RESUMEN
Synthetic ion transporters have attracted tremendous attention for their therapeutic potential against various ion-transport-related diseases, including cancer. Inspired by the structure and biological activities of natural products, we synthesized a small series of squaramide and thiourea derivatives of quinine and investigated their ion transport activities. The involvement of a quinuclidine moiety for the cooperative interactions of Cl- and H+ ions with the thiourea or squaramide moiety resulted in an effectual transport of these ions across membranes. The interference of ionic equilibrium by the potent Cl- ion carrier selectively induced cancer cell death by endorsing caspase-arbitrated apoptosis. In vivo assessment of the potent ionophore showed an efficient reduction in tumor growth with negligible immunotoxicity to other organs.
Asunto(s)
Antineoplásicos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Transporte Iónico/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Quinina/análogos & derivados , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Cloruros/metabolismo , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Protones , Quinina/farmacología , Quinina/uso terapéutico , Tiourea/análogos & derivados , Tiourea/farmacología , Tiourea/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
An unusual transformation of indoles to pyrazoles via an aromatic ring-opening strategy has been developed. The salient feature of this strategy involves the C2-N1 bond opening and concomitant cyclization reaction of the C2âC3 bond of the indole moiety with the tosylhydrazone, which proceeds under transition-metal and ligand free conditions. This ring-opening functionalization of indoles provides a wide scope of differently substituted pyrazoles.