Newly Synthesized Anticancer Purine Derivatives Inhibiting <i>p</i>-EIF4E Using Surface-Modified Lipid Nanovesicles
Reem T. Attia, Menna A. Ewida, Eman Khaled, Sherif Ashraf Fahmy, Iten M. Fawzy
Abstract
High Resolution Image Download MS PowerPoint Slide Translation of mRNA is one of the processes adopted by cancer cells to maintain survival via phosphorylated ( p )-eIF4E overexpression. Once p -eIF4E binds to the cap structure of mRNA, it advocates a nonstop translation process. In this regard, 15 new-based GMP analogs were synthesized to target eIF4E and restrain its binding to cap mRNA. The compounds were tested against three types of cancer cell lines: Caco-2, HepG-2, MCF-7, and normal kidney cells (Vero cells). Most of the compounds showed high potency against breast cancer cells (MCF-7), characterized by the highest cancer type for overexpression of p -eIF4E. Compound 4b was found to be the most active against three cell lines, colon (Caco-2), hepatic (HepG-2), and breast (MCF-7), with positive IC 50 values of 31.40, 27.15, and 21.71 μM, respectively. Then, chitosan-coated niosomes loaded with compound 4b (Cs/ 4b -NSs) were developed (as kinetically enhanced molecules) to improve the anticancer effects further. The prepared Cs/ 4b -NSs showed pronounced cytotoxicity compared to the free 4b against Caco2, Hepg2, and MCF-7 with IC 50 values of 16.15, 26.66, and 6.90 μM, respectively. Then, the expression of both the phosphorylated and nonphosphorylated western blot techniques was conducted on MCF-7 cells treated with the most active compounds (based on the obtained IC 50 values) to determine the total protein expression of both eIF4E and p -eIF4e. Interestingly, the selected most active compounds displayed 35.8–40.7% inhibition of p -eIF4E expression when evaluated on MCF-7 compared to Ribavirin (positive control). CS/ 4b -NSs showed the best inhibition (40.7%). The findings of the present joint in silico molecular docking, simulation dynamic studies, and experimental investigation suggest the potential use of niosomal nanovesicles as a promising nanocarrier for the targeted delivery of the newly synthesized compound 4b to eukaryotic initiation factor 4E. These outcomes support the possible use of Cs/ 4b -NSs in targeted cancer therapy.