Drifting of heme-coordinating group in imidazolylmethylxanthones leading to improved selective inhibition of CYP11B1.

2.50
Hdl Handle:
http://hdl.handle.net/10033/621089
Title:
Drifting of heme-coordinating group in imidazolylmethylxanthones leading to improved selective inhibition of CYP11B1.
Authors:
Gobbi, Silvia; Hu, Qingzhong; Zimmer, Christina; Belluti, Federica; Rampa, Angela; Hartmann, Rolf W. ( 0000-0002-5871-5231 ) ; Bisi, Alessandra
Abstract:
An abnormal increase in glucocorticoid levels is responsible for pathological disorders affecting different organs and systems, and the selective inhibition of appropriate steroidogenic enzymes represents a validated strategy to restore their physiological levels. In continuing our studies on CYP11B inhibitors, in this paper a small series of 6-substituted 3-imidazolylmethylxanthones was designed and synthesized, according to the data acquired from previously reported series of derivatives and from a purposely-performed docking study. The new compounds proved to be potent inhibitors of CYP11B isoforms, being effective on CYP11B1 in the low nanomolar range and improving selectivity with respect to CYP11B2, compared to previously reported related compounds. These data further confirmed that a suitable mutual arrangement of the imidazolylmethyl pharmacophore and a properly selected substituent on the xanthone core allows a fine tuning of the activity towards the different CYPs and further corroborate the role of the xanthone scaffold as a privileged structure in this field.
Affiliation:
HIPS, Helmholtz Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
Citation:
Drifting of heme-coordinating group in imidazolylmethylxanthones leading to improved selective inhibition of CYP11B1. 2017, 139:60-67 Eur J Med Chem
Journal:
European journal of medicinal chemistry
Issue Date:
2-Aug-2017
URI:
http://hdl.handle.net/10033/621089
DOI:
10.1016/j.ejmech.2017.07.078
PubMed ID:
28797884
Type:
Article
Language:
en
ISSN:
1768-3254
Appears in Collections:
publications of the department drug design and optimization (HIPS]DDOP)

Full metadata record

DC FieldValue Language
dc.contributor.authorGobbi, Silviaen
dc.contributor.authorHu, Qingzhongen
dc.contributor.authorZimmer, Christinaen
dc.contributor.authorBelluti, Federicaen
dc.contributor.authorRampa, Angelaen
dc.contributor.authorHartmann, Rolf W.en
dc.contributor.authorBisi, Alessandraen
dc.date.accessioned2017-09-04T13:33:12Z-
dc.date.available2017-09-04T13:33:12Z-
dc.date.issued2017-08-02-
dc.identifier.citationDrifting of heme-coordinating group in imidazolylmethylxanthones leading to improved selective inhibition of CYP11B1. 2017, 139:60-67 Eur J Med Chemen
dc.identifier.issn1768-3254-
dc.identifier.pmid28797884-
dc.identifier.doi10.1016/j.ejmech.2017.07.078-
dc.identifier.urihttp://hdl.handle.net/10033/621089-
dc.description.abstractAn abnormal increase in glucocorticoid levels is responsible for pathological disorders affecting different organs and systems, and the selective inhibition of appropriate steroidogenic enzymes represents a validated strategy to restore their physiological levels. In continuing our studies on CYP11B inhibitors, in this paper a small series of 6-substituted 3-imidazolylmethylxanthones was designed and synthesized, according to the data acquired from previously reported series of derivatives and from a purposely-performed docking study. The new compounds proved to be potent inhibitors of CYP11B isoforms, being effective on CYP11B1 in the low nanomolar range and improving selectivity with respect to CYP11B2, compared to previously reported related compounds. These data further confirmed that a suitable mutual arrangement of the imidazolylmethyl pharmacophore and a properly selected substituent on the xanthone core allows a fine tuning of the activity towards the different CYPs and further corroborate the role of the xanthone scaffold as a privileged structure in this field.en
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleDrifting of heme-coordinating group in imidazolylmethylxanthones leading to improved selective inhibition of CYP11B1.en
dc.typeArticleen
dc.contributor.departmentHIPS, Helmholtz Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.en
dc.identifier.journalEuropean journal of medicinal chemistryen

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