Intramolecular approach to some new D-ring-fused steroidal isoxazolidines by 1,3-dipolar cycloaddition: Synthesis, theoretical and in vitro pharmacological studies

E. Frank, Zoltán Mucsi, Mihály Szécsi, I. Zupkó, J. Wölfling, G. Schneider

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Intramolecular 1,3-dipolar cycloaddition of alkenyl oxime 5, obtained from trans-3β-acetoxy-16,17-secopregna-5,17(20)-dien-16-al 2 with hydroxylamine hydrochloride, was carried out under reflux in toluene to furnish a ca. 3:2 mixture of D-ring-fused isoxazolidine diastereomers 8 and 11a both with cis D/E ring junction stereochemistry. The corresponding reaction of 5 in the presence of a catalytic amount of BF3·OEt2 gave a single isomer 8 under milder conditions with an improved yield. The experimental findings on the thermally induced and BF3-catalysed transformations were supported by calculations of the proposed mechanism at the BLYP/6-31G(d) level of theory. Analogously, cyclization of D-secopregnene aldehyde 2 with N-substituted hydroxylamine derivatives (10b-e) under thermal conditions furnished N-functionalized isoxazolidines 11b-e diastereoselectively, via the corresponding alkenyl nitrones 7b-e. The activities of the 3-deacetylated compounds (9, 12b-e) were tested in vitro on rat testicular C 17,20-lyase: the radioligand incubation assay revealed that 9 exerted a moderate enzyme-inhibitory effect (IC50 = 26 μM), while the other derivatives were found to decrease the enzyme activity by only 68-83%. The antiproliferative activities of the structurally related isoxazolidine derivatives were also determined in vitro on three malignant human cell lines (HeLa, MCF7, and A431) by the microculture tetrazolium assay. The highest cytotoxic activities were displayed by the N-benzyl-substituted derivative 12e (IC50: 14.00, 23.18 and 8.76 μM on HeLa, MCF7 and A341 cells, respectively).

Original languageEnglish
Pages (from-to)2671-2681
Number of pages11
JournalNew Journal of Chemistry
Volume34
Issue number11
DOIs
Publication statusPublished - Nov 2010

Fingerprint

Cycloaddition
Derivatives
Hydroxylamine
Assays
Steroid 17-alpha-Hydroxylase
Stereochemistry
Oximes
Cyclization
Toluene
Enzyme activity
Aldehydes
Isomers
Rats
Enzymes
Cells

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Materials Chemistry

Cite this

@article{8cb50bb41a9e44e6adcedce3d671307d,
title = "Intramolecular approach to some new D-ring-fused steroidal isoxazolidines by 1,3-dipolar cycloaddition: Synthesis, theoretical and in vitro pharmacological studies",
abstract = "Intramolecular 1,3-dipolar cycloaddition of alkenyl oxime 5, obtained from trans-3β-acetoxy-16,17-secopregna-5,17(20)-dien-16-al 2 with hydroxylamine hydrochloride, was carried out under reflux in toluene to furnish a ca. 3:2 mixture of D-ring-fused isoxazolidine diastereomers 8 and 11a both with cis D/E ring junction stereochemistry. The corresponding reaction of 5 in the presence of a catalytic amount of BF3·OEt2 gave a single isomer 8 under milder conditions with an improved yield. The experimental findings on the thermally induced and BF3-catalysed transformations were supported by calculations of the proposed mechanism at the BLYP/6-31G(d) level of theory. Analogously, cyclization of D-secopregnene aldehyde 2 with N-substituted hydroxylamine derivatives (10b-e) under thermal conditions furnished N-functionalized isoxazolidines 11b-e diastereoselectively, via the corresponding alkenyl nitrones 7b-e. The activities of the 3-deacetylated compounds (9, 12b-e) were tested in vitro on rat testicular C 17,20-lyase: the radioligand incubation assay revealed that 9 exerted a moderate enzyme-inhibitory effect (IC50 = 26 μM), while the other derivatives were found to decrease the enzyme activity by only 68-83{\%}. The antiproliferative activities of the structurally related isoxazolidine derivatives were also determined in vitro on three malignant human cell lines (HeLa, MCF7, and A431) by the microculture tetrazolium assay. The highest cytotoxic activities were displayed by the N-benzyl-substituted derivative 12e (IC50: 14.00, 23.18 and 8.76 μM on HeLa, MCF7 and A341 cells, respectively).",
author = "E. Frank and Zolt{\'a}n Mucsi and Mih{\'a}ly Sz{\'e}csi and I. Zupk{\'o} and J. W{\"o}lfling and G. Schneider",
year = "2010",
month = "11",
doi = "10.1039/c0nj00150c",
language = "English",
volume = "34",
pages = "2671--2681",
journal = "New Journal of Chemistry",
issn = "1144-0546",
publisher = "Royal Society of Chemistry",
number = "11",

}

TY - JOUR

T1 - Intramolecular approach to some new D-ring-fused steroidal isoxazolidines by 1,3-dipolar cycloaddition

T2 - Synthesis, theoretical and in vitro pharmacological studies

AU - Frank, E.

