Conformational Design for 13α-Steroids

Schönecker, Bruno; Lange, C. C.; Kötteritzsch, Manuela; Günther, Wolfgang; Weston, Jennie; Anders, Ernst; Görls, Helmar

doi:10.1021/jo000108x

Cited by 87 publications

(63 citation statements)

References 29 publications

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“…The rigid structure of estrone contains two oxygen functionalities with well-defined distances, which are crucial in the binding of estrone or estradiol to its nuclear hormone receptors. In contrast with the natural 13b compound, the 13 epimer has a quasi-equatorial angular methyl group, a cis junction of rings C/D and a ring D that is directed to the b side 18 . Poirier et al reported the impact of inversion of the configuration at C-13 and/or C-17 of estradiols on their estrogenic activity 20 .…”

Section: B-hsd1 Inhibitionmentioning

confidence: 90%

“…13a-Derivatives (2b and 2c) were obtained by the epimerization of 1b or 1c using the literature methods 18 ,S3. 13a-Estrone (1a) was obtained by debenzylation of 1b S3 .…”

Section: Chemistrymentioning

confidence: 99%

“…Certain structural modifications of the estrane skeleton, such as the opening of ring D or inversion of the configuration at C-13, may lead to the complete loss of hormonal activity [18][19][20] . We recently described the synthesis and in vitro investigation of the 17b-HSD1-inhibitory activities of C-13 epimeric 17-(triazolylmethyl)carboxamido D-secoestrone derivatives bearing ether protecting groups on C-3 21 .…”

Section: Introductionmentioning

confidence: 99%

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Comparative investigation of thein vitroinhibitory potencies of 13-epimeric estrones and D-secoestrones towards 17β-hydroxysteroid dehydrogenase type 1

Herman

Szabó

Bacsa

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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The inhibitory effects of 13-epimeric estrones, D-secooxime and D-secoalcohol estrone compounds on human placental 17b-hydroxysteroid dehydrogenase type 1 isozyme (17b-HSD1) were investigated. The transformation of estrone to 17b-estradiol was studied by an in vitro radiosubstrate incubation method. 13a-Estrone inhibited the enzyme activity effectively with an IC 50 value of 1.2 mM, which indicates that enzyme affinity is similar to that of the natural estrone substrate. The 13b derivatives and the compounds bearing a 3-hydroxy group generally exerted stronger inhibition than the 13a and 3-ether counterparts. The 3-hydroxy13b-D-secoalcohol and the 3-hydroxy-13a-D-secooxime displayed an outstanding cofactor dependence, i.e. more efficient inhibition in the presence of NADH than NADPH. The 3-hydroxy13b-D-secooxime has an IC 50 value of 0.070 mM and is one of the most effective 17b-HSD1 inhibitors reported to date in the literature.

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Section: B-hsd1 Inhibitionmentioning

confidence: 90%

“…13a-Derivatives (2b and 2c) were obtained by the epimerization of 1b or 1c using the literature methods 18 ,S3. 13a-Estrone (1a) was obtained by debenzylation of 1b S3 .…”

Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comparative investigation of thein vitroinhibitory potencies of 13-epimeric estrones and D-secoestrones towards 17β-hydroxysteroid dehydrogenase type 1

Herman

Szabó

Bacsa

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…37 The unnatural 13α derivatives, with C/D cis ring annelation, are of stereochemical and biological interest. The 13α-estrone, 3-methyl (37) and 3-benzyl ethers (38) have been converted into their epimers (39, 40) and D-seco derivatives (41, 42) in the above-mentioned way (Scheme 9).…”

Section: Methodsmentioning

confidence: 99%

“…Earlier investigations revealed that the conformations of rings C and D are strongly influenced by the substitution pattern on ring D. 37 An X-ray crystallographic investigation showed the chair conformations of both rings C and D of a 16α-fluoro-17aα-arylamino-D-homoestrone derivative. 45 The cyclization of iminium salts of a D-secopregnene aldehyde led to a 16β-arylamino-17α-aminomethyl-17β-fluoro-D-homosteroid as a side-product.…”

Section: Scheme 12mentioning

confidence: 99%

Recent Developments in the Isolation and Synthesis of D‐Homosteroids and Related Compounds

Wölfling¹

2007

ChemInform

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Both naturally occurring and synthetic D-homologs of compounds with a sterane skeleton exhibit diverse biological activity. The main sources of isolation are plants and marine organisms. The synthetic D-homosteroids are potential leads for drug discovery. This review focuses on steroids with a six-membered carbocyclic ring D and related compounds, the isolation or syntheses of which were reported between the mid-1990s and mid-2006.

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Intramolecular γ‐Hydroxylations of Nonactivated CH Bonds with Copper Complexes and Molecular Oxygen

Schönecker

Zheldakova

Lange

et al. 2004

Chemistry A European J

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Copper(I) complexes incorporating the isomeric bidentate ligands IMPY (iminomethyl-2-pyridines) or AMPY (aminomethylene-2-pyridines) are quite unusual in their ability to bind and activate molecular oxygen. Using these complexes, hydroxylations of nonactivated CH, CH2, or CH3 groups in the gamma-position in relation to the imino-nitrogen atom, and with a specific orientation of one H atom with respect to the binuclear Cu-O species, can be achieved in synthetically useful yields. Through mechanistic studies employing conformationally well-defined molecules (for example, cyclic isoprenoids), coupled with solid-state X-ray structure analyses and force-field calculations, we postulate a seven-membered transition state for this reaction in which six atoms lie approximately in a plane. This plane is defined by the positions of the lone pairs on the nitrogen atoms, as well as the copper and the oxygen atoms. For a successful hydroxylation, one hydrogen atom should be located close to this plane. Prediction of the stereochemical course of these reactions is possible based on a simple geometrical criterion. The convenient introduction of IMPY and AMPY groups as auxiliaries into oxo and primary amino compounds and the simple hydrolysis after the hydroxylation procedure has allowed the synthesis of 3-hydroxy-1-oxo and 3-hydroxy-1-amino compounds. If desired, the 3-hydroxy-1-IMPY and -1-AMPY compounds can be reduced with NaBH4 to obtain 3-hydroxy-1-aminomethylpyridines. For a successful hydroxylation procedure, the method employed for the synthesis of the CuI complexes is very important. Starting either from CuI salts or from CuII salts with a subsequent reduction with benzoin/triethylamine may turn out to be the better way, depending on the ligand and the molecular structure.

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Conformational Design for 13α-Steroids

Cited by 87 publications

References 29 publications

Comparative investigation of thein vitroinhibitory potencies of 13-epimeric estrones and D-secoestrones towards 17β-hydroxysteroid dehydrogenase type 1

Comparative investigation of thein vitroinhibitory potencies of 13-epimeric estrones and D-secoestrones towards 17β-hydroxysteroid dehydrogenase type 1

Recent Developments in the Isolation and Synthesis of D‐Homosteroids and Related Compounds

Intramolecular γ‐Hydroxylations of Nonactivated CH Bonds with Copper Complexes and Molecular Oxygen

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