Efficient access to novel androsteno-17-(1′,3′,4′)-oxadiazoles and 17β-(1′,3′,4′)-thiadiazoles via N-substituted hydrazone and N, N′-disubstituted hydrazine intermediates, and their pharmacological evaluation in vitro

Dóra Kovács, J. Wölfling, Nikoletta Szabó, Mihály Szécsi, Renáta Minorics, I. Zupkó, E. Frank

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11 Citations (Scopus)

Abstract

A series of novel 17-exo-oxadiazoles and -thiadiazoles in the Δ5 androstene series were efficiently synthesized from pregnenolone acetate and pregnadienolone acetate via multistep pathways. 17β-(1′,3′,4′)-Oxadiazoles were obtained in high yields by the phenyliodonium diacetate-induced oxidative ring closure of semicarbazone and N-acylhydrazones derived from 3β-acetoxy- and 3β-hydroxyandrost-5-ene-17β-carbaldehydes. For the synthesis of analogous Δ16-17-oxadiazolyl derivatives, N,N′-disubstituted hydrazine intermediates were prepared from 3β-acetoxyandrosta-5,16-diene-17-carboxylic acid, which then underwent cyclodehydration in the presence of POCl3. The cyclization of steroidal N,N′-diacylhydrazines containing a saturated ring D with the Lawesson reagent afforded 17β-(1′,3′,4′)-thiadiazoles in good yields. Most of the products were subjected to deacetylation in basic media in order to enlarge the compound library available for pharmacological studies. All of these derivatives were screened in vitro for their antiproliferative effects against four malignant human adherent cell lines (HeLa, A2780, MCF7 and A431) by means of the MTT assay. The 3β-hydroxy derivatives of the newly-synthesized 17-exo-heterocycles were tested in vitro to investigate their inhibitory effects on rat testicular C17,20-lyase. One of the 1,3,4-oxadiazolyl derivatives proved to exert noteworthy enzyme-inhibitory action, with an IC50 (0.065 μM) of the same order of magnitude as that of abiraterone.

Original languageEnglish
Pages (from-to)13-29
Number of pages17
JournalEuropean Journal of Medicinal Chemistry
Volume98
DOIs
Publication statusPublished - Jun 15 2015

Fingerprint

hydrazine
Hydrazones
2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide
Acetates
Semicarbazones
Androstenes
Pharmacology
Thiadiazoles
Oxadiazoles
Derivatives
Pregnenolone
Lyases
Cyclization
Carboxylic Acids
Inhibitory Concentration 50
Libraries
Cell Line
Enzymes
Rats
Assays

Keywords

  • 1,3,4-Oxadiazole
  • 1,3,4-Thiadiazole
  • Antiproliferative activity
  • P450 inhibition
  • Steroids

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

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title = "Efficient access to novel androsteno-17-(1′,3′,4′)-oxadiazoles and 17β-(1′,3′,4′)-thiadiazoles via N-substituted hydrazone and N, N′-disubstituted hydrazine intermediates, and their pharmacological evaluation in vitro",
abstract = "A series of novel 17-exo-oxadiazoles and -thiadiazoles in the Δ5 androstene series were efficiently synthesized from pregnenolone acetate and pregnadienolone acetate via multistep pathways. 17β-(1′,3′,4′)-Oxadiazoles were obtained in high yields by the phenyliodonium diacetate-induced oxidative ring closure of semicarbazone and N-acylhydrazones derived from 3β-acetoxy- and 3β-hydroxyandrost-5-ene-17β-carbaldehydes. For the synthesis of analogous Δ16-17-oxadiazolyl derivatives, N,N′-disubstituted hydrazine intermediates were prepared from 3β-acetoxyandrosta-5,16-diene-17-carboxylic acid, which then underwent cyclodehydration in the presence of POCl3. The cyclization of steroidal N,N′-diacylhydrazines containing a saturated ring D with the Lawesson reagent afforded 17β-(1′,3′,4′)-thiadiazoles in good yields. Most of the products were subjected to deacetylation in basic media in order to enlarge the compound library available for pharmacological studies. All of these derivatives were screened in vitro for their antiproliferative effects against four malignant human adherent cell lines (HeLa, A2780, MCF7 and A431) by means of the MTT assay. The 3β-hydroxy derivatives of the newly-synthesized 17-exo-heterocycles were tested in vitro to investigate their inhibitory effects on rat testicular C17,20-lyase. One of the 1,3,4-oxadiazolyl derivatives proved to exert noteworthy enzyme-inhibitory action, with an IC50 (0.065 μM) of the same order of magnitude as that of abiraterone.",
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author = "D{\'o}ra Kov{\'a}cs and J. W{\"o}lfling and Nikoletta Szab{\'o} and Mih{\'a}ly Sz{\'e}csi and Ren{\'a}ta Minorics and I. Zupk{\'o} and E. Frank",
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T1 - Efficient access to novel androsteno-17-(1′,3′,4′)-oxadiazoles and 17β-(1′,3′,4′)-thiadiazoles via N-substituted hydrazone and N, N′-disubstituted hydrazine intermediates, and their pharmacological evaluation in vitro

