RESUMEN
An expanded set of diversely substituted 1,2,4-oxadiazole-containing primary aromatic sulfonamides was synthesized and tested for inhibition of human carbonic anhydrase I, II, IX and XII isoforms. The initial biochemical profiling revealed a significantly more potent inhibition of cancer-related, membrane-bound isoform hCA IX (reaching into submicromolar range), on top of potent inhibition of hCA XII that is another cancer target. The observed structure-activity relationships have been rationalized by molecular modeling. Comparative single-concentration profiling of the carbonic anhydrase inhibitors synthesized for antiproliferative effects against normal (ARPE-19) and cancer (PANC-1) cell lines under chemically induced hypoxia conditions revealed several candidate compounds selectively targeting cancer cells. More in-depth characterization of these leads revealed two structurally related compounds that showed promising selective cytotoxicity against pancreatic cancer (PANC-1) and melanoma (SK-MEL-2) cell lines.
Asunto(s)
Anhidrasa Carbónica IX/antagonistas & inhibidores , Inhibidores de Anhidrasa Carbónica/síntesis química , Neoplasias/tratamiento farmacológico , Oxadiazoles/farmacología , Sulfonamidas/farmacología , Anhidrasas Carbónicas/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Descubrimiento de Drogas , Humanos , Hipoxia , Melanoma/tratamiento farmacológico , Melanoma/patología , Neoplasias/patología , Oxadiazoles/química , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
A series of novel aromatic primary sulfonamides decorated with diversely substituted 1,2,4-oxadiazole periphery groups has been prepared using a parallel chemistry approach. The compounds displayed a potent inhibition of cytosolic hCA II and membrane-bound hCA IX isoforms. Due to a different cellular localization of the two target enzymes, the compounds can be viewed as selective inhibition tools for either isoform, depending on the cellular permeability profile. The SAR findings revealed in this study has been well rationalized by docking simulation of the key compounds against the crystal structures of the relevant hCA isoforms.