Stereoselective synthesis and antiproliferative activity of monoterpene-fused 2-imino-1,3-oxazines

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Abstract

Background: In the recent years the 2-imino-1,3-thiazine and 2-iminothiazolidine ring systems can be found as moieties in biologically relevant compounds, including BACE1 inhibitors, or cannabinoid receptor agonists, while monoterpene-based 2-imino-1,3-thiazines, prepared from chiral 1,3-amino alcohols exhibiting pronounced antiproliferative activity. Methods: The antiproliferative activities of the prepared compounds were determined in vitro against a panel of human adherent cancer cell lines including HeLa, MCF7 and A431 by MTT assay. Results: Starting from pinane-, apopinane-and carane-based β-amino acid derivatives, 1,3-amino alcohols were prepared via two-step syntheses. The reactions of the product 1,3-amino alcohols and aryl isothiocyanates yielded γ-hydroxythioureas, which were transformed to monoterpene-fused 2-imino-1,3-oxazines via base-catalysed ring closure. The antiproliferative activities of these 2-imino-1,3-oxazines were examined and the structure-activity relationships were studied from the aspects of the type and stereochemistry of the monoterpene ring and the substituent effects on the 1,3-oxazine ring system. The N-unsubstituted monoterpene-based derivatives exhibited considerable antiproliferative activity against a panel of human adherent cancer cell lines (HeLa, MCF7 and A431). Conclusions: A mild and efficient method has been developed for the synthesis of 2-imino-1,3-oxazines by the ring closure of thiourea adducts of 1,3-amino alcohols. The resulting 1,3-oxazines exert marked antiproliferative action on a panel of human cancer cell lines.

Original languageEnglish
Pages (from-to)612-619
Number of pages8
JournalCurrent Organic Synthesis
Volume14
Issue number4
DOIs
Publication statusPublished - Jun 1 2017

Fingerprint

Oxazines
Monoterpenes
Amino Alcohols
Thiazines
Cells
Cell Line
Isothiocyanates
Cannabinoid Receptor Agonists
Derivatives
Neoplasms
Thiourea
Stereochemistry
Structure-Activity Relationship
Assays
oxazine 1
Amino Acids

Keywords

  • 1, 3-amino alcohol
  • 1, 3-oxazine
  • Antiproliferative
  • Asymmetric synthesis
  • Enantiopure chiral templates
  • Monoterpene

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry

Cite this

@article{55ce46c7233a42dd8c89c052b96956a2,
title = "Stereoselective synthesis and antiproliferative activity of monoterpene-fused 2-imino-1,3-oxazines",
abstract = "Background: In the recent years the 2-imino-1,3-thiazine and 2-iminothiazolidine ring systems can be found as moieties in biologically relevant compounds, including BACE1 inhibitors, or cannabinoid receptor agonists, while monoterpene-based 2-imino-1,3-thiazines, prepared from chiral 1,3-amino alcohols exhibiting pronounced antiproliferative activity. Methods: The antiproliferative activities of the prepared compounds were determined in vitro against a panel of human adherent cancer cell lines including HeLa, MCF7 and A431 by MTT assay. Results: Starting from pinane-, apopinane-and carane-based β-amino acid derivatives, 1,3-amino alcohols were prepared via two-step syntheses. The reactions of the product 1,3-amino alcohols and aryl isothiocyanates yielded γ-hydroxythioureas, which were transformed to monoterpene-fused 2-imino-1,3-oxazines via base-catalysed ring closure. The antiproliferative activities of these 2-imino-1,3-oxazines were examined and the structure-activity relationships were studied from the aspects of the type and stereochemistry of the monoterpene ring and the substituent effects on the 1,3-oxazine ring system. The N-unsubstituted monoterpene-based derivatives exhibited considerable antiproliferative activity against a panel of human adherent cancer cell lines (HeLa, MCF7 and A431). Conclusions: A mild and efficient method has been developed for the synthesis of 2-imino-1,3-oxazines by the ring closure of thiourea adducts of 1,3-amino alcohols. The resulting 1,3-oxazines exert marked antiproliferative action on a panel of human cancer cell lines.",
keywords = "1, 3-amino alcohol, 1, 3-oxazine, Antiproliferative, Asymmetric synthesis, Enantiopure chiral templates, Monoterpene",
author = "Z. Szakonyi and I. Zupk{\'o} and F. F{\"u}l{\"o}p",
year = "2017",
month = "6",
day = "1",
doi = "10.2174/1570179414666161116110813",
language = "English",
volume = "14",
pages = "612--619",
journal = "Current Organic Synthesis",
issn = "1570-1794",
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number = "4",

}

TY - JOUR

T1 - Stereoselective synthesis and antiproliferative activity of monoterpene-fused 2-imino-1,3-oxazines

AU - Szakonyi, Z.

