Modulation of Cytochromes P450 with Xanthone-Based Molecules: From Aromatase to Aldosterone Synthase and Steroid 11β-Hydroxylase Inhibition
| Autor: | Christina Zimmer, Alessandra Bisi, Rolf W. Hartmann, Qingzhong Hu, Silvia Gobbi, Matthias Negri, Federica Belluti, Angela Rampa |
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| Přispěvatelé: | Silvia Gobbi, Qingzhong Hu, Matthias Negri, Christina Zimmer, Federica Belluti, Angela Rampa, Rolf W. Hartmann, Alessandra Bisi |
| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular Aldosterone synthase Stereochemistry Xanthones medicine.medical_treatment Aldosterone Synthase Steroid Small Molecule Libraries Structure-Activity Relationship chemistry.chemical_compound Cricetinae Drug Discovery Xanthone medicine Animals Cytochrome P-450 CYP11B2 Humans Structure–activity relationship Aromatase Virtual screening Aldosterone biology Aromatase Inhibitors Chemistry Imidazoles Steroid 17-alpha-Hydroxylase Fibroblasts Biochemistry biology.protein Steroid 11-beta-Hydroxylase Molecular Medicine Pharmacophore Cytochromes P450 |
| Zdroj: | Journal of Medicinal Chemistry. 56:1723-1729 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm301844q |
| Popis: | Imidazolylmethylflavones previously reported by us as aromatase inhibitors proved to be able to interact with aldosterone synthase (CYP11B2), a cytochrome P450 enzyme involved in the biosynthesis of the mineralcorticoid hormone aldosterone, and were used to obtain a pharmacophore model for this enzyme. Here, in the search for potential ligands for CYP11B2 and the related CYP11B1, a virtual screening of a small compounds library of our earlier synthesized aromatase inhibitors was performed and, according to the results and the corresponding biological data, led to the design and synthesis of a series of xanthones derivatives carrying an imidazolylmethyl substituent in position 1 and different substituents in position 4. Some very potent inhibitors were obtained; in particular, the 4-chlorine derivative was active in the low nanomolar or subnanomolar range on CYP11B2 and CYP11B1, respectively, proving that xanthone can be considered as an excellent scaffold, whose activity can be directed to different targets when appropriately functionalized. |
| Databáze: | OpenAIRE |
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