title: Novel 4-(4-aryl)cyclohexyl-1-(2-pyridyl)piperazines as Delta(8)-Delta(7) sterol isomerase (emopamil binding protein) selective ligands with antiproliferative activity.
abstract: To find Delta(8)-Delta(7) sterol isomerase (EBP) selective ligands, various arylpiperazines previously studied and structurally related to some sigma receptors ligands were preliminarily screened. Consequently, a novel series of 2- or 2,6-disubstituted (CH(3), CH(3)O, 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 sigma receptors. The most selective 2,6-dimethoxy derivative (cis-33) demonstrated the highest potency (EC(50) = 12.9 microM) 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 as a starting point for developing new anticancer drugs.
authors.affiliation: Dipartimento Farmacochimico, Universita degli Studi di Bari, Via Orabona, 4, I-70125 Bari, Italy. berardi@farmchim.uniba.it
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardi
authors.forename: Carmen
authors.initials: C
authors.lastname: Abate
authors.forename: Savina
authors.initials: S
authors.lastname: Ferorelli
authors.forename: Anna F
authors.initials: AF
authors.lastname: de Robertis
authors.forename: Marcello
authors.initials: M
authors.lastname: Leopoldo
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Colabufo
authors.forename: Mauro
authors.initials: M
authors.lastname: Niso
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013251:Steroid Isomerases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D010879:Piperazines; D011725:Pyridines; D013251:Steroid Isomerases; C022669:delta(8)-delta(7)-sterol isomerase