article · Pharmaceuticals
A new series of indoline-2-one derivatives was designed, synthesised, and evaluated as potential VEGFR-2 inhibitors for cancer treatment. Laboratory testing revealed that several derivatives exhibited potent anti-proliferative effects against breast and liver cancer cell lines, matching or outperforming the standard drug sunitinib. Among these, five compounds showed strong VEGFR-2 inhibitory actions. The most potent derivative, named 17a, successfully halted liver cancer cells at the S phase of the cell cycle and boosted overall cell death by 3.5-fold. Compound 17a also increased the expression of apoptotic markers caspase-3, caspase-9, and BAX while reducing levels of Bcl-2. Furthermore, molecular docking demonstrated strong binding within the VEGFR-2 active site, and computational profiling indicated that the compounds satisfy standard rules for drug-likeness and oral bioavailability.
VEGFR-2 plays a major role in cancer progression and tumour blood vessel growth. Identifying new molecules that block this target helps scientists discover more effective cancer therapies. The observed ability of these compounds to curb tumour cell growth, trigger natural cell death mechanisms, and satisfy standard criteria for oral drug-likeness provides useful starting points for developing targeted anticancer treatments.
This research operates at an early laboratory discovery stage. It provides chemical leads that could interest pharmaceutical companies and oncology biotechnology firms developing small-molecule therapies for liver and breast cancers. Real-world application remains distant, as the compounds have only undergone in vitro cell line testing and in silico modelling, meaning they require extensive preclinical safety, toxicity, and in vivo efficacy studies before advancing toward clinical development.
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A new series of indoline-2-one derivatives was designed and synthesized based on the essential pharmacophoric features of VEGFR-2 inhibitors. Anti-proliferative activities were assessed for all derivatives against breast (MCF-7) and liver (HepG2) cancer cell lines, using sunitinib as a reference agent. The most potent anti-proliferative derivatives were evaluated for their VEGFR-2 inhibition activity. The effects of the most potent inhibitor, 17a, on cell cycle, apoptosis, and expression of apoptotic markers (caspase-3&-9, BAX, and Bcl-2) were studied. Molecular modeling studies, such as docking simulations, physicochemical properties prediction, and pharmacokinetic profiling were performed. The results revealed that derivatives 5b, 10e, 10g, 15a, and 17a exhibited potent anticancer activities with IC50 values from 0.74–4.62 µM against MCF-7 cell line (sunitinib IC50 = 4.77 µM) and from 1.13–8.81 µM against HepG2 cell line (sunitinib IC50 = 2.23 µM). Furthermore, these compounds displayed potent VEGFR-2 inhibitory activities with IC50 values of 0.160, 0.358, 0.087, 0.180, and 0.078 µM, respectively (sunitinib IC50 = 0.139 µM). Cell cycle analysis demonstrated the ability of 17a to induce a cell cycle arrest of the HepG2 cells at the S phase and increase the total apoptosis by 3.5-fold. Moreover, 17a upregulated the expression levels of apoptotic markers caspase-3 and -9 by 6.9-fold and 3.7-fold, respectively. In addition, 17a increased the expression level of BAX by 2.7-fold while decreasing the expression level of Bcl-2 by 1.9-fold. The molecular docking simulations displayed enhanced binding interactions and similar placement as sunitinib inside the active pocket of VEGFR-2. The molecular modeling calculations showed that all the test compounds were in accordance with Lipinski and Veber rules for oral bioavailability and had promising drug-likeness behavior.
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DOI: 10.3390/ph15111416
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