title: Exploring new chemical functionalities to improve aromatase inhibition of steroids.
abstract: In this work, new potent steroidal aromatase inhibitors both in microsomes and in breast cancer cells have been found. The synthesis of the 3,4-(ethylenedioxy)androsta-3,5-dien-17-one (12), a new steroid containing a heterocycle dioxene fused in the A-ring, led to the discovery of a new reaction for which a mechanism is proposed. New structure-activity relationships were established. Some 5β-steroids, such as compound 4β,5β-epoxyandrostan-17-one (9), showed aromatase inhibitory activity, because they adopt a similar A-ring conformation as those of androstenedione, the natural substrate of aromatase. Moreover, new chemical features to increase planarity were disclosed, specifically the 3α,4α-cyclopropane ring, as in 3α,4α-methylen-5α-androstan-17-one (5) (IC50=0.11μM), and the Δ(9-11) double bond in the C-ring, as in androsta-4,9(11)-diene-3,17-dione (13) (IC50=0.25μM). In addition, induced-fit docking (IFD) simulations and site of metabolism (SoM) predictions helped to explain the recognition of new potent steroidal aromatase inhibitors within the enzyme. These insights can be valuable tools for the understanding of the molecular recognition process by the aromatase and for the future design of new steroidal inhibitors.
authors.affiliation: Pharmaceutical Chemistry Group, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal.
authors.forename: Carla L
authors.initials: CL
authors.lastname: Varela
authors.affiliation: UCIBIO.REQUIMTE, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
authors.forename: Cristina
authors.initials: C
authors.lastname: Amaral
authors.affiliation: UCIBIO.REQUIMTE, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
authors.forename: Georgina
authors.initials: G
authors.lastname: Correia-da-Silva
authors.affiliation: Pharmaceutical Chemistry Group, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal.
authors.forename: Saul C
authors.initials: SC
authors.lastname: Costa
authors.affiliation: CNC.IBILI, Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, Portugal.
authors.forename: Rui A
authors.initials: RA
authors.lastname: Carvalho
authors.affiliation: Laboratorio di Chimica Farmaceutica, Dipartimento di Scienze della Salute, Università Magna Græcia di Catanzaro, Viale Europa, 88100 Catanzaro, Italy.
authors.forename: Giosuè
authors.initials: G
authors.lastname: Costa
authors.affiliation: Laboratorio di Chimica Farmaceutica, Dipartimento di Scienze della Salute, Università Magna Græcia di Catanzaro, Viale Europa, 88100 Catanzaro, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.affiliation: UCIBIO.REQUIMTE, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
authors.forename: Natércia A A
authors.initials: NA
authors.lastname: Teixeira
authors.affiliation: Pharmaceutical Chemistry Group, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal; CNC.IBILI, University of Coimbra, Portugal. Electronic address: etavares@ff.uc.pt.
authors.forename: Elisiário J
authors.initials: EJ
authors.lastname: Tavares-da-Silva
authors.affiliation: Pharmaceutical Chemistry Group, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal; CNC.IBILI, University of Coimbra, Portugal. Electronic address: froleira@ff.uc.pt.
authors.forename: Fernanda M F
authors.initials: FM
authors.lastname: Roleira
mesh_terms: D000731:Androstanes / Q000737:chemistry* / Q000494:pharmacology*; D000735:Androstenedione / Q000737:chemistry* / Q000494:pharmacology*; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000201:enzymology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D062105:Molecular Docking Simulation; D013256:Steroids / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000731:Androstanes; D047072:Aromatase Inhibitors; D013256:Steroids; D000735:Androstenedione; C018454:androstan-17-one; D001141:Aromatase
keywords: Aromatase inhibitors; Induced-fit docking; Molecular modeling; Steroids; Structure–activity relationships; Synthesis