AU - Kovács, Dóra

AU - Wölfling, J.

AU - Szabó, Nikoletta

AU - Szécsi, Mihály

AU - Minorics, Renáta

AU - Zupkó, I.

AU - Frank, E.

PY - 2015/6/15

Y1 - 2015/6/15

N2 - A series of novel 17-exo-oxadiazoles and -thiadiazoles in the Δ5 androstene series were efficiently synthesized from pregnenolone acetate and pregnadienolone acetate via multistep pathways. 17β-(1′,3′,4′)-Oxadiazoles were obtained in high yields by the phenyliodonium diacetate-induced oxidative ring closure of semicarbazone and N-acylhydrazones derived from 3β-acetoxy- and 3β-hydroxyandrost-5-ene-17β-carbaldehydes. For the synthesis of analogous Δ16-17-oxadiazolyl derivatives, N,N′-disubstituted hydrazine intermediates were prepared from 3β-acetoxyandrosta-5,16-diene-17-carboxylic acid, which then underwent cyclodehydration in the presence of POCl3. The cyclization of steroidal N,N′-diacylhydrazines containing a saturated ring D with the Lawesson reagent afforded 17β-(1′,3′,4′)-thiadiazoles in good yields. Most of the products were subjected to deacetylation in basic media in order to enlarge the compound library available for pharmacological studies. All of these derivatives were screened in vitro for their antiproliferative effects against four malignant human adherent cell lines (HeLa, A2780, MCF7 and A431) by means of the MTT assay. The 3β-hydroxy derivatives of the newly-synthesized 17-exo-heterocycles were tested in vitro to investigate their inhibitory effects on rat testicular C17,20-lyase. One of the 1,3,4-oxadiazolyl derivatives proved to exert noteworthy enzyme-inhibitory action, with an IC50 (0.065 μM) of the same order of magnitude as that of abiraterone.

AB - A series of novel 17-exo-oxadiazoles and -thiadiazoles in the Δ5 androstene series were efficiently synthesized from pregnenolone acetate and pregnadienolone acetate via multistep pathways. 17β-(1′,3′,4′)-Oxadiazoles were obtained in high yields by the phenyliodonium diacetate-induced oxidative ring closure of semicarbazone and N-acylhydrazones derived from 3β-acetoxy- and 3β-hydroxyandrost-5-ene-17β-carbaldehydes. For the synthesis of analogous Δ16-17-oxadiazolyl derivatives, N,N′-disubstituted hydrazine intermediates were prepared from 3β-acetoxyandrosta-5,16-diene-17-carboxylic acid, which then underwent cyclodehydration in the presence of POCl3. The cyclization of steroidal N,N′-diacylhydrazines containing a saturated ring D with the Lawesson reagent afforded 17β-(1′,3′,4′)-thiadiazoles in good yields. Most of the products were subjected to deacetylation in basic media in order to enlarge the compound library available for pharmacological studies. All of these derivatives were screened in vitro for their antiproliferative effects against four malignant human adherent cell lines (HeLa, A2780, MCF7 and A431) by means of the MTT assay. The 3β-hydroxy derivatives of the newly-synthesized 17-exo-heterocycles were tested in vitro to investigate their inhibitory effects on rat testicular C17,20-lyase. One of the 1,3,4-oxadiazolyl derivatives proved to exert noteworthy enzyme-inhibitory action, with an IC50 (0.065 μM) of the same order of magnitude as that of abiraterone.

KW - 1,3,4-Oxadiazole

KW - 1,3,4-Thiadiazole

KW - Antiproliferative activity

KW - P450 inhibition

KW - Steroids

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JO - European Journal of Medicinal Chemistry

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