PUB - Publikationen an der Universität Bielefeld

A series of new coumarins was synthesized via an efficient protocol-triethylamine-promoted metal-free regioselective divergent C-N bond formation and/or cascade heterocyclization reactions of 4-chloro-3-formylcoumarin, coumarin-derived phenacyl bromide, and 4-chloro-3-nitrocoumarin with primary amines. These reactions proceeded under mild conditions, and fused pyrido-/pyrimidino-/pyrrolocoumarins, aminocoumarins, and bis-coumarins were isolated in high yields without column chromatography work-up. The main SNAr reaction involves an addition-elimination mechanism, followed by a cyclization process. Molecular structural elucidation was achieved through NMR and ESI-MS analyses. The synthesized derivatives were evaluated for their in vitro cytotoxicity against four human cancer cell lines. 4-[(5-Bromopyrimidin-2-yl)amino]-2-oxo-2Hchromene-3-carbaldehyde (7) and N-{3-[(3-nitro-2-oxo-2H-chromen-4-yl)amino]-phenyl}acetamide (10a) emerged as suitable lead molecules. Compound 7 displayed pronounced cytotoxicity against Caco-2 colon cancer cells (IC50 = 8.62 +/- 0.36 mu M) and was found to induce a significant G2/M phase cell cycle arrest (24.7%) and apoptosis (37.95%) compared to the untreated control (13.3% and 0.67%, respectively). Coumarin 10a exhibited a dual mechanism of action. It demonstrated good antiangiogenic activity by inhibiting the VEGFR-2 enzyme with an IC50 of 175 +/- 9.0 nM, which correlates with its molecular docking against 4ASD, showing a binding affinity of -8.3 kcal/mol, forming a significant hydrogen bond between the NHCOCH3 fragment and the key residue Asp1046 in the VEGFR-2 active site. Additionally, compound 10a significantly suppressed the migratory ability of Caco-2 cells in a wound healing assay. These findings, together with its favorable physicochemical properties and DFT-based reactivity descriptors (high electrophilicity and polarizability), highlight coumarin 10a as a suitable lead for further optimization in antiangiogenic and anticancer drug development.