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

[ Vol. 14 , Issue. 4 ]

Author(s):

Zsolt Szakonyi, Istvan Zupko and Ferenc Fulop   Pages 612 - 619 ( 8 )

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.

Affiliation:

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Szeged, H-6720 Szeged, Eotvos utca 6, Department of Pharmacodynamics and Biopharmacy, University of Szeged, H-6720 Szeged, Eotvos u. 6, MTA-SZTE Stereochemistry Research Group, Hungarian Academy of Sciences, Eotvos u. 6, H-6720 Szeged

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