387-79-1Relevant articles and documents
Modified bile acids and androstanes—Novel promising inhibitors of human cytochrome P450 17A1
Dzichenka, Yaraslau,Shapira, Michail,Yantsevich, Aliaksei,Cherkesova, Tatsiana,Grbovi?, Ljubica,Savi?, Marina,Usanov, Sergey,Jovanovi?-?anta, Suzana
, (2021)
Cytochromes P450 are key enzymes for steroid hormone biosynthesis in human body. They are considered as targets for the screening of novel high efficient drugs. The results of screening of bile acids and androstane derivatives toward human recombinant steroid 17α-hydroxylase/17,20-lyase (CYP17A1) are presented in this paper. A group of steroids, binding with micromolar or submicromolar affinity (in a range from 9 μM – less than 0.1 μM), was identified. Results presented here showed that these steroidal compounds are able to decrease rate of hydroxylation of essential CYP17A1 substrate – progesterone, while some compounds completely inhibited enzyme activity. Structure-activity relationship (SAR) analysis based on in vitro and in silico studies showed that high affinity of the enzyme to bile acids derivatives is correlated with side chain hydrophobicity and presence of hydroxyl or keto group at C3 position. From the other side, bile acid-derived compounds with more polar side chain or substituents at C7 and C12 positions possess higher Kd values. Among androstane-derived steroids couple of Δ5-steroids with hydroxyl group at C3 position, as well as 16,17-secosteroids, were found to be high affinity ligands of this enzyme. The data obtained could be useful for the design of novel highly efficient inhibitors of CYP17A1, since the bile acids-derived compounds are for first time recognized as effective CYP17A1 inhibitors.
The Involvement of an O2-Derived Nucleophilic Species in Acyl-Carbon Cleavage, Catalysed by Cytochrome P-45017α: Implications for Related P-450 Catalysed Fragmentation Reactions
Robichaud, Peter,Wright, J. Neville,Akhtar, Muhammad
, p. 1501 - 1504 (1994)
The postulated iron peroxy species involved in acyl-carbon fission by 17α-hydroxylase-17,20-lyase (P-45017α) was trapped by an aldehyde analogue, partial 9, that was cleaved by the enzyme 10 times faster than the side-chain of the natural substrate 1.
Effects of fluorine substitution on substrate conversion by cytochromes P450 17A1 and 21A2
Aubé, Jeffrey,Bart, Aaron G.,Scott, Emily E.,Vogt, Caleb D.,Yadav, Rahul
supporting information, p. 7664 - 7669 (2021/09/22)
Cytochromes P450 17A1 (CYP7A1) and 21A2 (CYP21A2) catalyze key reactions in the production of steroid hormones, including mineralocorticoids, glucocorticoids, and androgens. With the ultimate goal of designing probes that are selectively metabolized to each of these steroid types, fluorinated derivatives of the endogenous substrates, pregnenolone and progesterone, were prepared to study the effects on CYP17A1 and CYP21A2 activity. In the functional assays, the hydroxylase reactions catalysed by each of these enzymes were blocked when fluorine was introduced at the site of metabolism (positions 17 and 21 of the steroid core, respectively). CYP17A1, furthermore, performed the 17,20-lyase reaction on substrates with a fluorine installed at the 21-position. Importantly, none of the substitutions examined herein prevented compound entry into the active sites of either CYP17A1 or CYP21A2 as demonstrated by spectral binding assays. Taken together, the results suggest that fluorine might be used to redirect the metabolic pathways of pregnenolone and progesterone to specific types of steroids.
Inherent steroid 17α,20-lyase activity in defunct cytochrome P450 17A enzymes
Gonzalez, Eric,Johnson, Kevin M.,Pallan, Pradeep S.,Phan, Thanh T.N.,Zhang, Wei,Lei, Li,Wawrzak, Zdzislaw,Yoshimoto, Francis K.,Egli, Martin,Peter Guengerich
, p. 541 - 556 (2018/02/14)
Cytochrome P450 (P450) 17A1 catalyzes the oxidations of progesterone and pregnenolone and is the major source of androgens. The enzyme catalyzes both 17α-hydroxylation and a subsequent 17α,20-lyase reaction, and several mechanisms have been proposed for the latter step. Zebrafish P450 17A2 catalyzes only the 17α-hydroxylations. We previously reported high similarity of the crystal structures of zebrafish P450 17A1 and 17A2 and human P450 17A1. Five residues near the heme, which differed, were changed. We also crystallized this five-residue zebrafish P450 17A1 mutant, and the active site still resembled the structure in the other proteins, with some important differences. These P450 17A1 and 17A2 mutants had catalytic profiles more similar to each other than did the wildtype proteins. Docking with these structures can explain several minor products, which require multiple enzyme conformations. The 17α-hydroperoxy (OOH) derivatives of the steroids were used as oxygen surrogates. Human P450 17A1 and zebrafish P450s 17A1 and P450 17A2 readily converted these to the lyase products in the absence of other proteins or cofactors (with catalytically competent kinetics) plus hydroxylated 17α-hydroxysteroids. The 17α-OOH results indicate that a "Compound I" (FeO3+) intermediate is capable of formation and can be used to rationalize the products. We conclude that zebrafish P450 17A2 is capable of lyase activity with the 17α-OOH steroids because it can achieve an appropriate conformation for lyase catalysis in this system that is precluded in the conventional reaction.
Further syntheses of cyproterone acetate
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Page/Page column 16; 27; 29; 31, (2010/02/07)
The present invention relates to improved methods for synthesising cyproterone acetate (17α-Acetoxy-6-chloro-1α, 2α-methylene-4,6-pregnadiene-3,20-dione) from solasodine. The methods of the invention are shorter as those of the prior art and therefore more economic.
15β-Hydroxysteroids (part V). Steroids of the human perinatal period: The synthesis of 3β, 15β, 17α-trihydroxy-5-pregnen-20- one from 15β, 17α-dihydroxy-4-pregnen-3,20-dione
Joannou,Reeder
, p. 18 - 21 (2007/10/03)
A simple three-step synthetic method is reported on the conversion of Δ4-3-ketosteroids to the corresponding 3β- hydroxy-Δ5-steroid analogues. 17α-Hydroxy-4-pregnen-3,20-dione (10a) was used as a model to develop a method for the synthesis of 3β,17α-dihydroxy-5-pregnen-20-one (16). The major problem being the synthesis of 3,17α-diacetoxy-3,5-pregnadien-20-one (14) was solved by acetylating using a mixture of acetic anhydride and perchloric acid. The conversion of 15β,17α-dihydroxy-4-pregnen- 3,20-dione (8), product of Penicillium citrinum fermentation, to the desired 3β, 15β, 17α-trihydroxy-5-pregnen-20-one (1), is described using a modification of this method. Reaction of 8 with acetic anhydride and perchloric acid in ethyl acetate gave 3,15β,17α-triacetoxy-3,5-pregnadien-20-one (17) which on reduction with sodium borohydrice gave 5-pregnen-3β,15β,17α, 20(S + R)-tetrols (18a and 18b); however, reduction of 17 with a mixture of sodium borohydride and potassium bicarbonate gave after basic hydrolysis with metanolic sodium hydroxide the desired product 3β,15β,17α-trihydroxy-5-pregnen-20-one (1) in good yield (54%).
3β-11α-17-TRIHYDROXY-5-PREGNEN-20-ONE 11-HEMISUCCINATE AS A HAPTENE FOR RIA OF ''17α-HYDROXYPREGNENOLONE''
Kasal, Alexander,Pokora, Jenny,Zajicek, Jaroslav
, p. 1340 - 1347 (2007/10/02)
6β,17-Dihydroxy-3α,5-cyclo-5α-pregnan-20-one (VII) and 17-hydroxy-6β-methoxy-3α,5-cyclo-5α-pregnan-20-one (IX) were hydroxylated into the position 11α using Rhizopus nigricans fungi culture, and then selectively converted into haptene XIII for the RIA determination of 3β,17-dihydroxypregn-5-en-20-one (IV).
The Reaction of Enols with Superoxide Anion Radicals: Preparation of Tertiary α-Ketols
Betancor, Carmen,Francisco, Cosme G.,Freire, Raimundo,Suarez, Ernesto
, p. 947 - 948 (2007/10/02)
Pregnan-20-ones (1) and (4) and 3β-hydroxy-5α-cholestan-6-one (7) react with KO2 and 18-crown-6 benzene solution and under an oxygen atmosphere at 6-7 deg C to give the corresponding α-hydroperoxides (2), (5), and (8) which after treatment with Ph3P gives α-ketols (3), (6), and (9) in good yields.
A Ready Conversion of a Pregnane-20-carboxaldehyde to 17α-Hydroxypregnan-20-ones and Pregn-16-en-20-ones
Biancini, Bruno,Caciagli, Valerio,Centini, Felice,Eletti-Bianchi, Giancarlo,Re, Luciano
, p. 1829 - 1835 (2007/10/02)
Reaction of (20S)-5α-chloro-3β-hydroxypregnane-20-carboxaldehyde (9, prepared in two steps from stigmasterol) with oxygen and potassium tert-butoxide, followed by trimethyl phosphite treatment, afforded 5α-chloro-3β,17α-dihydroxypregnan-20-one (6) and 3β,17α-dihydroxypregn-5-en-20-one (7).This mixture was converted into 7 by potassium hydroxide treatment, and into 17α-hydroxypregn-4-ene-3,20-dione (8) by reaction with pyridinium dichromate followed by potassium hydroxide treatment.Bromination-dehydrobromination of 9, in one or two steps, afforded (Z)- and (E)-5α-chloro-3β-hydroxypregn-17(20)-ene-20-carboxaldehyde (11).Reaction of 11 with oxygen and potassium hydroxide gave 5α-chloro-3β-hydroxypregn-16-en-20-one (12), which was converted to 3β-hydroxypregna-15,6-dien-20-one (13) by further potassium hydroxide treatment, and to pregna-4,16-diene-3,20-dione (14) by Oppenauer reaction using excess aluminium isopropoxide.
