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  • Physiology genetics and biochemistry of CYP A br


    Physiology, genetics, and leukotriene mg of CYP17A1
    Clinical presentation and diagnosis
    Acknowledgements I thank Dr. Hwei-Ming Peng for assistance with preparing Fig. 3. This work was supported by grant R01GM086596 from the National Institutes of Health.
    Introduction Prostate cancer is an age-related disease and a major cause of cancer-related mortality worldwide. It is androgen dependent in the majority of cases and can be treated with androgen ablation. Steroidal precursors are transformed to preandrogens by the 17α-hydroxylase-C17,20-lyase enzyme (P45017α), which is highly active in both testes and adrenals [1]. Inhibitors of this enzyme can block androgen synthesis in its early steps, and may be suitable for pharmacological treatment of androgen dependent disorders, among them the prostate cancer [2], [3], [4]. In the past decades a large number of compounds were developed as P45017α inhibitors [5], [6]. The most promising compounds have been designed by the ligand-base approach. These are steroidal derivatives possessing heterocycle on the C-17 position. Heterocycles containing sp2 hybrid N were demonstrated to be the most effective coordinating groups to the heme iron of the enzyme active center. The Δ16,17 double bond can significantly increase inhibitory potency [7]. Abiraterone [17-(3-pyridyl)androsta-5,16-dien-3β-ol] and Galeterone [17-(1H-benzimidazole-1-yl)androsta-5,16-dien-3β-ol] have become the most successful drug candidates of this group of compounds [8], [9]. We previously described the synthesis of series of C-17β heterocyclic steroids, and investigated their inhibitory activity against C17,20-lyase in vitro[10], [11], [12], [13], [14], [15]. As a continuation of our research program we set out to prepare 1,4-substituted-1,2,3-triazolyl derivatives in the androstane series, in which the heterocycle is attached to the steroid C-17 position. The Huisgen 1,3-dipolar cycloaddition of organic azides and terminal alkynes has been of considerable interest in recent years following the independent introduction of Cu(I) catalysis in 2002 by the research groups of Sharpless [16] and Meldal [17]. The catalyst dramatically improves both the rate and the regioselectivity of the reaction leading exclusively to 1,4-disubstituted 1,2,3-triazoles. The position and steric orientation of the azide group are determined by the synthetic method applied. The C-17 azide group is generally in the α position, because the nucleophilic exchange reaction of 17β-tosylate or mesylate by sodium azide takes place with Walden inversion [18]. Here we decided to synthesize not only the 17α-azides, but a novel series of 17β-azide epimers, as starting materials for CuAAC in order to obtain novel 1,4-disubstituted triazolyl androstane derivatives with varied terminal alkynes as reagents. We set out to obtain answers to the following questions: (1) how the CuAAC process influenced by the steric structure of the steroidal azides, and (2) how the inhibitory activity against C17,20-lyase in the C-17 epimer series differ.
    Results and discussion
    Summary P45017α is a pivotal enzyme of steroid biosynthesis. Inhibition of its C17,20-lyase activity leads to suppressed androgen production, which can be applied for antiandrogen therapies. Results on C17,20-lyase inhibitory effect of our new aryl-substituted 17-triazolyl androstenes revealed that compounds bearing a 17α-heterocyclic side chain may also have substantial affinity to this enzyme. Our results verified that extension of the C-17 side chain may improve inhibitory potential. In addition, an azido group on the steroidal C-17 atom is a suitable pharmacophore in the inhibition of the C17,20-lyase activity. The potent inhibition of the azido compound is an interesting finding worth further investigations.
    Acknowledgements The work of Anita Kiss was supported by a PhD Fellowship of the Talentum Fund of Richter Gedeon Plc. (Budapest). Financial support from the Economic Development and Innovation Operative Programme of Hungary (GINOP-2.3.2-15-2016-00038) is gratefully acknowledged. This research was supported by the Hungarian Scientific Research Fund (OTKA K109107).