Karali, Nilgün; Ballıkaya, Sedat; İyikesici, Mehmet Salih; Kuruca, SerapAchieving optimal therapeutic efficacy in colorectal cancer (CRC) remains challenging, highlighting the need for novel treatment strategies. This study evaluated whether radiofre quency (RF) hyperthermia enhances the anticancer effects of sunitinib malate and a newly synthesized tyrosine kinase (TK) inhibitor (compound 4). HCT116 CRC cells and BEAS-2B normal epithelial cells were treated with increasing concentrations of both agents in the presence or absence of RF exposure using a mobile RF device. Cell viability and death were assessed by MTT assay and flow cytometry (Annexin V/PI). RF exposure was associated with reduced viability and increased cell death in HCT116 cells (p < 0.05). Flow cytometric analysis confirmed that RF exposure may contribute to the observed reduction in viability. Notably, the findings suggest a possible beneficial contribution of RF hyperthermia to the observed cytotoxic effects, particularly near the IC50 concentration. In contrast, BEAS-2B cells maintained high viability with no significant changes (p > 0.05). These findings sug gest that RF exposure may contribute to the observed cytotoxic responses in CRC cells while exerting limited effects on non-malignant cells, suggesting a promising strategy for targeted therapy.