AU - Zupkó, I.

AU - Fülöp, F.

PY - 2017/6/1

Y1 - 2017/6/1

N2 - Background: In the recent years the 2-imino-1,3-thiazine and 2-iminothiazolidine ring systems can be found as moieties in biologically relevant compounds, including BACE1 inhibitors, or cannabinoid receptor agonists, while monoterpene-based 2-imino-1,3-thiazines, prepared from chiral 1,3-amino alcohols exhibiting pronounced antiproliferative activity. Methods: The antiproliferative activities of the prepared compounds were determined in vitro against a panel of human adherent cancer cell lines including HeLa, MCF7 and A431 by MTT assay. Results: Starting from pinane-, apopinane-and carane-based β-amino acid derivatives, 1,3-amino alcohols were prepared via two-step syntheses. The reactions of the product 1,3-amino alcohols and aryl isothiocyanates yielded γ-hydroxythioureas, which were transformed to monoterpene-fused 2-imino-1,3-oxazines via base-catalysed ring closure. The antiproliferative activities of these 2-imino-1,3-oxazines were examined and the structure-activity relationships were studied from the aspects of the type and stereochemistry of the monoterpene ring and the substituent effects on the 1,3-oxazine ring system. The N-unsubstituted monoterpene-based derivatives exhibited considerable antiproliferative activity against a panel of human adherent cancer cell lines (HeLa, MCF7 and A431). Conclusions: A mild and efficient method has been developed for the synthesis of 2-imino-1,3-oxazines by the ring closure of thiourea adducts of 1,3-amino alcohols. The resulting 1,3-oxazines exert marked antiproliferative action on a panel of human cancer cell lines.

AB - Background: In the recent years the 2-imino-1,3-thiazine and 2-iminothiazolidine ring systems can be found as moieties in biologically relevant compounds, including BACE1 inhibitors, or cannabinoid receptor agonists, while monoterpene-based 2-imino-1,3-thiazines, prepared from chiral 1,3-amino alcohols exhibiting pronounced antiproliferative activity. Methods: The antiproliferative activities of the prepared compounds were determined in vitro against a panel of human adherent cancer cell lines including HeLa, MCF7 and A431 by MTT assay. Results: Starting from pinane-, apopinane-and carane-based β-amino acid derivatives, 1,3-amino alcohols were prepared via two-step syntheses. The reactions of the product 1,3-amino alcohols and aryl isothiocyanates yielded γ-hydroxythioureas, which were transformed to monoterpene-fused 2-imino-1,3-oxazines via base-catalysed ring closure. The antiproliferative activities of these 2-imino-1,3-oxazines were examined and the structure-activity relationships were studied from the aspects of the type and stereochemistry of the monoterpene ring and the substituent effects on the 1,3-oxazine ring system. The N-unsubstituted monoterpene-based derivatives exhibited considerable antiproliferative activity against a panel of human adherent cancer cell lines (HeLa, MCF7 and A431). Conclusions: A mild and efficient method has been developed for the synthesis of 2-imino-1,3-oxazines by the ring closure of thiourea adducts of 1,3-amino alcohols. The resulting 1,3-oxazines exert marked antiproliferative action on a panel of human cancer cell lines.

KW - 1, 3-amino alcohol

KW - 1, 3-oxazine

KW - Antiproliferative

KW - Asymmetric synthesis

KW - Enantiopure chiral templates

KW - Monoterpene

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U2 - 10.2174/1570179414666161116110813

DO - 10.2174/1570179414666161116110813

M3 - Article

VL - 14

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EP - 619

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JF - Current Organic Synthesis

SN - 1570-1794

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