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 2b and 2e compounds were the most active molecules on Hep3B (IC(50) = 5.46 and 12.58 µM, respectively). The 3D results revealed that both 2b and 2e structures confuse the surface of Hep3B cancer cell lines’ spheroid formation and force these cells to aggregate into a globular-shaped spheroid. The 2b and 2e 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 2b and 2e 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 2b and 2e compounds in CA-4 in preventing cancer progression.