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  • In order to improve the methodology of

    2024-04-02

    In order to improve the methodology of the synthesis of steroidal derivatives, our goal was the investigation of aza-Michael addition of different N-nucleophiles to 16-dehydropregnenolone in the presence of [DBU][OAc] as catalyst and reaction medium. Michael addition of electron deficient steroidal alkenes, e.g. 16-dehydropregnenolone provides an efficient route for the introduction of heteroatoms into the side chain of steroids and often leads to compounds with pharmacological effect. Michael adducts of 16-dehydropregnenolone with different alcohols showed anti-oxidant and anti-dyslipidemic activity [8]. 16α-Heteroaryl-pregnenolone derivatives were found to be effective in vitro against cervical HeLa, prostate DU 205 and breast cancer MCF-7 cell lines [9]. Others are potential DPP-4 inhibitors, which can be used for the treatment of A-71623 mg type 2 [10]. The synthesis of these compounds were often effected by hetero-Michael addition using BF3·Et2O catalyst or microwave irradiation. Gould and co-workers described the synthesis of 16α-amino-substituted pregnanes using KOH as catalyst [11]. Kumar and co-workers carried out aza-Michael addition of 16-DHP mainly with aliphatic primary amines, in this case the amine served both as reactant and solvent [10]. At the same time, this method cannot be used for the addition of solid amines. During the present work, we compared this strategy with the use of a basic ionic liquid as solvent and catalyst. The enzyme 17α-hydroxylase-C17,20-lyase (P45017α) is a key regulatory enzyme in androgen biosynthesis. Inhibitors of P45017α have potential application for the treatment of androgen-dependent diseases, the steroid type compounds are similar in structure to the natural substrates of this enzyme. Highly selective inhibitors, for example abiraterone [12] and galeterone [13] contain N-heterocyclic ring at C-17. Earlier studies support that the coordination of the lone pair of nitrogen in the heterocyclic ring with the heme iron of P45017α results in tight binding. Several steroid inhibitors were developed in the last years with different modifications mainly at the C-17 side chain [14]. On the other hand, incorporation of substrates with α orientation at C-16 may also interact with the enzyme’s active site [15], so we decided to explore the C17,20-lyase inhibitory effect of some of the 16α-amino-pregnenolone derivatives obtained via the ionic liquid catalyzed aza-Michael addition.
    Experimental
    Results and discussion
    Conclusions A series of 16-dehydropregnenolone derivatives were synthesized via an ionic liquid promoted aza-Michael addition of different N-nucleophiles. A DBU based ionic liquid was found to be efficient and reusable catalyst of the conjugate addition. The Michael adducts were screened for their inhibitory effect of P45017αin vitro and 3p was the most active in this study. The X-ray structure of 3f confirmed the α-disposition of the C-16 substituent.
    Acknowledgments
    Cytochrome P-450 enzymes (CYPs), due to high homology inclusive of a common heme–iron motif, present a major challenge to the discovery of target-selective inhibitors. The potent CYP17 inhibitor, abiraterone acetate, inhibits cortisol biosynthesis and produces side-effects associated with MES at effective doses. Our metalloenzyme inhibitor design strategy, which focuses on the metal-binding group (MBG), has produced some of the most selective CYP17, and fungal CYP51A1 (lanosterol 14α-demethylase) inhibitors reported for the potential treatment of prostate cancer and fungal infections, respectively. This iterative technology approach synergistically combines the application of inorganic chemistry with classical medicinal chemistry (i.e., in silico-derived MBGs are affixed to progressable chemical scaffolds). The process is exemplified in wherein starting point is a reported potent inhibitor of rat CYP17 lyase (IC=0.029μM) and hydroxylase (IC=0.14μM) as well as the human enzyme (ICs are 0.05 and 0.22μM for lyase and hydroxylase activities, respectively). Given its potency, lyase selectivity, and physicochemical properties, imidazole was chosen as a non-steroidal starting point to more lyase-selective CYP17 inhibitors. A survey of potential alternative MBGs [e.g., less basic 4-(1,2,3-triazole)] was followed by further scaffold optimization of the naphthyl-triazolyl-butanol inhibitor series as described below.