AU - Mucsi, Zoltán

AU - Szécsi, Mihály

AU - Zupkó, I.

AU - Wölfling, J.

AU - Schneider, G.

PY - 2010/11

Y1 - 2010/11

N2 - Intramolecular 1,3-dipolar cycloaddition of alkenyl oxime 5, obtained from trans-3β-acetoxy-16,17-secopregna-5,17(20)-dien-16-al 2 with hydroxylamine hydrochloride, was carried out under reflux in toluene to furnish a ca. 3:2 mixture of D-ring-fused isoxazolidine diastereomers 8 and 11a both with cis D/E ring junction stereochemistry. The corresponding reaction of 5 in the presence of a catalytic amount of BF3·OEt2 gave a single isomer 8 under milder conditions with an improved yield. The experimental findings on the thermally induced and BF3-catalysed transformations were supported by calculations of the proposed mechanism at the BLYP/6-31G(d) level of theory. Analogously, cyclization of D-secopregnene aldehyde 2 with N-substituted hydroxylamine derivatives (10b-e) under thermal conditions furnished N-functionalized isoxazolidines 11b-e diastereoselectively, via the corresponding alkenyl nitrones 7b-e. The activities of the 3-deacetylated compounds (9, 12b-e) were tested in vitro on rat testicular C 17,20-lyase: the radioligand incubation assay revealed that 9 exerted a moderate enzyme-inhibitory effect (IC50 = 26 μM), while the other derivatives were found to decrease the enzyme activity by only 68-83%. The antiproliferative activities of the structurally related isoxazolidine derivatives were also determined in vitro on three malignant human cell lines (HeLa, MCF7, and A431) by the microculture tetrazolium assay. The highest cytotoxic activities were displayed by the N-benzyl-substituted derivative 12e (IC50: 14.00, 23.18 and 8.76 μM on HeLa, MCF7 and A341 cells, respectively).

AB - Intramolecular 1,3-dipolar cycloaddition of alkenyl oxime 5, obtained from trans-3β-acetoxy-16,17-secopregna-5,17(20)-dien-16-al 2 with hydroxylamine hydrochloride, was carried out under reflux in toluene to furnish a ca. 3:2 mixture of D-ring-fused isoxazolidine diastereomers 8 and 11a both with cis D/E ring junction stereochemistry. The corresponding reaction of 5 in the presence of a catalytic amount of BF3·OEt2 gave a single isomer 8 under milder conditions with an improved yield. The experimental findings on the thermally induced and BF3-catalysed transformations were supported by calculations of the proposed mechanism at the BLYP/6-31G(d) level of theory. Analogously, cyclization of D-secopregnene aldehyde 2 with N-substituted hydroxylamine derivatives (10b-e) under thermal conditions furnished N-functionalized isoxazolidines 11b-e diastereoselectively, via the corresponding alkenyl nitrones 7b-e. The activities of the 3-deacetylated compounds (9, 12b-e) were tested in vitro on rat testicular C 17,20-lyase: the radioligand incubation assay revealed that 9 exerted a moderate enzyme-inhibitory effect (IC50 = 26 μM), while the other derivatives were found to decrease the enzyme activity by only 68-83%. The antiproliferative activities of the structurally related isoxazolidine derivatives were also determined in vitro on three malignant human cell lines (HeLa, MCF7, and A431) by the microculture tetrazolium assay. The highest cytotoxic activities were displayed by the N-benzyl-substituted derivative 12e (IC50: 14.00, 23.18 and 8.76 μM on HeLa, MCF7 and A341 cells, respectively).

UR - http://www.scopus.com/inward/record.url?scp=78049306126&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78049306126&partnerID=8YFLogxK

U2 - 10.1039/c0nj00150c

DO - 10.1039/c0nj00150c

M3 - Article

AN - SCOPUS:78049306126

VL - 34

SP - 2671

EP - 2681

JO - New Journal of Chemistry

JF - New Journal of Chemistry

SN - 1144-0546

IS - 11

ER -