Synthesis of Substituted Cinnamido Linked Quinazolinone Congeners as Potential Anticancer Agents via Mitochondrial Dependent Intrinsic Apoptotic Pathway

Author(s):

Kesari L. Manasa, Mohd A. Saifi, Yellaiah Tangella, Chandraiah Godugu and Mallika Alvala*   Pages 1935 - 1948 ( 14 )

Abstract:

<P>Background: The synthesis of novel heterocyclic scaffolds with amide functionality is a key research area due to their plethora of medicinal applications. The present study aims to explore the synthesis of new cinnamido linked quinazolinone congeners and their potential as anticancer agents. </P><P> Methods: Cytotoxicity evaluation, Cell cycle analysis, JC-1 staining, ROS, Annexin V assays, AO/EB, DAPI nuclear staining, Colony-forming assay and Western blot analysis. </P><P> Results: Among the synthesized compounds, 5eb and 5fc have shown promising cytotoxic activity with an IC50 value of 3.89&#177;1.01&#181;M and 4.05&#177;0.62&#181;M against HeLa cell lines. The flow-cytometry analysis demonstrated that the compound 5eb arrested the sub-G1 phase of the cell cycle and induced apoptosis. Furthermore, the compound 5eb triggered the collapse of mitochondrial membrane potential (&#916;&#936;m), which was assessed by JC-1 staining and also induced the generation of Reactive Oxygen Species. An increase in the expression of proapoptotic proteins such as Bax, p53, cleaved PARP and cleaved caspase-3 by 5eb confirmed the activation of the mitochondrial-dependent intrinsic apoptosis pathway. </P><P> Conclusion: Our results suggest that compound 5eb and 5fc of cinnamido linked quinazolinone derivatives could serve as potential leads in the development of novel chemotherapeutic agents.</P>

Keywords:

Quinazolinones, cinnamic acids, cinnamides, cytotoxicity, apoptosis mechanism, cancer.

Affiliation:

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad-500037, Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad-500037, Fluoro-Agrochemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad-500037, Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad-500037

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