Synthesis of 6β-[(2‘-Aminoethyl)carboxamidomethyl]estradiol and Preparation of Estradiol Probes

Adamczyk, Maciej; Johnson, Donald D.; Reddy, Rajarathnam E.

doi:10.1021/bc970203l

Cited by 16 publications

(6 citation statements)

References 22 publications

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“…This may flatten the B-ring and gives rise to a mixture of syn-and anti-isomers (Rao et al, 1998). In case of amide bondages at the ring system, it should be noticed that the native electronic environment might be altered (Adamczyk et al, 1998b). By use of polyether or pure aliphatic spacer groups, also the hydrophilicity of these linkers must be considered.…”

Section: Discussionmentioning

confidence: 99%

Concepts for the Syntheses of Biotinylated Steroids. Part II: 17β-Estradiol Derivatives as Immunochemical Probes

et al. 2000

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Biotinylated 17beta-estradiol (E2) derivatives are helpful probes for a better understanding of biospecific E2 interactions with steroid-binding proteins such as the estrogen receptor and anti-steroid antibodies. We describe synthetic strategies for the biotinylation of E2 toward the 3, 6alpha, and 7alpha positions using biotinyl-N-hydroxysuccinimide esters with different spacers, varying in structure and chain length. Key reaction for biotinylation at the 3 position is the regioselective ether formation of the phenolate E2 anion with a linker mesylate without protecting the 17beta-hydroxyl group. The 6alpha position is accessible via a 3,17beta protected 6alpha-hydroxy E2, prepared by stereospecific sodium borohydride reduction of 6-oxo E2. Direct cyanoethylation of the alcohol followed by reduction to the amine allows the biotinylation to 6alpha-O-coupled cyanoethyloxy linker E2 derivatives. Alternatively, 6alpha-O-coupled cyanoalkyloxy polyether linker E2 probes are obtained by a Williamson ether synthesis of the alcohol precursor with omega-t-butyl-dimethylsilyloxy-5-oxa-nonylmesylate. Cyanoethylation of the desilylated compound and further reduction of the nitrile led to the terminal amine. Reductive amination of the 3, 17beta acetylated 6-oxo E2 compound with 6-cyanoethyloxyhexyl ammonium acetate yields in a mixture of 6alpha/beta-N-alkylated E2 nitriles. The epimers are separated by reversed-phase HPLC and the 6alpha-compound subsequently reduced to the terminal amine. The 7alpha-biotinylated E2 compound is derived from 7alpha-(11'-undecyl-N-methyl-N-butylamide) E2, which is already known from literature. Subsequently, the 3 and 17beta positions are protected, and the amide is reduced to the 7alpha-(11'-undecanol) compound. Further cyanoethylation and reduction led to the 11'-amino-ethyloxyundecyl E2. Using (1)H NMR analysis, it could be shown that the biotin moiety of the biotinylated 6alpha- and 7alpha-E2 derivatives has an axial position which results in a vertical orientation of the substituent toward the alpha-face of the planar tetracyclic backbone. Thus, a negligible alteration of the original structure of the upper beta-face offers the feasibility of applying the 6alpha- and 7alpha-derivatives as optimal tracers in competitive immunoassays.

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Section: Discussionmentioning

confidence: 99%

Concepts for the Syntheses of Biotinylated Steroids. Part II: 17β-Estradiol Derivatives as Immunochemical Probes

et al. 2000

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“…However, there are no recent reports of the introduction of an alkyl side chain to C-6 of estrogens. A 1998 paper describes the synthesis of the 6-carboxymethyl derivative by way of a Reformatzky reaction of 6-oxoestradiol (65) (Scheme 4.1) [30].…”

Section: Modifications At C-6mentioning

confidence: 99%

Homologation of Estrone or Estradiol. Appending a Carbon Substituent Into the 3-hydroxyestra-1,3,5-triene Skeleton

