title: Novel sigma binding site ligands as inhibitors of cell proliferation in breast cancer.
abstract: Sigma receptors, namely sigma1 and sigma2, have been shown to be expressed in a variety of human cell lines playing a role in cell growth. In the human breast, they are absent in normal mammary tissue but expressed in tumors, particularly in the proliferating stage. The study presented here concerns nine newly synthesized ligands for sigma receptors. The compounds are of general structure consisting of: five (1alpha/1beta-arylalkyl)quinolizidines including two thioisosteres and four spiro-[3,4-dihydro-1,2,4-benzotriazino-3,4'-(1'-substituted) piperidines]. These compounds exhibited varying degrees of affinity for sigma receptors and were able to inhibit the growth of MCF-7 and MDA-MB 231 human breast cancer cell lines, in vitro. Good to moderate binding to at receptors occurred with all tested ligands. However, affinity for sigma2 appeared more evident with compounds FN/C-2 and FN/C-4 (spiro-[3,4-dihydro-1,2,4-benzotriazino-3,4'-(1'-substituted) piperidines] derivatives). In addition, higher cytotoxic activity of FN/C-2 and FN/C-4 with IC50 values below 100 microM in MCF-7 and lower than 40 microM in MDA-MB 231 was revealed. The data from the current study show that these novel sigma receptor ligands exhibit interesting cytotoxic activity and suggest their potential for development as antitumor agents.
authors.affiliation: Laboratory of Pharmacology and Neuroscience, National Institute for Cancer Research, Largo R. Benzi 10, 16132, Genoa, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Barbieri
authors.forename: Anna
authors.initials: A
authors.lastname: Sparatore
authors.forename: Angela
authors.initials: A
authors.lastname: Alama
authors.forename: Federica
authors.initials: F
authors.lastname: Novelli
authors.forename: Cristina
authors.initials: C
authors.lastname: Bruzzo
authors.forename: Fabio
authors.initials: F
authors.lastname: Sparatore
mesh_terms: D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006131:Growth Inhibitors / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008024:Ligands; D017480:Receptors, sigma / Q000378:metabolism*
chemical_list: D006131:Growth Inhibitors; D008024:Ligands; D017480:Receptors, sigma