Synthesis and cytotoxicity evaluation of 2-Phenyl-1H-benzo[de]isoquinoline-1,3(2H)-dione derivatives as apoptosis inducers with probable anticancer effects

Abstract

Due to the resistance and exertion of severe side effects of current anticancer drugs, development of new anticancer agents is one of the main goals in medicinal chemistry. Apoptosis process is occurred in all organisms to control their cell numbers and to omit extra or damaged cells. Caspases are an enzyme family that precedes apoptosis. Activation of caspases results in irreversible apoptotic cell deat h. Naphthalimide derivatives as DNA intercalators have exhibited high anticancer activities against various cell lines. Some naphthalimides such as amonafide have demonstrated remarkable potency in clinical trials. In the current work, a new series of naphthalimide-based anticancer agents were synthesized. Then, the cytotoxic was evaluated by MTT assay in vitro . Three cancerous cell lines were utilized namely AGS (human gastric carcinoma), HT29 (colorectal cancer), PC3 (prostate cancer) and the obtained results were compared to the doxorubicin as reference drug. In order to study the structure activity relationships of the target compounds, various substituents such as Cl, F, NO 2 and -OCH 3 were introduced on the phenyl ring. Generally, electron withdrawing substituents caused better anticancer activity compared to doxorubicin. Some selected derivatives activated the caspase 3 more than control drug and also influenced on mitochondrial membrane potential (MMP) and reduced it. It means that these compounds may induce the apoptosis n via the intrinsic pathway. Production of intracellular reactive oxygen species (ROS) was also investigated and the obtained results showed that the most of the tested compounds induced the production of free radicals less than control drug. Normal 0 false false false EN-US X-NONE FA /* Style Definitions */ table.MsoNormalTable {mso-style-name:Table Normal; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin-top:0cm; mso-para-margin-right:0cm; mso-para-margin-bottom:10.0pt; mso-para-margin-left:0cm; line-height:115%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:Calibri,sans-serif; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;}