Exo-heterociklusos szteroidok szintézise

Translated title of the contribution: Synthesis of exo-heterocyclic steroids

Research output: Contribution to journalArticle

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Abstract

Medical applications of cardenolides and bufadienolides are associated with high risk, due to their exceptional toxicity and the small difference between therapeutic and toxic doses. In the past few years increasing attention has been paid to the synthesis of cardenolide analogues which are expected to have better therapeutic indices. The exo-heterocyclic compounds with N heteroatom at the position C-17 of steroids display a high inhibitory activity toward 17α-hydroxylase/C17,20-lyase, the enzyme responsible for the conversion of the C21 steroids to the C19 androgens. The presence of unsaturated 3-keton in the ring A of steroids inhibits the 5α-reductase enzyme. Therefore we reasoned that anchoring a heterocycle on the ring D to unsaturated 3-ketosteroids would produce novel steroid derivatives, potential inhibitors of both 5α-reductase and P450 17α. For the formation of tetrahydrooxazinone ring attached to the C-17β position of the steroidal skeleton we have chosen the basic cyclization reaction of the α,γ-halogenalkyl N-arylurethanes in alkaline media. Elongation of the side chain with a hydroxymethyl group on C-21 of 1 was accomplished by condensation with ethyl formate followed by reduction to the triols in the reaction media. Selective 21-p-tosyloxymethyl-pregn-5-ene- 3β,20β-diol 3-acetate (2c) formation and subsequent reaction with phenyl isocyanate led to the required starting material (2d). During alkaline methanolysis of the 21-p-tosyloxymethyl-20β-arylurethanes a cyclization takes place, in the course of which N-phenyltetrahydrooxazinone-2′ derivatives (3a-f) are formed (Scheme 1). The acid-catalyzed reactions of 21-azidomethyl-20-hydroxy- and 21-hydroxymethyl-20-azidosteroids (2i and 5b) with substituted aromatic aldehydes led to the androst-5-en-3β-ols substituted in position 17β with dihydrooxazine residues (6a-e, 7a-e) (Scheme 2). The 21-azido-20-hydroxy- and 21-hydroxy-20-azidosteroids (8e and 9b) under similar conditions led to the formation of androst-5-en-3β-ols, containing oxazoline heterocycles (10a-d and 11a-d) (Scheme 3). Reductive amination reactions of androst-5-en-3β-ol-17-one (12) with 1,2- or 1,3-aminoalcohols led to 17β-(ω-hydroxyalkyl)amino-androst-5-en- 3β-ols (13,14). These compounds reacted with diphenylcarbonate, in the course of which N-steroidal oxazoline (15) and tetrahydrooxazinone-2′ derivatives (16) were formed (Scheme 4). In vitro biological experiments of our newly synthesized steroid compounds were carried out.

Original languageHungarian
Pages (from-to)40-42
Number of pages3
JournalMagyar Kemiai Folyoirat, Kemiai Kozlemenyek
Volume109-110
Issue number1
Publication statusPublished - Mar 2004

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Heterocyclic Steroids
Steroids
Cardenolides
Cyclization
Derivatives
Bufanolides
Oxidoreductases
Ketosteroids
Heterocyclic Compounds
Amination
Lyases
Poisons
Medical applications
Enzymes
Mixed Function Oxygenases
Aldehydes
Androgens
Toxicity
Elongation
Condensation

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Exo-heterociklusos szteroidok szintézise. / Schneider, G.; Wölfling, J.; Mernyák, E.; Tóth, István.

In: Magyar Kemiai Folyoirat, Kemiai Kozlemenyek, Vol. 109-110, No. 1, 03.2004, p. 40-42.

