Anticancer Activity of Thiophene Carboxamide Derivatives as CA-4 Biomimetics: Synthesis, Biological Potency, 3D Spheroid Model, and Molecular Dynamics Simulation.

The present study aimed to synthesize thiophene carboxamide derivatives, which are considered biomimetics of the anticancer medication Combretastatin A-4 (CA-4), and compare the similarity in the polar surface area (PSA) between the novel series and CA-4. Our results showed that the PSA of the most synthesized structures was biomimetic to CA-4, and similar chemical and biological properties were observed against Hep3B cancer cell line. Among the synthesized series and compounds were the most active molecules on Hep3B (IC = 5.46 and 12.58 µM, respectively). The 3D results revealed that both and structures confuse the surface of Hep3B cancer cell lines' spheroid formation and force these cells to aggregate into a globular-shaped spheroid. The and showed a comparable interaction pattern to that observed for CA-4 and colchicine within the tubulin-colchicine-binding pocket. The thiophene ring, due to holding a high aromaticity character, participated critically in that observed interaction profile and showed additional advanced interactions over CA-4. The and tubulin complexes showed optimal dynamics trajectories within a time scale of 100 ns at 300 K temperature, which asserts their high stability and compactness. Together, these findings revealed the biomimetic role of and compounds in CA-4 in preventing cancer progression.