Many naturally occurring xanthones are chiral and present a wide range of biological and pharmacological activities. Some of them have been exhaustively studied and subsequently, obtained by synthesis. In order to obtain libraries of compounds for structure activity relationship (SAR) studies as well as to improve the biological activity, new bioactive analogues and derivatives inspired in natural prototypes were synthetized. Bioactive natural xanthones compromise a large structural multiplicity of compounds, including a diversity of chiral derivatives. Thus, recently an exponential interest in synthetic chiral derivatives of xanthones (CDXs) has been witnessed. The synthetic methodologies can afford structures that otherwise could not be reached within the natural products for biological activity and SAR studies. Another reason that justifies this trend is that both enantiomers can be obtained by using appropriate synthetic pathways, allowing the possibility to perform enantioselectivity studies. In this work, a literature review of synthetic CDXs is presented. The structures, the approaches used for their synthesis and the biological activities are described, emphasizing the enantioselectivity studies.
A new series of thirty‐two new enantiomerically pure derivatives of xanthones (3–34) were synthesized for antitumor evaluation. Two carboxyxanthones (1 and 2) were used as chemical substrates and coupled with selected chiral building blocks (43–62), achieving yields and enantiomeric excess (ee) values higher than 92 and 99 %, respectively. Carboxyxanthones 1 and 2 were synthesized, by a multi‐step synthetic pathway via diaryl ether intermediate (Ullman reaction), being compound 2 described here for the first time. The evaluation of the growth inhibitory activity allowed to find active chiral compounds for all the tested cells lines, and to establish structure‐activity relationship (SAR) considerations. In some cases, the growth inhibitory effects demonstrated to be dependent on the stereochemistry of the compounds. Interestingly, the most active compound (12) and its enantiomer (11) demonstrated high enantioselectivity for MCF‐7 breast adenocarcinoma cell line. In addition, in vitro DNA crosslinking ability was assessed and the results correlated with in vitro cytotoxicity.
The enantioresolution and determination of the enantiomeric purity of 32 new xanthone derivatives, synthesized in enantiomerically pure form, were investigated on (S,S)-Whelk-O1 chiral stationary phase (CSP). Enantioselectivity and resolution (α and R ) with values ranging from 1.41-6.25 and from 1.29-17.20, respectively, were achieved. The elution was in polar organic mode with acetonitrile/methanol (50:50 v/v) as mobile phase and, generally, the (R)-enantiomer was the first to elute. The enantiomeric excess (ee) for all synthesized xanthone derivatives was higher than 99%. All the enantiomeric pairs were enantioseparated, even those without an aromatic moiety linked to the stereogenic center. Computational studies for molecular docking were carried out to perform a qualitative analysis of the enantioresolution and to explore the chiral recognition mechanisms. The in silico results were consistent with the chromatographic parameters and elution orders. The interactions between the CSP and the xanthone derivatives involved in the chromatographic enantioseparation were elucidated.
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