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Phenylalanine- and tryptophan-based hydrazone hybrids targeting the VEGF axis and caspase-mediated apoptosis: Design,
Merve Camci Eren1, Özge Sultan Zengin2, Gül Özhan2
1Istanbul University Faculty of Pharmacy, Pharmaceutical Chemistry Department, 34116 Istanbul, Türkiye.
Abstract:
Lung cancer remains a leading cause of cancer-related mortality worldwide, highlighting the urgent need for effective and selective therapeutic agents. In this study, novel phenylalanine and tryptophan-derived hydrazone hybrids (9a-h and 10a-h) against lung cancer were designed, synthesized and characterized via analytic and spectral methods (FT-IR, 1H NMR, 13C NMR APT, and LC-MS/HR-MS). Cytotoxic activities of synthesized compounds were evaluated against human non-small cell lung cancer (NSCLC) (A549 and PC9) cells and human healthy lung epithelial BEAS-2B cells. Among the hydrazone hybrids, phenylalanine derivative compound 9d exhibited the most potent and selective cytotoxic effect against NSCLC cells, with IC50 values of 15.60 μM for A549 and 22.49 μM for PC9, and high selectivity indices (SI = 76.92 and 53.36, respectively). Mechanistic studies revealed that these compounds induce apoptosis in A549 cells, with a concomitant decrease in VEGF-A levels and downregulation of VEGFR-1 and 2 expression; this indicates a direct modulation of the tumor-autonomous VEGF signaling axis. Additionally, the compounds significantly activated caspase-3/7, 8, and 9 enzymes, confirming the triggering of both intrinsic and extrinsic apoptotic pathways. Furthermore, intracellular reactive oxygen species (ROS) accumulation and mitochondrial membrane potential (MMP) depolarization were distinctly induced by compounds 10d and 10g, suggesting an additional mitochondrial stress-mediated mechanism of action within this series. Molecular docking simulations were performed to evaluate binding affinity within the VEGFR-2 active site. In vitro and in silico results identified compound 9d as a promising lead structure for further optimization of selective lung cancer therapeutics. Future studies were targeted at further optimizing drug-like properties and exploring downstream signaling kinetics.
Insights
Novel hydrazone hybrids targeting lung cancer were synthesized. Compound 9d showed potent and selective cytotoxicity against non-small cell lung cancer (NSCLC) cells by inducing apoptosis and modulating VEGF signaling.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Pharmacology
Background:
- Lung cancer is a major cause of cancer mortality globally, necessitating the development of novel therapeutic strategies.
- Existing treatments face challenges with efficacy and selectivity, driving research into new drug candidates.
Purpose of the Study:
- To design, synthesize, and evaluate novel phenylalanine and tryptophan-derived hydrazone hybrids for their potential as lung cancer therapeutics.
- To investigate the cytotoxic effects and underlying mechanisms of action of these compounds against non-small cell lung cancer (NSCLC) cell lines.
Main Methods:
- Synthesis and characterization of novel hydrazone hybrids using analytical and spectral techniques (FT-IR, NMR, LC-MS/HR-MS).
- In vitro evaluation of cytotoxic activity against NSCLC (A549, PC9) and healthy lung epithelial (BEAS-2B) cells.
- Mechanistic studies including apoptosis induction assays, VEGF-A level assessment, caspase activity analysis, ROS generation, mitochondrial membrane potential studies, and molecular docking simulations.
Main Results:
- Compound 9d, a phenylalanine derivative, demonstrated potent and selective cytotoxicity against NSCLC cells (IC50 values: 15.60 μM for A549, 22.49 μM for PC9) with high selectivity indices.
- The compounds induced apoptosis in A549 cells, decreased VEGF-A levels, and downregulated VEGFR-1/2 expression, indicating modulation of the VEGF signaling axis.
- Compounds 10d and 10g induced intracellular ROS accumulation and mitochondrial membrane potential depolarization, suggesting additional mechanisms of action.
Conclusions:
- Compound 9d is identified as a promising lead structure for developing selective lung cancer therapeutics.
- The synthesized hydrazone hybrids exhibit potential by inducing apoptosis and modulating key signaling pathways involved in lung cancer progression.
- Further optimization of drug-like properties and exploration of downstream signaling kinetics are warranted for future development.
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