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.

11β-hydroxylase deficiency disorders

“…Ngày nay, một vài các nghiên cứu thử nghiệm liệu pháp gen (Q. Zhang et al, 2016;Gobbi et al, 2016;Martiny,Miteva 2013) điều trị bệnh TSTTBS do thiếu hụt 21-hydroxylase trên mô hình động vật đang được tiến hành như nghiên cứu chuyển gen thiếu hụt 21-hydroxylase vào chuột và chuyển gen CYP21A2 vào vector adenovirus hoặc trực tiếp vào tuyến thượng thận trên các mô hình động vật khác, nhưng chưa tiến hành thử nghiệm trên người.…”

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

“…Moreover, a series of pyridylmethyl isoxazole derivatives ( Figure 1) endowed with nanomolar inhibition potency on CYP11B1 and a better selectivity factor over aldosterone synthase with respect to metyrapone were very recently described [14]. In recent papers we reported the design and synthesis of two different series of 1imidazolylmethylxanthones (1-ImiXs), carrying different substituents either in position 4 [15] or in position 6 [16] of the central core, as potent inhibitors of CYP11B enzymes ( Figure 2). These compounds were designed on the basis of the hits retrieved from a virtual screening of our aromatase (CYP19) inhibitors library of compounds on CYP11B2, used as starting point for subsequent optimisation, taking into account the different features emerged from the pharmacophore search.…”

“…For the synthesis of the studied 6-substituted 3-ImiX 1a-i, the corresponding 3-methylxanthones 2ai were brominated with N-bromosuccinimide (NBS) and subsequently reacted with imidazole (Scheme 1). Compounds 2a [16], 2b,c,f,g [24] and 2e [25] were previously described and were synthesized according to literature procedures. 3-bromo-6-methylxanthen-9-one (2d) was obtained by reduction of the nitro group of 2a, followed by diazotization and treatment with HBr and CuBr (Scheme 2), while 3-(cyclopropylmethoxy)-6-methylxanthen-9-one (2h) and 3-methyl-6phenoxyxanthen-9-one (2i) were prepared by treating the 3-chloro derivative 2c with cyclopropylmethanol/phenol sodium salt in dioxane or dimethylformamide (DMF) (Scheme 2).…”