Novel 4-(4-Aryl)cyclohexyl-1-(2-pyridyl)piperazines as Delta(8)-Delta(7) Sterol Isomerase (Emopamil Binding Protein) Selective Ligands with Antiproliferative Activity

摘要

To find Delta(8)-Delta(7) sterol isomerase (EBP) selective ligands, various arylpiperazines previously studied and structurally related to some a 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 a receptors. The most selective 2,6-dimethoxy derivative (cis-33) demonstrated the highest potency (EC50 = 12.9 mu M) and efficacy (70%) in inhibiting proliferation of human prostate cancer PC-3 cell line. Among the reference compounds, sigma(2) agonist 36 (PB28) reached the maximum efficacy (100%), suggesting the contribution of the sigma(2) 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 its a starting point for developing new anticancer drugs.