title: Design, synthesis, and 3D QSAR of novel potent and selective aromatase inhibitors.
abstract: The design, synthesis, and biological evaluation of a series of new aromatase inhibitors bearing an imidazole or triazole ring linked to a fluorene (A), indenodiazine (B), or coumarin scaffold (C) are reported. Properly substituted coumarin derivatives displayed the highest aromatase inhibitory potency and selectivity over 17-alpha-hydroxylase/17-20 lyase. The modeling of the aromatase inhibition data by Comparative Molecular Field Analysis (CoMFA/GOLPE 3D QSAR approach) led to the development of a PLS model with good fitting and predictive powers (n = 22, ONC = 3, r(2) = 0.949, s = 0.216, and q(2) = 0.715). The relationship between aromatase inhibition and the steric and electrostatic fields generated by the examined azole inhibitors enables a clear understanding of the nature and spatial location of the main interactions modulating the aromatase inhibitory potency.
authors.affiliation: Dipartimento Farmaco-Chimico, University of Bari, via Orabona 4, I-70125 Bari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Leonetti
authors.forename: Angelo
authors.initials: A
authors.lastname: Favia
authors.forename: Angela
authors.initials: A
authors.lastname: Rao
authors.forename: Rosaria
authors.initials: R
authors.lastname: Aliano
authors.forename: Anja
authors.initials: A
authors.lastname: Paluszcak
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001141:Aromatase / Q000737:chemistry; D047072:Aromatase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D001141:Aromatase; D013254:Steroid 17-alpha-Hydroxylase