Abstract
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.
Highlights
Cancer is one of the most formidable health burdens with increasing annual frequency worldwide [1]
The results demonstrate that the particle size of the prepared microspheres was uniform
Compounds 4a-o and 7a-e were subjected to in vitro anti-proliferative assessment against HT-29, ZR-75 and A549 human cancer cell lines
Summary
Cancer is one of the most formidable health burdens with increasing annual frequency worldwide [1]. Indoline-2,3-diones 1a-c were refluxed with 99% hydrazine hydrate in methanol to obtain the corresponding hydrazone derivatives 2a-c.The reaction of hydrazones 2a-c with different substituted benzaldehydes 3a-e in ethanol in the presence of a catalytic amount of glacial acetic acid furnished the target derivatives 4a-o with 67–83% yields (S3 File).
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