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

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.