20, 21‐Azirdin‐Steroide: Reaktion von Derivaten der Oxime von 5‐Pregnen‐20‐on,9β,10α‐5‐Pregnen‐20‐on und 9β,10α‐5,7‐Pregnadien‐20‐on mit Lithiumaluminiumhydrid und von 3β‐Hydroxy‐5‐pregnen‐20‐on‐oxim mit Grignard‐Verbindungen
Abstract:20,21-Aziridine Steroids: Reaction of Derivatives of the Oximes of 5-Pregnen-
20-one, 9 /3,10a-5-Pregnen-20-one and 9 /3,lOa-5,7-Pregnadiene-2O-one with Lithium Aluminium Hydride, and of 3 /3-Hydroxy-5-pregnen-ZO-one Oxime with GrignardReagents. -Suwznzary. Reduction of 3P-hydroxy-5-pregnen-20-one oximc (2) with LiAlH4 in tctrahydrofuran yielded 20P-amino-5-pregnen-3p-01 (I), 20u-amino-5-pregncn-3~-01 (3), ZOP, 21imino-5-pregnen-3p-01 (6) and 20a, 21-imino-5-pregnen-3j?-ol (9). The aziridines 6 and 9 were sepa… Show more
“…The stereochemistry at C20 was assigned and the presence of the 17α-OH group was confirmed by comparison of the 1 H and 13 C NMR data with those of 2 and 3 . In the case of the 20 S compounds, the 18-methyl singlet is shifted to higher field compared to the corresponding 20 R diastereomers. , In the case of the 1:1 diastereomeric mixture 8 separation of the isomers was not possible. 1 …”
Section: Chemistrymentioning
confidence: 98%
“…Starting from the corresponding oximes (Scheme ), the aziridines 4 − 8 were obtained via the same method as described for 2 and 3 . For all compounds, a 1:1 diastereomeric mixture (20 R :20 S ) was obtained, which was separated for 4 − 7 by FCC (flash column chromatography) and HPLC.…”
In the search for potent inhibitors of P450 17, the key enzyme in androgen biosynthesis, a series of steroidal inhibitors were synthesized and tested toward rat and human P450 17. Small aliphatic heterocycles (aziridine, oxirane, thiirane, diaziridine, diazirine, azetidine) were introduced into the 17beta-position of anstrost-5-en-3beta-ol. After identifying that aziridine is the most suitable functional group to coordinate with the heme iron, modifications of the steroidal skeleton were performed for further optimization. A wide range of inhibitory potencies toward P450 17 were found for the 21 test compounds. The most potent inhibitors toward the human and rat enzyme were aziridine compounds 3 (IC(50) rat: 0.21 microM, K(i) = 3 nM; IC(50) human: 0.54 microM, K(i) = 8 nM), 5 (IC(50) rat: 0.43 microM, K(i) = 7 nM; IC(50) human: 0.29 microM, K(i) = 4 nM), and 8 (21R:21S = 1:1; IC(50) rat: 0.53 microM, K(i) = 9 nM; IC(50) human: 0.40 microM, K(i) = 6 nM) which were more potent than the reference ketoconazole (IC(50) rat: 67 microM; IC(50) human: 0.74 microM). The inhibitory potency depends markedly on the stereochemistry at C20 of the inhibitors. This effect is more pronounced for the rat enzyme. Tested for selectivity, the highly potent inhibitors show poor inhibitory activity toward P450 arom, P450 scc, P450 TxA(2), and 5alpha-reductase. Tested for in vivo activity, 3 and 8 (0.019 mmol/kg) decreased the plasma testosterone concentration in rats by 81% and 84% after 2 h.
“…The stereochemistry at C20 was assigned and the presence of the 17α-OH group was confirmed by comparison of the 1 H and 13 C NMR data with those of 2 and 3 . In the case of the 20 S compounds, the 18-methyl singlet is shifted to higher field compared to the corresponding 20 R diastereomers. , In the case of the 1:1 diastereomeric mixture 8 separation of the isomers was not possible. 1 …”
Section: Chemistrymentioning
confidence: 98%
“…Starting from the corresponding oximes (Scheme ), the aziridines 4 − 8 were obtained via the same method as described for 2 and 3 . For all compounds, a 1:1 diastereomeric mixture (20 R :20 S ) was obtained, which was separated for 4 − 7 by FCC (flash column chromatography) and HPLC.…”
In the search for potent inhibitors of P450 17, the key enzyme in androgen biosynthesis, a series of steroidal inhibitors were synthesized and tested toward rat and human P450 17. Small aliphatic heterocycles (aziridine, oxirane, thiirane, diaziridine, diazirine, azetidine) were introduced into the 17beta-position of anstrost-5-en-3beta-ol. After identifying that aziridine is the most suitable functional group to coordinate with the heme iron, modifications of the steroidal skeleton were performed for further optimization. A wide range of inhibitory potencies toward P450 17 were found for the 21 test compounds. The most potent inhibitors toward the human and rat enzyme were aziridine compounds 3 (IC(50) rat: 0.21 microM, K(i) = 3 nM; IC(50) human: 0.54 microM, K(i) = 8 nM), 5 (IC(50) rat: 0.43 microM, K(i) = 7 nM; IC(50) human: 0.29 microM, K(i) = 4 nM), and 8 (21R:21S = 1:1; IC(50) rat: 0.53 microM, K(i) = 9 nM; IC(50) human: 0.40 microM, K(i) = 6 nM) which were more potent than the reference ketoconazole (IC(50) rat: 67 microM; IC(50) human: 0.74 microM). The inhibitory potency depends markedly on the stereochemistry at C20 of the inhibitors. This effect is more pronounced for the rat enzyme. Tested for selectivity, the highly potent inhibitors show poor inhibitory activity toward P450 arom, P450 scc, P450 TxA(2), and 5alpha-reductase. Tested for in vivo activity, 3 and 8 (0.019 mmol/kg) decreased the plasma testosterone concentration in rats by 81% and 84% after 2 h.
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