Sulfur-Containing Monoterpenoids as Potential Antithrombotic Drugs: Research in the Molecular Mechanism of Coagulation Activity Using Pinanyl Sulfoxide as an Example.

Liliya E Nikitina,Aliya V Khaliullina,Sergei V Boichuk,Vladimir V Klochkov,Olga T Shipina,Andrei V Bodrov,Sergei V Kiselev,Valeriya A Startseva,Leisan F Galiullina,Zulfiya R Azizova,Inna V Fedyunina,Olga A Lodochnikova

doi:10.3389/fphar.2018.00116

Abstract

In this article we present the synthesis of enantiomerically pure sulfoxide and study the influence of this compound on hemostasis. Detailed NMR studies and molecular dynamics simulations using sodium dodecyl sulfate (SDS) membrane models indicated that the bicyclic fragment of sulfoxide was embedded into the SDS micelle whereas the -SO(CH2)2OH fragment remained on the surface of the micelle and was in contact with the solvent. We also found that the pro-coagulative activity of sulfoxide was due to its ability to inhibit platelet activation and inhibited the catalytic activity of phospholipid surface which was involved in formation of coagulation clotting factor complexes.

Highlights

It is well-known that ischemic heart disease and ischemic strokes are the world leaders among the cardiovascular diseases
In this article we present the synthesis of enantiopure sulfoxide 2a and study the influence of this compound on hemostasis
According to results of previous researches, optically active sulfoxides of the terpene series were prepared by the oxidation of the corresponding sulfides using various oxidizing agents, including m-chloroperbenzoic acid (Binns et al, 1985; Annunziata et al, 1987; Eschler et al, 1988; Pyne et al, 1989; Arai et al, 1991), sodium periodate (Vargas-Díaz et al, 2005), air oxygen (Nikitina et al, 2001), as well as by the Kagan-Modena and Bolm asymmetric oxidation methods (Yang et al, 1994; Aversa et al, 2002; Demakova et al, 2012a,b)

Summary

INTRODUCTION

It is well-known that ischemic heart disease and ischemic strokes are the world leaders among the cardiovascular diseases. The changes in the vascular wall caused by atherosclerosis promote the activation of platelets and coagulation hemostasis, which lead to the formation of a thrombus substantially reducing or completely blocking the blood flow. Activation of platelets and coagulation hemostasis caused by atherosclerosis lead to formation of thrombus. Despite sodium citrate or heparin are commonly used as the anticoagulants of blood products preservation, the stabilizing effects of these compounds are insufficient due to formation of the platelets microvesicles. Sulfur is biogenic element and sulfur-containing compounds are widely represented both in natural products and synthetic biologically active substances. Combination of terpene fragment and biogenic sulfur-containing functional groups into one molecule allows to obtain new compounds with biologically active properties. In this article we present the synthesis of enantiopure sulfoxide 2a and study the influence of this compound on hemostasis

MATERIALS AND METHODS

RESULTS

DISCUSSION