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    Novel 4-((3-fluorobenzyl)oxy)benzohydrazide derivatives as promising anti-prostate cancer agents: Synthesis, characterization and in vitro & in silico biological activity studies
    (Elsevier, 2025) Çakır, Furkan; Ateşoğlu, Şeyma; Köse, Aytekin; Ghaffari-Moghaddam, Mansour; Akbaş, Fahri; Kuran, Ebru Didem; Ulusoy Güzeldemirci, Nuray; Kılınç, Namık; Tokalı, Feyzi Sinan; Şenol, Halil
    In this study, ten novel halogenated arylidenehydrazide derivatives were synthesized and characterized through 1H, 13C APT, 19F NMR, HSQC, HMBC, HRMS, and FT-IR techniques. Cytotoxic evaluations against PC3 prostate cancer and HUVEC cell lines identified compounds 8 and 14 as lead candidates, achieving IC50 values of 4.49 mu M and 4.78 mu M, respectively, with notable selectivity indexes of 12.15 and 11.78, underscoring their specificity against PC3 cells. Molecular docking studies targeting AR, VEGFR1, EGFR, and VEGFR2 suggested potential inhibitory mechanisms, with compounds 8 and 14 displaying substantial binding affinities for AR and VEGFR1. Compound 8 achieved IFD scores of -12.900 kcal/mol for AR and -10.895 kcal/mol for VEGFR1, while compound 14 recorded scores of -10.323 kcal/mol and -10.379 kcal/mol, respectively. Complementary MM-GBSA analyses revealed favorable binding energies, with compound 8 yielding Delta G values of -76.60 kcal/mol (AR) and -78.08 kcal/mol (VEGFR1) and compound 14 showing -80.67 kcal/mol (AR) and -78.61 kcal/mol (VEGFR1). MD simulations confirmed complex stability over 50 ns, indicating that compound 14 exhibited enhanced binding stability with key residues in AR and VEGFR1. ADME predictions highlighted drug-like properties, particularly for compounds 8 and 14, with high lipophilicity and favorable absorption characteristics, despite low aqueous solubility. SAR analysis emphasized the beneficial impact of halogen substitutions on potency and selectivity, establishing compounds 8 and 14 as promising candidates for further therapeutic development.
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    Synthesis and Anticancer Activity of Novel Derivatives of ?,?-Unsaturated Ketones Based on Oleanolic Acid: in Vitro and in Silico Studies against Prostate Cancer Cells
    (John Wiley and Sons Inc, 2023) Şenol, Halil; Ghaffari-Moghaddam, Mansour; Bulut, Şeyma; Akbaş, Fahri; Topçu, Gülaçtı
    Herein, new derivatives of ?,?-unsaturated ketones based on oleanolic acid (4 a–i) were designed, synthesized, characterized, and tested against human prostate cancer (PC3). According to the in vitro cytotoxic study, title compounds (4 a–i) showed significantly lower toxicity toward healthy cells (HUVEC) in comparison with the reference drug doxorubicin. The compounds with the lowest IC50 values on PC3 cell lines were 4 b (7.785 ?M), 4 c (8.869 ?M), and 4 e (8.765 ?M). The results of the ADME calculations showed that the drug-likeness parameters were within the defined ranges according to Lipinski's and Jorgensen's rules. For the most potent compounds 4 b, 4 c, and 4 e, a molecular docking analysis using the induced fit docking (IFD) protocol was performed against three protein targets (PARP, PI3K, and mTOR). Based on the IFD scores, compound 4 b had the highest calculated affinity for PARP1, while compound 4 c had higher affinities for mTOR and PI3K. The MM-GBSA calculations showed that the most potent compounds had high binding affinities and formed stable complexes with the protein targets. Finally, a 50 ns molecular dynamics simulation was performed to study the behavior of protein target complexes under in silico physiological conditions.