RESUMEN
We report a practical two-step approach involving a Ugi 4-CR/ azide-alkyne cycloaddition for the synthesis of biaryl-containing cyclophanes. The series represents an extension of our previously reported macrocycles as an effort to enhance the anti-proliferative activity of this scaffold. In this variant, we incorporate a biphenyl moiety in the framework, thus enhancing the macrocycle size, lipophilicity, and structural diversity. Macrocycles were tested against different cell lines, being more cytotoxic against prostate (PC-3 and DU-145) and breast (MCF-7) tumor cells. Gratifyingly, the most active compound showed a significative enhancement of PC-3 growth inhibition with respect to our previous series, reaffirming the potential anti-proliferative activity of this kind of cyclophanes.
Asunto(s)
Antineoplásicos/síntesis química , Éteres Cíclicos/síntesis química , Piperidinas/síntesis química , Triazoles/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Compuestos de Bifenilo/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Reacción de Cicloadición , Ensayos de Selección de Medicamentos Antitumorales , Éteres Cíclicos/farmacología , Humanos , Piperidinas/farmacología , Relación Estructura-ActividadRESUMEN
Synthesis of biaryl-containing macrocycles has been carried out through a four-step approach comprising two Ugi four component reactions and a Suzuki-Miyaura macrocyclization. This protocol allowed the synthesis of 12- and 14-membered macrocycles. Cytotoxic activity evaluation showed that some of the molecules were effective against leukemia, glioblastoma and lung cancer cell lines (IC50 = 4.0, 5.9 and 7.6, respectively).