Design, Synthesis, Biological Evaluation, Molecular Docking, and Molecular Dynamics Simulation Studies of Fmoc-L-Lysine Carboxamides as Promising Cytotoxic Agents

Background Despite advancements in treatment modalities, the search for new cytotoxic agents remains vital in the fight against cancer. This ongoing effort aims to introduce novel molecules that serve as potent cytotoxic agents while minimizing adverse effects.Objective The objective of the study is to design, synthesize, and evaluate Fmoc-L-Lysine Carboxamides for cytotoxic activities.Methods The title compounds 4a-l were synthesized by esterification followed by reduction of Fmoc-Lys (Boc)-OH to alcohol, then coupled with various aryl/alkyl/alicyclic carboxylic acids. These compounds were then analysed using 13C NMR, 1H NMR, FT-IR, and Mass spectroscopic techniques and evaluated for cytotoxic activity by MTT assay, apoptosis induction, cell cycle analysis, EGFR-TK inhibition activity, molecular docking, and molecular dynamics simulation studies.Results The results obtained by MTT assay indicated that compounds 4f and 4i demonstrated significant cytotoxicity against A549 and SKOV3 cell lines, with IC50 values of 2.75 and 1.91 mu M compared to doxorubicin. Further, the analysis of the Cell cycle and apoptosis proposed that 4f arrested the cell cycle in the G0/G1 phase, whereas 4i arrested the cell cycle in the G2/M phase and triggered apoptosis in cancer cells. Notably, compound 4i demonstrated the highest inhibition of EGFR with IC50, 0.189 mu M, and acted as its potential inhibitor. Molecular docking and dynamics simulation studies further confirmed the stability of 4i in the active site of EGFR.Conclusion Overall, these results suggested that the synthesized derivatives offer a promising approach for the advancement of new and effective cancer therapies.