Research output: Contribution to journalArticle

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abstract = "Medical applications of cardenolides and bufadienolides are associated with high risk, due to their exceptional toxicity and the small difference between therapeutic and toxic doses. In the past few years increasing attention has been paid to the synthesis of cardenolide analogues which are expected to have better therapeutic indices. The exo-heterocyclic compounds with N heteroatom at the position C-17 of steroids display a high inhibitory activity toward 17α-hydroxylase/C17,20-lyase, the enzyme responsible for the conversion of the C21 steroids to the C19 androgens. The presence of unsaturated 3-keton in the ring A of steroids inhibits the 5α-reductase enzyme. Therefore we reasoned that anchoring a heterocycle on the ring D to unsaturated 3-ketosteroids would produce novel steroid derivatives, potential inhibitors of both 5α-reductase and P450 17α. For the formation of tetrahydrooxazinone ring attached to the C-17β position of the steroidal skeleton we have chosen the basic cyclization reaction of the α,γ-halogenalkyl N-arylurethanes in alkaline media. Elongation of the side chain with a hydroxymethyl group on C-21 of 1 was accomplished by condensation with ethyl formate followed by reduction to the triols in the reaction media. Selective 21-p-tosyloxymethyl-pregn-5-ene- 3β,20β-diol 3-acetate (2c) formation and subsequent reaction with phenyl isocyanate led to the required starting material (2d). During alkaline methanolysis of the 21-p-tosyloxymethyl-20β-arylurethanes a cyclization takes place, in the course of which N-phenyltetrahydrooxazinone-2′ derivatives (3a-f) are formed (Scheme 1). The acid-catalyzed reactions of 21-azidomethyl-20-hydroxy- and 21-hydroxymethyl-20-azidosteroids (2i and 5b) with substituted aromatic aldehydes led to the androst-5-en-3β-ols substituted in position 17β with dihydrooxazine residues (6a-e, 7a-e) (Scheme 2). The 21-azido-20-hydroxy- and 21-hydroxy-20-azidosteroids (8e and 9b) under similar conditions led to the formation of androst-5-en-3β-ols, containing oxazoline heterocycles (10a-d and 11a-d) (Scheme 3). Reductive amination reactions of androst-5-en-3β-ol-17-one (12) with 1,2- or 1,3-aminoalcohols led to 17β-(ω-hydroxyalkyl)amino-androst-5-en- 3β-ols (13,14). These compounds reacted with diphenylcarbonate, in the course of which N-steroidal oxazoline (15) and tetrahydrooxazinone-2′ derivatives (16) were formed (Scheme 4). In vitro biological experiments of our newly synthesized steroid compounds were carried out.",
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N2 - Medical applications of cardenolides and bufadienolides are associated with high risk, due to their exceptional toxicity and the small difference between therapeutic and toxic doses. In the past few years increasing attention has been paid to the synthesis of cardenolide analogues which are expected to have better therapeutic indices. The exo-heterocyclic compounds with N heteroatom at the position C-17 of steroids display a high inhibitory activity toward 17α-hydroxylase/C17,20-lyase, the enzyme responsible for the conversion of the C21 steroids to the C19 androgens. The presence of unsaturated 3-keton in the ring A of steroids inhibits the 5α-reductase enzyme. Therefore we reasoned that anchoring a heterocycle on the ring D to unsaturated 3-ketosteroids would produce novel steroid derivatives, potential inhibitors of both 5α-reductase and P450 17α. For the formation of tetrahydrooxazinone ring attached to the C-17β position of the steroidal skeleton we have chosen the basic cyclization reaction of the α,γ-halogenalkyl N-arylurethanes in alkaline media. Elongation of the side chain with a hydroxymethyl group on C-21 of 1 was accomplished by condensation with ethyl formate followed by reduction to the triols in the reaction media. Selective 21-p-tosyloxymethyl-pregn-5-ene- 3β,20β-diol 3-acetate (2c) formation and subsequent reaction with phenyl isocyanate led to the required starting material (2d). During alkaline methanolysis of the 21-p-tosyloxymethyl-20β-arylurethanes a cyclization takes place, in the course of which N-phenyltetrahydrooxazinone-2′ derivatives (3a-f) are formed (Scheme 1). The acid-catalyzed reactions of 21-azidomethyl-20-hydroxy- and 21-hydroxymethyl-20-azidosteroids (2i and 5b) with substituted aromatic aldehydes led to the androst-5-en-3β-ols substituted in position 17β with dihydrooxazine residues (6a-e, 7a-e) (Scheme 2). The 21-azido-20-hydroxy- and 21-hydroxy-20-azidosteroids (8e and 9b) under similar conditions led to the formation of androst-5-en-3β-ols, containing oxazoline heterocycles (10a-d and 11a-d) (Scheme 3). Reductive amination reactions of androst-5-en-3β-ol-17-one (12) with 1,2- or 1,3-aminoalcohols led to 17β-(ω-hydroxyalkyl)amino-androst-5-en- 3β-ols (13,14). These compounds reacted with diphenylcarbonate, in the course of which N-steroidal oxazoline (15) and tetrahydrooxazinone-2′ derivatives (16) were formed (Scheme 4). In vitro biological experiments of our newly synthesized steroid compounds were carried out.

AB - Medical applications of cardenolides and bufadienolides are associated with high risk, due to their exceptional toxicity and the small difference between therapeutic and toxic doses. In the past few years increasing attention has been paid to the synthesis of cardenolide analogues which are expected to have better therapeutic indices. The exo-heterocyclic compounds with N heteroatom at the position C-17 of steroids display a high inhibitory activity toward 17α-hydroxylase/C17,20-lyase, the enzyme responsible for the conversion of the C21 steroids to the C19 androgens. The presence of unsaturated 3-keton in the ring A of steroids inhibits the 5α-reductase enzyme. Therefore we reasoned that anchoring a heterocycle on the ring D to unsaturated 3-ketosteroids would produce novel steroid derivatives, potential inhibitors of both 5α-reductase and P450 17α. For the formation of tetrahydrooxazinone ring attached to the C-17β position of the steroidal skeleton we have chosen the basic cyclization reaction of the α,γ-halogenalkyl N-arylurethanes in alkaline media. Elongation of the side chain with a hydroxymethyl group on C-21 of 1 was accomplished by condensation with ethyl formate followed by reduction to the triols in the reaction media. Selective 21-p-tosyloxymethyl-pregn-5-ene- 3β,20β-diol 3-acetate (2c) formation and subsequent reaction with phenyl isocyanate led to the required starting material (2d). During alkaline methanolysis of the 21-p-tosyloxymethyl-20β-arylurethanes a cyclization takes place, in the course of which N-phenyltetrahydrooxazinone-2′ derivatives (3a-f) are formed (Scheme 1). The acid-catalyzed reactions of 21-azidomethyl-20-hydroxy- and 21-hydroxymethyl-20-azidosteroids (2i and 5b) with substituted aromatic aldehydes led to the androst-5-en-3β-ols substituted in position 17β with dihydrooxazine residues (6a-e, 7a-e) (Scheme 2). The 21-azido-20-hydroxy- and 21-hydroxy-20-azidosteroids (8e and 9b) under similar conditions led to the formation of androst-5-en-3β-ols, containing oxazoline heterocycles (10a-d and 11a-d) (Scheme 3). Reductive amination reactions of androst-5-en-3β-ol-17-one (12) with 1,2- or 1,3-aminoalcohols led to 17β-(ω-hydroxyalkyl)amino-androst-5-en- 3β-ols (13,14). These compounds reacted with diphenylcarbonate, in the course of which N-steroidal oxazoline (15) and tetrahydrooxazinone-2′ derivatives (16) were formed (Scheme 4). In vitro biological experiments of our newly synthesized steroid compounds were carried out.

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