Chiral Derivatives of Xanthones: Investigation of the Effect of Enantioselectivity on Inhibition of Cyclooxygenases (COX-1 and COX-2) and Binding Interaction with Human Serum Albumin

Carla Fernandes,Salette Reis,Madalena Pinto,Paula Pinto,Andreia Palmeira,M Saraiva,Inês Ramos,Carlos Afonso,Honorina Cidade,Carlos Carneiro,Maria Tiritan

doi:10.3390/ph10020050

Abstract

Searching of new enantiomerically pure chiral derivatives of xanthones (CDXs) with potential pharmacological properties, particularly those with anti-inflammatory activity, has remained an area of interest of our group. Herein, we describe in silico studies and in vitro inhibitory assays of cyclooxygenases (COX-1 and COX-2) for different enantiomeric pairs of CDXs. The evaluation of the inhibitory activities was performed by using the COX Inhibitor Screening Assay Kit. Docking simulations between the small molecules (CDXs; known ligands and decoys) and the enzyme targets were undertaken with AutoDock Vina embedded in PyRx—Virtual Screening Tool software. All the CDXs evaluated exhibited COX-1 and COX-2 inhibition potential as predicted. Considering that the (S)-(−)-enantiomer of the nonsteroidal anti-inflammatory drug ketoprofen preferentially binds to albumin, resulting in lower free plasma concentration than (R)-(+)-enantiomer, protein binding affinity for CDXs was also evaluated by spectrofluorimetry as well as in in silico. For some CDXs enantioselectivity was observed.

Highlights

A key role of chirality in drug design and development is associated with significant effects on the behavior of this kind of compounds in vivo, with enantiomers being able to interact differently with proteins, and other chiral biomolecules [1,2]
The effect of chiral derivatives of xanthones (CDXs) previously obtained in our group [40,41] as inhibitors of membrane located enzymes that might be involved in inflammatory processes, namely COX-1 and COX-2, was evaluated
Three enantiomeric pairs of CDXs were chosen to study the inhibitory effect of both enantiomers of each pair face to biological targets in order to evaluate potency and enantioselectivity

Summary

Introduction

A key role of chirality in drug design and development is associated with significant effects on the behavior of this kind of compounds in vivo, with enantiomers being able to interact differently with proteins, and other chiral biomolecules [1,2]. These events can be translated into implications in pharmacokinetics (PK) [3], pharmacodynamics (PD) [4] as well as in toxicity [5]. Enantioselectivity can be considered an essential issue to take into several times more potent than the racemate and etodolac, in which the (S)-enantiomer has consideration when studying chiral compounds

Methods

Results

Conclusion