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Current Organic Synthesis

Editor-in-Chief

ISSN (Print): 1570-1794
ISSN (Online): 1875-6271

Research Article

Stereoselective Synthesis and Antiproliferative Activity of Monoterpene-Fused 2- Imino-1,3-oxazines

Author(s): Zsolt Szakonyi*, Istvan Zupko and Ferenc Fulop

Volume 14 , Issue 4 , 2017

Page: [612 - 619] Pages: 8

DOI: 10.2174/1570179414666161116110813

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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 ϒ-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: Monoterpene, asymmetric synthesis, enantiopure chiral templates, 1, 3-amino alcohol, 1, 3-oxazine, antiproliferative.

Graphical Abstract

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