Synthesis and Anti-Inflammatory Evaluation of a Library of Chiral Derivatives of Xanthones Conjugated with Proteinogenic Amino Acids

Abstract

In recent decades, the relationship between drug chirality and biological activity has been assuming enormous importance in medicinal chemistry. Particularly, chiral derivatives of xanthones (CDXs) have interesting biological activities, including enantioselective anti-inflammatory activity. Herein, the synthesis of a library of CDXs is described, by coupling a carboxyxanthone (1) with both enantiomers of proteinogenic amino esters as chiral building blocks (2–31), following the chiral pool strategy. The coupling reactions were performed at room temperature with good yields (from 44 to 99.9%) and very high enantiomeric purity, with most of them presenting an enantiomeric ratio close to 100%. To afford the respective amino acid derivatives (32–61), the ester group of the CDXs was hydrolyzed in mild alkaline conditions. Consequently, in this work, sixty new derivatives of CDXs were synthetized. The cytocompatibility and anti-inflammatory activity in the presence of M1 macrophages were studied for forty-four of the new synthesized CDXs. A significant decrease in the levels of a proinflammatory cytokine targeted in the treatment of several inflammatory diseases, namely interleukin 6 (IL-6), was achieved in the presence of many CDXs. The amino ester of L-tyrosine (X1AELT) was the most effective in reducing IL-6 production (52.2 ± 13.2%) by LPS-stimulated macrophages. Moreover, it was ≈1.2 times better than the D-enantiomer. Indeed, enantioselectivity was observed for the majority of the tested compounds. Thus, their evaluation as promising anti-inflammatory drugs should be considered.

Evaluation of Antitumor Activity of Xanthones Conjugated with Amino Acids

“…The levels of a proinflammatory cytokine targeted in the treatment of several inflammatory diseases were significantly decreased in the presence of many CDXs. Enantioselectivity could be observed for the majority of the evaluated enantiomeric pairs [15]. Here, the aim of this study was to screen a library of previously synthesized CDXs in a panel of cancer cell lines to identify the most promising compounds for further study as possible chemotherapy drugs, as well as to analyze their effect on parameters, like the mechanism of cell death, cell cycle, and metabolism, and verify whether the compounds under study were substrates of Pgp, one of the main mechanisms of resistance in cancer therapy.…”

“…Nevertheless, one of the main biological activities reported within this class of compounds is their antitumor activity [12][13][14]. Xanthone is an aromatic oxygenated heterocyclic molecule, with a dibenzo-γ-pirone scaffold, known as 9H-xanthen-9-one, which permits chemical modifications in different positions of the molecule scaffold, including the association of the chiral moiety, allowing for the preparation of libraries of derivatives for enantioselective structure-activity relationships [14,15]. The rule of stereochemistry in the biological activity of natural or synthetic compounds has been demonstrated over the years and can be considered one of the main roads for the discovery and development of new drugs [8].…”

“…The rule of stereochemistry in the biological activity of natural or synthetic compounds has been demonstrated over the years and can be considered one of the main roads for the discovery and development of new drugs [8]. The enantiomers generally have different pharmacokinetic and/or pharmacodynamic properties, and the use of single enantiomers has often demonstrated advantages in terms of efficacy, potency, selectivity, and safety [15][16][17][18]. Thus, the enantioselectivity is recommended to be evaluated in the early stage of drug development [18,19].…”

“…The xanthone nucleus is considered a privileged structure, given its ability to have diverse substituents and, consequently, bind to several biotargets [12], and its association with a chiral moiety can improve the potency and the selectivity of their derivatives in the biological activity [11,15,20,21]. The introduction of amino acids into natural products is expected to improve both pharmacodynamics and pharmacokinetics of these compounds and minimize their adverse effects [22].…”

“…The association of xanthone with amino acids as potential anticancer and DNA-binding agents has been reported, but the enantioselectivity was not explored [24]. Recently, we reported the synthesis of a library of sixty chiral derivatives of xanthones (CDXs) based on coupling a carboxyxanthone with amino esters and amino acids following the chiral pool strategy [15]. The cytocompatibility and anti-inflammatory activity were studied for forty-four of the newly synthesized CDXs.…”