To find Δ8-Δ7 sterol isomerase (EBP) selective ligands, various arylpiperazines previously studied and structurally related to some σ receptors ligands were preliminarily screened. Consequently, a novel series of 2- or 2,6-disubstituted (CH3, CH3O, Cl, F) cis- and trans-4-(4-aryl)cyclohexyl-1-(2-pyridyl)piperazines was developed. Radioreceptor binding assays evidenced cis-19, cis-30 and cis-33 as new ligands with nanomolar affinity toward EBP site and a good selectivity relative to EBP-related σ receptors. The most selective 2,6-dimethoxy derivative (cis-33) demonstrated the highest potency (EC50 ) 12.9 μM) and efficacy (70%) in inhibiting proliferation of human prostate cancer PC-3 cell line. Among the reference compounds, σ2 agonist 36 (PB28) reached the maximum efficacy (100%), suggesting the contribution of the σ2 receptor to the antiproliferative activity. This novel class of EBP inhibitors represents a valuable tool for investigating the last steps of cholesterol biosynthesis and related pathologies, as well as a starting point for developing new anticancer drugs.
Novel 4-(-4-Aryl)cyclohexyl-1-(2-pyridyl)piperazines as delta8-delta7 sterol isomerase ( Emopamil Binding Protein) selective ligands with antiprolifative activity
BERARDI, Francesco;ABATE, CARMEN rosa;FERORELLI, Savina;LEOPOLDO, Marcello;NISO, MAURO;PERRONE, Roberto
2008-01-01
Abstract
To find Δ8-Δ7 sterol isomerase (EBP) selective ligands, various arylpiperazines previously studied and structurally related to some σ receptors ligands were preliminarily screened. Consequently, a novel series of 2- or 2,6-disubstituted (CH3, CH3O, Cl, F) cis- and trans-4-(4-aryl)cyclohexyl-1-(2-pyridyl)piperazines was developed. Radioreceptor binding assays evidenced cis-19, cis-30 and cis-33 as new ligands with nanomolar affinity toward EBP site and a good selectivity relative to EBP-related σ receptors. The most selective 2,6-dimethoxy derivative (cis-33) demonstrated the highest potency (EC50 ) 12.9 μM) and efficacy (70%) in inhibiting proliferation of human prostate cancer PC-3 cell line. Among the reference compounds, σ2 agonist 36 (PB28) reached the maximum efficacy (100%), suggesting the contribution of the σ2 receptor to the antiproliferative activity. This novel class of EBP inhibitors represents a valuable tool for investigating the last steps of cholesterol biosynthesis and related pathologies, as well as a starting point for developing new anticancer drugs.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
