Synthesis and molecular docking of novel non-Cytotoxic, anti-Angiogenic sulfonyl coumarin derivatives against hepatocellular carcinoma cells In Vitro

Resistance to conventional cytotoxic therapeutics, emphasize the need for efforts to develop non-cytotoxic targeted molecular therapies directed against the pathways involved in the angiogenesis. In this work a new series of coumarin derivatives was synthesized starting from 2-oxo-2H-coumarin-6-sulfonyl chloride (1), 6-nitro-2-oxo-2H-coumarin-3-sulfonyl chloride (10) and 6-amino coumarin-2-one (19). The tested compounds 4, 5, 8, 12, 13 and 14 were non-cytotoxic against hepatocellular carcinoma cells (HepG2) using MMT. These non-cytotoxic compounds were evaluated as anti-angiogenic agent. Results revealed that compounds 8 and 12 exhibited MMP-independent anti-migratory activity, while compounds 4, 5, 8, 13 and 14 induced MMP-dependent anti-migratory activity against hepatocellular carcinoma. Therefore, these coumarin molecules can be utilized as lead compounds to develop potential non-toxic angiogenesis inhibitors and small molecular ligands to target (HepG2). Compound 4 considered a promising anti-angiogenic agent, where it exhibited MMP-dependent anti-migratory activity and down regulated CD105. Furthermore, the molecular docking of the tested compounds was carried out in order to investigate their binding pattern with the prospective target, MMP-2 (PDB-code: 1HOV). The docking results indicate that all tested compounds exhibited better docking score and good fitting inside the active side of MMP-2 (PDB-code: 1HOV) which was in concomitant with biological results.