title: Targeting Steroidogenic Cytochromes P450 (CYPs) with 6-Substituted 1-Imidazolylmethylxanthones.
abstract: Abnormally high corticosteroid levels are responsible for the onset of serious hormone-related diseases, and the inhibition of their biosynthesis by targeting cytochrome P450 (CYP) isoforms CYP11B1 and CYP11B2 has emerged as a promising strategy to restore healthy physiological levels of corticosteroids. With the aim of exploiting the xanthone scaffold as a privileged structure in medicinal chemistry and to further explore the chemical space of inhibitors of these CYPs, a small library of imidazolylmethylxanthones was designed based on the results of a previously described compound series. Assuming the capacity for an additional interaction with these enzymes, a properly selected substituent was introduced at position 6 of the xanthone core, maintaining the key imidazolylmethyl moiety at position 1. The 6-fluoro and 6-nitro derivatives [1-(1H-imidazol-1-yl)methyl-6-fluoro-9H-xanthen-9-one (1 a) and 1-(1H-imidazol-1-yl)methyl-6-nitro-9H-xanthen-9-one (1 d), respectively] proved to be active in the low nanomolar range, showing selectivity toward the related steroidogenic enzymes CYP19 and CYP17, even if the problem of selectivity between the two CYP11B isoforms remains unsolved. On the other hand, the 6-chloro derivative 1-(1H-imidazol-1-yl)methyl-6-chloro-9H-xanthen-9-one (1 b) was found to be a fairly potent and somewhat selective CYP19 inhibitor, confirming the versatility of the scaffold.
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy. silvia.gobbi@unibo.it.
authors.forename: Silvia
authors.identifier: 0000-0001-9044-5377
authors.initials: S
authors.lastname: Gobbi
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University & Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Universitätscampus E8 1, 66123, Saarbrücken, Germany.|Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University & Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Universitätscampus E8 1, 66123, Saarbrücken, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Zimmer
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Belluti
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Rampa
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University & Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Universitätscampus E8 1, 66123, Saarbrücken, Germany.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy. alessandra.bisi@unibo.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bisi
mesh_terms: D000305:Adrenal Cortex Hormones / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014966:Xanthenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000305:Adrenal Cortex Hormones; D007093:Imidazoles; D014966:Xanthenes; D003577:Cytochrome P-450 Enzyme System
keywords: 11-β-hydroxylase; aldosterone synthase; aromatase; cytochromes P450; oxygen heterocycles