Braune¹,

Deb²,

Hase³

et al. 2007

COC

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“…For the most commonly used carboxymethyloxime derivatives the altered hybridization (sp 2 vs sp 3 ) is unfavorable, since the double bond in the chemical bridge denies free rotation, flattens the B-ring and gives rise to a mixture of syn-and antiisomers (Rao et al, 1998). Additionally, it should be noticed that the native electronic environment might be altered in case of amide bondages at the ring system (Adamczyk et al, 1998). By use of polyether or pure aliphatic spacer groups the hydrophilicity should also be considered.…”

Section: Introductionmentioning

confidence: 99%

“…A total of 1.5 equiv of (n-Bu) 3 P was added, and the mixture was stirred for 2.5 h. A yellow oil was isolated. IR (neat): 2980, 2880 (CH aliphat ), 1730 (17-OAc), 1670 (3-CdO), 1610 (CdC conj ), 1190, 1160 [(n-Bu) 3 P, (n-Bu) 3…”

Section: Introductionmentioning

confidence: 99%

Concepts for the Syntheses of Biotinylated Steroids. Part I: Testosterone Derivatives as Immunochemical Probes

et al. 2000

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We describe synthetic strategies for the biotinylation of testosterone (T) at positions 3, 7alpha, 17alpha, and 19. These T probes are able to mimic ligand binding and may provide for a better understanding of the biospecific interaction with steroid-binding proteins such as the androgen receptor, anti-steroid antibodies, or steroid-binding serum globulins. For the 7alpha- and 17alpha-derivatives, biotinyl-N-hydroxy-succinimide esters with different types of spacer chains were used. The 3-biotin hydrazone derivative was produced using N-(epsilon-biotinyl)-caproyl hydrazide, whereas for the 19-biotinylation, a biotinyl-1-N-diamino-3, 6-dioxaoctane-amide was applied. Key reaction for the biotinylation at position 3 is the oximation of the 3-oxo function. The 17alpha-position is accessible by the reaction of the 3-protected 4-androsten-17-epoxide with oxygen in the beta-position, followed by nucleophilic ring opening with cyanide which provides the 17alpha-cyanomethyl derivative. The key step is the regioselective ketal protection of the 3-oxo function of androst-4-ene-3,17-dione using a stannoxane catalyst. An alternative pathway for the insertion of biotin at the 19-position was established by the synthesis of 17beta-hydroxy-androst-4-en-3-one-19-yl carboxymethyl ether. After activation by the carbodiimide method, the compound reacts with aminoterminal biotin derivatives. The copper(I)-catalyzed 1,6 Michael addition of 17-acetoxy-6,7-dehydro-T leads to 7alpha-derivatives by use of omega-silyl protected hydroxylalkyl-modified Grignard reagents. A functional group interconversion using the Staudinger reaction transforms the azide function into a primary omega-amino group. The absolute configurations of the different biotinylated derivatives were investigated by (1)H NMR studies. For the 7alpha-biotinylated T series, additionally, an X-ray analysis proved the axial position of the spacer group. This results in a vertical orientation of the biotin moiety toward the alpha-face of the planar tetracyclic backbone. Thus, a negligible alteration of the original structure of the upper beta-face offers the feasibility of applying the 7alpha-derivatives as optimal immunochemical tracers in competitive immunoassays. Biotinylated T derivatives should be also suitable for ligand-binding studies to the androgen receptor or to sex hormone-binding globulin.

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Synthesis of 6β-[(2‘-Aminoethyl)carboxamidomethyl]estradiol and Preparation of Estradiol Probes

Cited by 16 publications

References 22 publications

Concepts for the Syntheses of Biotinylated Steroids. Part II: 17β-Estradiol Derivatives as Immunochemical Probes

Concepts for the Syntheses of Biotinylated Steroids. Part II: 17β-Estradiol Derivatives as Immunochemical Probes

Homologation of Estrone or Estradiol. Appending a Carbon Substituent Into the 3-hydroxyestra-1,3,5-triene Skeleton

Concepts for the Syntheses of Biotinylated Steroids. Part I: Testosterone Derivatives as Immunochemical Probes

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