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  • Küçük Resim
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    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, Serap
    In 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.
  • Küçük Resim
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    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, Nilgün
    In 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.