article · PLoS ONE
New chemical compounds based on isatin, known as hydrazonoindolin-2-ones, were synthesised and evaluated for their ability to suppress cancer cell growth. When tested against human colon, breast, and lung cancer cell lines, several variants demonstrated stronger anti-proliferative effects than the established reference drug sunitinib. The most potent molecule, designated compound 7e, was shown to induce cell death mechanisms by increasing caspase 3 and 7 activity, altering the cell division cycle, and raising phosphorylated tyrosine levels. To improve delivery, compound 7e was encapsulated into biodegradable polymer microspheres with high loading efficiency. These microspheres exhibited a continuous, zero-order release of the compound over 21 days in laboratory tests. Furthermore, microencapsulation improved anti-proliferative potency against lung cancer cells compared to the unformulated compound.
Developing new cancer therapies relies on identifying compounds that effectively halt tumour growth while ensuring they can be delivered steadily over extended periods. Showing that novel synthetic molecules outperform existing therapeutics in laboratory models, while being compatible with sustained-release carrier systems, provides a valuable foundation for designing longer-acting and more potent anticancer formulations.
This work could interest pharmaceutical companies and drug delivery developers seeking early-stage oncology candidates and sustained-release microformulations. As an early-stage study tested only in cultured cancer cell lines and laboratory release assays, the technology remains distant from real-world application, requiring comprehensive in vivo pharmacokinetic, efficacy, and safety studies before advancing toward clinical development.
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The synthesis and molecular characterization of new isatin-based hydrazonoindolin-2-ones 4a-o and 7a-e are reported. The in vitro anti-proliferative potential of the synthesized compounds 4a-o and 7a-e was examined against HT-29 (colon), ZR-75 (breast) and A549 (lung) human cancer cell lines. Compounds 7b, 7d and 7e were the most active congeners against the tested human cancer cell lines with average IC50 values of 4.77, 3.39 and 2.37 μM, respectively, as compared with the reference isatin-based drug, sunitinib, which exhibited an average IC50 value of 8.11 μM. Compound 7e was selected for further pharmacological evaluation in order to gain insight into its possible mechanism of action. It increased caspase 3/7 activity by 2.4- and 1.85-fold between 4 and 8 h of treatment, respectively, at 10 μM and it caused a decrease in the percentage of cells in the G1 phase of the cell cycle with a corresponding increase in the S-phase. In addition, compound 7e increased phosphorylated tyrosine (p-Tyr) levels nearly two-fold with an apparent IC50 value of 3.8 μM. The 7e-loaded PLGA microspheres were prepared using a modified emulsion-solvent diffusion method. The average encapsulation efficiency of the 7e-loaded PLGA microspheres was 85% ± 1.3. While, the in vitro release profile of the 7e-loaded microspheres was characterized by slow and continuous release of compound 7e during 21 days and the release curve was fitted to zero order kinetics. Incorporation of 7e into PLGA microspheres improved its in vitro anti-proliferative activity toward the human cancer cell line A549 after 120 h incubation period with an IC50 value less than 0.8 μM.
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DOI: 10.1371/journal.pone.0181241
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