title: Design, synthesis, and structure-activity relationships of azolylmethylpyrroloquinolines as nonsteroidal aromatase inhibitors.
abstract: A small library of both [2,3-h] and [3,2-f] novel pyrroloquinolines equipped with an azolylmethyl group was designed and synthesized as nonsteroidal CYP19 aromatase inhibitors. The results showed that azolylmethyl derivatives 11, 13, 14, 21, and 22 exhibited an inhibitory potency on aromatase comparable to that of letrozole chosen as a reference compound. When assayed on CYP11B1 (steroid-11β-hydroxylase) and CYP17 (17α-hydroxy/17,20-lyase), compound 22 was found to be the best and most selective CYP19 inhibitor of them all. In a panel of nine human cancer cell lines, all compounds were either slightly cytotoxic or not at all. Docking simulations were carried out to inspect crucial enzyme/inhibitor interactions such as hydrophobic interactions, hydrogen bonding, and heme iron coordination. This study, along with the prediction of the pharmacokinetics of compounds 11, 13, 14, 21, and 22, demonstrates that the pyrroloquinoline scaffold represents a starting point for the development of new pyrroloquinoline-based aromatase inhibitors.
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova , 35131 Padova, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Ferlin
authors.forename: Davide
authors.initials: D
authors.lastname: Carta
authors.forename: Roberta
authors.initials: R
authors.lastname: Bortolozzi
authors.forename: Razieh
authors.initials: R
authors.lastname: Ghodsi
authors.forename: Adele
authors.initials: A
authors.lastname: Chimento
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Pezzi
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
authors.forename: Nina
authors.initials: N
authors.lastname: Hanke
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.forename: Giampietro
authors.initials: G
authors.lastname: Viola
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047072:Aromatase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001393:Azoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004967:Estrogens / Q000494:pharmacology; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D001393:Azoles; D004967:Estrogens; D011758:Pyrroles; D011804:Quinolines; D013254:Steroid 17-alpha-Hydroxylase; D013252:Steroid 11-beta-Hydroxylase