Hybridization Approach Applied to Umbelliferon and Vanilloids toward New Inhibitors of Carbonic Anhydrases IX and XII with In Vitro Antiproliferative and Anti-inflammatory Activities

High Resolution Image Download MS PowerPoint Slide Human carbonic anhydrases (hCAs) IX and XII have emerged as promising therapeutic targets and are overexpressed in hypoxic tumors. Leveraging the chemotype of umbelliferon ( UMB ), as a selective hCAs IX and XII inhibitor, we designed and synthesized several hybrids ( 7 – 33 ) connecting UMB natural scaffold with vanilloids by using methylene spacers or triazole linkers. These hybrids demonstrated nanomolar inhibitory activity against the tumor-associated hCAs IX and XII. Molecular modeling and dynamics simulations revealed stable hydrogen bonding and hydrophobic interactions. In vitro evaluation of human bronchial epithelial (BEAS-2B) and lung adenocarcinoma (A549) cell lines showed selective cytotoxicity against cancer cells. Selected compounds induced G1 cell cycle arrest, reduced expression of the metastasis-associated markers CD9 and epithelial cell adhesion molecule, and exhibited cytoprotective and anti-inflammatory effects in BEAS-2B cells. Collectively, these findings identify UMB -vanilloid hybrids as promising candidates for the development of novel therapeutics for nonsmall cell lung cancer.