Modulation of cytochromes P450 with xanthone-based molecules: from aromatase to aldosterone synthase and steroid 11β-hydroxylase inhibition.
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.
Department of Pharmacy and Biotechnologies, University of Bologna, Via Belmeloro, 6, I-40126 Bologna, Italy. silvia.gobbi@unibo.it
Silvia
S
Gobbi
Qingzhong
Q
Hu
Matthias
M
Negri
Christina
C
Zimmer
Federica
F
Belluti
Angela
A
Rampa
Rolf W
RW
Hartmann
Alessandra
A
Bisi
D000818:Animals; D047072:Aromatase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006224:Cricetinae; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D054852:Small Molecule Libraries / Q000737:chemistry; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors*; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D044004:Xanthones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D047072:Aromatase Inhibitors; D007093:Imidazoles; D054852:Small Molecule Libraries; D044004:Xanthones; D013254:Steroid 17-alpha-Hydroxylase; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase