63-05-8Relevant articles and documents
Structural Basis for Featuring of Steroid Isomerase Activity in Alpha Class Glutathione Transferases
Tars, Kaspars,Olin, Birgit,Mannervik, Bengt
, p. 332 - 340 (2010)
Glutathione transferases (GSTs) are abundant enzymes catalyzing the conjugation of hydrophobic toxic substrates with glutathione. In addition to detoxication, human GST A3-3 displays prominent steroid double-bond isomerase activity; e.g. transforming Δ5-androstene-3-17-dione into Δ4-androstene-3-17-dione (AD). This chemical transformation is a crucial step in the biosynthesis of steroids, such as testosterone and progesterone. In contrast to GST A3-3, the homologous GST A2-2 does not show significant steroid isomerase activity. We have solved the 3D structures of human GSTs A2-2 and A3-3 in complex with AD. In the GST A3-3 crystal structure, AD was bound in an orientation suitable for the glutathione (GSH)-mediated catalysis to occur. In GST A2-2, however, AD was bound in a completely different orientation with its reactive double bond distant from the GSH-binding site. The structures illustrate how a few amino acid substitutions in the active site spectacularly alter the binding mode of the steroid substrate in relation to the conserved catalytic groups and an essentially fixed polypeptide chain conformation. Furthermore, AD did not bind to the GST A2-2-GSH complex. Altogether, these results provide a first-time structural insight into the steroid isomerase activity of any GST and explain the 5000-fold difference in catalytic efficiency between GSTs A2-2 and A3-3. More generally, the structures illustrate how dramatic diversification of functional properties can arise via minimal structural alterations. We suggest a novel structure-based mechanism of the steroid isomerization reaction.
Acid- and Base-Catalyzed Isomerization of Androst-5-ene-3,17-dione and 17α-Ethynyl-17β-hydroxy-5-estren-3-one
Perera, S. K.,Dunn, W. A.,Fedor, L. R.
, p. 2816 - 2821 (1980)
Isomerization of androst-5-ene-3,17-dione (1) to androst-4-ene-3,17-dione (2) and of 17α-ethynyl-17β-hydroxy-5-estren-3-one (3) to 17α-ethynyl-17β-hydroxy-4-estren-3-one (4) is kinetically general acid-base catalyzed; 1 is more reactive than 3.Deuterium solvent kinetic isotope effects, k(H2O)/k(D2O), of ca.6 for tertiary amine catalyzed isomerization indicate rate-determining protonation of dienolate ions.The greater reactivity of 1 than 3, catalyzed by tertiary amines, is probably due to a greater concentration of the 1 dienolate ion than of the 3 dienolate ion.Ethanolamine, but not tris(hydroxymethyl)aminomethane, catalyzes isomerization of 1 and 3 via Schiff-base formation.Curvilinear pseudo-first-order plots for isomerization of 1 and 3 catalyzed by DCl/D2O indicate that partitioning of dienols is kinetically important.
Determination of the Microscopic Rate Constants for the Base-Catalyzed Conjugation of 5-Androstene-3,17-dione
Pollack, Ralph M.,Zeng, Baifei,Mack, Joseph P. G.,Eldin, Sherif
, p. 6419 - 6423 (1989)
The hydroxide ion catalyzed isomerization of 5-androstene-3,17-dione (1) to 4-androstene-3,17-dione (2) proceeds through the formation of an intermediate dienolate ion (1-1).This dienolate ion has been observed in the ultraviolet spectrum (λmax ca. 256 nm) during the isomerization reaction.Rate constants for the formation of the dienolate ion and both its reversion to reactant (1) and its conversion to product (2) in aqueous solution were measured.In addition, the rate of exchange of the C-6 protons of 2 in D2O/MeOD was determined.These results enable a complete description of the reaction profile to be made, including all rate constants and the pKa values for 1 (12.7) and 2 (16.1).The possible relevance of these results to the mechanism of action of the enzyme 3-oxo-Δ5-steroid isomerase is briefly discussed.
Activity and inhibition of 3-beta-hydroxysteroid dehydrogenase/delta-5-4-isomerase in human skin
Toth,Szecsi,Julesz,Faredin
, p. 160 - 168 (1997)
Activity and inhibition of 3β-hydroxysteroid dehydrogenase/Δ5-4-isomerase, a key enzyme of biosynthesis of androgenic steroids, in human skin were studied. Whole-width dermal tissue specimens excised from various regions of the male and female body were investigated with an in vitro radioenzyme assay method using dehydroepiandrosterone as substrate. The Michaelis-Menten constant of the enzyme was found to be K(m) = 10 nM and the maximal velocity was V(max) = 0.625 pmol produced 4-androstene-3,17-dione/mg protein/20 min. Activity of 3β-hydroxysteroid dehydrogenase/Δ5-4-isomerase in male inguinal skin (n = 8) was 0.132-0.412, in female abdominal skin (n = 4) 0.140-0.255, in perineal skin (n = 4) 0.138-0.962 pmol/mg protein/20 min. The synthetic steroids cyproterone acetate, 4-MA and epostane proved to be potent inhibitors, IC50 values were 150, 6.2 and 1.45 nM, respectively.
REGIO- AND STEREOSELECTIVE 1,4-REDUCTIONS OF METHYLATED, CROSS-CONJUGATED STEROIDAL CYCLOHEXADIENONES
Kuenzer, H.,Stahnke, M.,Sauer, G.,Wiechert, R.
, p. 3859 - 3862 (1990)
Regio- and stereoselectivities in conjugate reductions of steroidal 3-oxo-1,4-diene substrates, effected either directly by Fe(CO)5-NaOH-H2O in methanol solution or in two steps by NaBH4 reduction/Jones oxidation, depend on the substitution pattern of ring A.C(1) and C(2) methylated derivatives furnish Δ1-products with 5β-stereochemistry, whereas C(4) methylated and unsubstituted steroids both afford Δ4-derivatives.
Synthesis of Visible-Light–Activated Hypervalent Iodine and Photo-oxidation under Visible Light Irradiation via a Direct S0→Tn Transition
Matsuda, Yu,Matsumoto, Koki,Nagasawa, Sho,Nakajima, Masaya,Nemoto, Tetsuhiro
, p. 235 - 239 (2022/03/16)
Heavy atom-containing molecules cause a photoreaction by a direct S0→Tn transition. Therefore, even in a hypervalent iodine compound with a benzene ring as the main skeleton, the photoreaction proceeds under 365–400nm wavelength light, where UV-visible spectra are not observed by usual measurement method. Some studies, however, report hypervalent iodine compounds that strongly absorb visible light. Herein, we report the synthesis of two visible light-absorbing hypervalent iodines and their photooxidation properties under visible light irradiation. We also demonstrated that the S0→Tn transition causes the photoreaction to proceed under wavelengths in the blue and green light region.
Synthesis of Cardiotonic Steroids Oleandrigenin and Rhodexin B
Fejedelem, Zachary,Carney, Nolan,Nagorny, Pavel
, p. 10249 - 10262 (2021/07/31)
This article describes a concise synthesis of cardiotonic steroids oleandrigenin (7) and its subsequent elaboration into the natural product rhodexin B (2) from the readily available intermediate (8) that could be derived from the commercially available steroids testosterone or DHEA via three-step sequences. These studies feature an expedient installation of the β16-oxidation based on β14-hydroxyl-directed epoxidation and subsequent epoxide rearrangement. The following singlet oxygen oxidation of the C17 furan moiety provides access to oleandrigenin (7) in 12 steps (LLS) and a 3.1% overall yield from 8. The synthetic oleandrigenin (7) was successfully glycosylated with l-rhamnopyranoside-based donor 28 using a Pd(II)-catalyst, and the subsequent deprotection under acidic conditions provided cytotoxic natural product rhodexin B (2) in a 66% yield (two steps).
Electrochemically Enabled One-Pot Multistep Synthesis of C19 Androgen Steroids
Sommer, Florian,Kappe, C. Oliver,Cantillo, David
supporting information, p. 6044 - 6049 (2021/03/15)
The synthesis of many valuable C19 androgens can be accomplished by removal of the C17 side chain from more abundant corticosteroids, followed by further derivatization of the resulting 17-keto derivative. Conventional chemical reagents pose significant drawbacks for this synthetic strategy, as large amounts of waste are generated, and quenching of the reaction mixture and purification of the 17-ketosteroid intermediate are typically required. Herein, we present mild, safe, and sustainable electrochemical strategies for the preparation of C19 steroids. A reagent and catalyst free protocol for the removal of the C17 side chain of corticosteroids via anodic oxidation has been developed, enabling several one-pot, multistep procedures for the synthesis of androgen steroids. In addition, simultaneous anodic C17 side chain cleavage and cathodic catalytic hydrogenation of a steroid has been demonstrated, rendering a convenient and highly atom economic procedure for the synthesis of saturated androgens.
Platinum-Catalyzed α,β-Desaturation of Cyclic Ketones through Direct Metal–Enolate Formation
Chen, Ming,Dong, Guangbin
supporting information, p. 7956 - 7961 (2021/03/01)
The development of a platinum-catalyzed desaturation of cyclic ketones to their conjugated α,β-unsaturated counterparts is reported in this full article. A unique diene-platinum complex was identified to be an efficient catalyst, which enables direct metal-enolate formation. The reaction operates under mild conditions without using strong bases or acids. Good to excellent yields can be achieved for diverse and complex scaffolds. A wide range of functional groups, including those sensitive to acids, bases/nucleophiles, or palladium species, are tolerated, which represents a distinct feature from other known desaturation methods. Mechanistically, this platinum catalysis exhibits a fast and reversible α-deprotonation followed by a rate-determining β-hydrogen elimination process, which is different from the prior Pd-catalyzed desaturation method. Promising preliminary enantioselective desaturation using a chiral-diene-platinum complex has also been obtained.
A sodium trifluoromethanesulfinate-mediated photocatalytic strategy for aerobic oxidation of alcohols
Zhu, Xianjin,Liu, Can,Liu, Yong,Yang, Haijun,Fu, Hua
, p. 12443 - 12446 (2020/10/30)
A sodium trifluoromethanesulfinate-mediated photocatalytic strategy for the aerobic oxidation of alcohols has been developed for the first time, and the photoredox aerobic oxidation of secondary and primary alcohols provided the corresponding ketones and carboxylic acids, respectively, in high to excellent yields.
