New hydrazonoindolin-2-ones: Synthesis, exploration of the possible anti-proliferative mechanism of action and encapsulation into PLGA microspheres

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.

Synthesis and biological evaluation of certain hydrazonoindolin-2-one derivatives as new potent anti-proliferative agents

“…The anti-proliferative activity of the title compounds 3a-e, 5a-e, 7a-c, and 10a-l towards cancer cell lines, normal cell lines, and multidrug-resistant lung cancer NCI-H69AR cell line was determined using CellTiter-Glo TM Luminescent cell viability assay according to the previously published procedures 14,15 .…”

“…Cell cycle effects of the synthesised compounds 7b and 10e were determined adopting the reported procedures 14,15 .…”

“…Recently, our research group has paid much attention to develop many novel small molecules based on the indolin-2-one core as potent anticancer agents [14][15][16][17][18][19][20][21][22] . In 2017, we reported two studies 14,15 regarding development of hydrazonoindolin-2-onebased derivatives and evaluation of their anti-proliferative activity against A549 (lung), HT-29 (colon), and ZR-75 (breast) human cancer cell lines, beside evaluation of their pro-apoptotic activity. In the first study 14 , a series of hydrazonoindolin-2-ones were synthesized with general structure of III [3-((-benzylidene)hydrazono)indolin-2-one] (Figure 2).…”

“…In 2017, we reported two studies 14,15 regarding development of hydrazonoindolin-2-onebased derivatives and evaluation of their anti-proliferative activity against A549 (lung), HT-29 (colon), and ZR-75 (breast) human cancer cell lines, beside evaluation of their pro-apoptotic activity. In the first study 14 , a series of hydrazonoindolin-2-ones were synthesized with general structure of III [3-((-benzylidene)hydrazono)indolin-2-one] (Figure 2). The SAR study concerning compounds III suggested that incorporation of lipophilic groups, as methoxy groups, enhances the anti-proliferative activity.…”

“…Based on the aforementioned findings and in connection with our research program on the development of indolin-2-one-based anticancer candidates [14][15][16][17][18][19][20][21][22] , it was thought worthwhile to extend our investigations to probe certain hydrazonoindolin-2-ones displaying promising anti-proliferative activity. In this study, we reported the design and synthesis of different series of hydrazonoindolin-2-ones 3a-e, 5a-e, 7a-c, and 10a-l, adopting three distinctive strategies to develop such derivatives (Figure 2).…”