Synthesis, Cytotoxicity and Anti−Proliferative Activity Against AGS Cells of New 3(2H)−Pyridazinone Derivatives Endowed with a Piperazinyl Linker

Novel twenty−three 3(2H)−pyridazinone derivatives were designed and synthesized based on the chemical requirements related to the anti−proliferative effects previously demonstrated within this scaffold. The introduction of a piperazinyl linker between the pyridazinone nucleus and the additional (un)substituted phenyl group led to some compounds endowed with a limited cytotoxicity against human gingival fibroblasts (HGFs) and good anti−proliferative effects against gastric adenocarcinoma cells (AGS) as evaluated by MTT and LDH assays, using doxorubicin as a positive control. Successive analyses revealed that the two most promising representative compounds (12 and 22) could exert their effects by inducing oxidative stress as demonstrated by the hydrogen peroxide release and the morphological changes (cell blebbing) revealed by light microscopy analysis after the haematoxylin−eosin staining. Moreover, to further assess the apoptotic process induced by compounds 12 and 22, Bax expression was measured by flow cytometry. These findings enlarged our knowledge of the structural requirements in this scaffold to display valuable biological effects against cancerous cell lines.

Synthesis, Molecular Docking and Biological Activity Evaluation of Alkoxy Substituted Chalcone Derivatives: Potential Apoptosis Inducing Agent on MCF-7 Cells

Introduction:: In this contribution, a series of alkoxy substituted chalcone were successfully designed, synthesized, spectroscopically characterized and evaluated for their cytotoxicity potential in inhibiting the growth of MCF-7 cells. Objective:: In order to investigate the influence between electron density in conjugated π-systems and biological activities, different withdrawing substituent namely nitro (NO2), cyano (C≡N) and trifluoromethyl (CF3) were introduced in chalcone-based molecular system. Methods:: All the derivatives were then tested on MCF-7 cell line using the fluorescence microscopy-based cytotoxicity analyses. Results:: The preliminary findings showed that both –NO2 and –CF3 substituents revealed their potential to inhibit the growth of MCF-7 with IC50 values of 14.75 and 13.75 μg/ml, respectively. In addition, the morphological changes of MCF-7 cells were observed in response to alkoxy substituted chalcone treatment through an induction of apoptosis pathway with cell blebbing, phosphatidylserine exposure and autophagic activity with acidification of lysosomal structure. Intermolecular interaction based on in silico investigation on nitro, trifluoromethyl and cyano based chalcones exhibited several types of interactions with tumor necrosis factor receptor (PDB: 1EXT) protein and high hydrogen bond in the molecule-receptor interaction have given significant impact towards their toxicity on MCF-7 cells. Conclusion:: Significantly, these types of chalcones exhibited ideal and high potential to be further developed as anti-cancer agents.