Design and Synthesis of 1-(4-Bromo-2-(Pyrrolidine-1-Yl) Benzyl) Piperidine-Based Derivatives as Anti-Tubulin Agents.

Background: Piperidines are among the essential synthetic fragments for designing drugs and play a significant role in the pharmaceutical industry. The synthesis of newer derivatives by incorporating different amines paves the way for the introduction of novel drug combinations for current cancer treatments.

Method: The new combinations of 1-(4-bromo-2-(pyrrolidine-1-yl) benzyl) piperidine derivatives were synthesized by adding various amino groups. All the synthesized derivatives were characterized using NMR and LC-MS. The anti-cancer activity of all the synthesized derivatives was studied on three different cell lines, A549 (lung cancer), HCT-116 (colon cancer), and MCF-7(breast cancer), using an MTT assay. The most potent compounds, 7h and 7k were further evaluated for cell cycle and tubulin polymerization inhibitory activity. Further, in-silico analysis for the same properties was performed using molecular docking using MM/GBSA and validated by RMSD.

Results: All the synthesized derivatives showed selective cytotoxic potential against different cancer cell lines. Most of the derivatives displayed comparable anticancer potential in comparison to 5-FU. The most potent derivative, 7h, further arrests the cancer cells in the G2/M phase and prevents tubulin polymerization. The same was further confirmed using molecular docking on the colchicine binding site.

Conclusion: The derivative that arrests the cancer cells in the G2/M phase of the cell cycle and induces depolymerization can be developed as a good lead for further development.