Novel perspective substances with selective anti-aggregant action

Abstract

Aim. To study the influence of new sulfur-containing derivatives of β-pinene on the platelet aggregation ability and coagulant activity of human serum in vitro. Methods. A series of sulfides and sulfoxides have been synthesized based on β-pinene. Sulfides have been synthesized by the electrophilic addition reaction of thiols to the double bond of β-pinene in the presence of ZnCl 2. Sulfides were oxidized to sulfoxides by such oxidizing agents as sodium periodate, meta-Chloroperoxybenzoic acid, selenium dioxide with hydrogen peroxide and sulfuryl chloride in combination with ethyl alcohol. The best result was achieved by asymmetric oxidation method using the Ti(O-i-Pr) 4/(R)-mandelic acid /t-BuOOH oxidation system. Structure of synthesized compounds was ascertained by 1Н and 13С nuclear magnetic resonance, chromatomass spectrometry and X-ray structural analysis. Clotting activity of synthesized substances was evaluated by platelets aggregating rates and standard surface-dependent coagulation tests. Venous blood from patients with ischemic heart disease and evident changes in hemostasis system were used to determine spontaneous platelets aggregation and serum clotting activity. The induced platelets aggregation was studied on serum obtained from healthy donors. Results. The basic substance (β-pinene) did not influence the hemostasis system status in patients with ischemic heart disease. The substances synthesized on its basis have shown high anti-aggregatory activity: spontaneous velocity and aggregation coefficient reduced significantly and even reached normal values in some cases. Besides, they reduced the serum clotting activity, normalized activated partial thromboplastin time, prothrombin time international normalized ratio. However, the activity of thrombin was not influenced. The most water-soluble sulfoxide showed the most activity and almost completely inhibited spontaneous and collagen-induced and arachidonic acid-induced platelet aggregation, as well as better reduced the serum clotting activity in patients with ischemic heart disease compared to other synthesized substances. Conclusion. Taking into account low toxicity of thioterpenoids, the novel substances can be described as potentially promising drugs for medical treatment and prevention of thrombophilia and as agents for blood stabilization.

Keywords

β-pinene / sulfides and sulfoxides / platelets / anti-aggregating and anti-coagulating activity

References

[1] Аникиенок М.О., Никитина Л.Е., Ильинская О.Н. Характеристика токсических и генотоксических эффектов новых производных карановой и ментановой структур по отношению к бактериям // Вестн. Татарстан. отделения Рос. эколог. академии. - 2006. - Т. 1, №27. - С. 23-26.

[2] Арефьев А.В., Старцева В.А., Никитина Л.Е. Разработка синтетического подхода к диастереомерно чистым сульфоксидам пинанового ряда // Химия в интересах устойчивого развития. - 2012. - Т. 20. - С. 249-252.

[3] Арефьев А.В., Старцева В.А., Никитина Л.Е. и др. Получение и изучение свойств двух полиморфных модификаций бета-гидроксисульфоксида пинанового ряда // ЖОХ. - 2012. - Т. 82, вып. 3. - С. 447-452.

[4] Киселёв С.В., Зубаиров Д.М., Киршин С.В. Влияние радиационного воздействия на взаимодействие протромбина с фрагментами клеточных мембран // Бюлл. эксп. биол. и мед. - 2002. - №11. - С. 515-518.

[5] Кисёлев С.В., Зубаиров Д.М., Тимербаев В.Н. Взаимодействие фактора Х человека с тканевым тромбопластином // Биомед. хим. - 2003. - Т. 49, №5. - С. 443-450.

[6] Никитина Л.Е., Диева С.А., Племенков В.В. 7,7-диметил-2,10-эпоксибицикло[3.1.1]гептан. Синтез, структура и продукты раскрытия эпоксидного цикла // ЖОХ. - 2001. - Т. 71, вып. 8. - С. 1233-1237.

[7] Никитина Л.Е., Артёмова Н.П., Старцева В.А. Природные и тиомодифицированнные монотерпеноиды. - Germany: LAP LAMBERT, 2012. - 167 с.

[8] Born G. Aggregation of blood platelets by adenosine diphosphate and its reversal // Nature (London). - 1962. - Vol. 194. - P. 927-929.

[9] Farzaneh M., Ahmadzadeh M., Hadian J. et al. Chemical composition and antifungal activity of the essential oils of three species of Artemisia on some soilborne phytopathogens // Commun. Agric. Appl. Biol. Sci. - 2006. - Vol. 71, iss. 3. - P. 1327-1333.

[10] Hechler B., Lenain N., Marchese P. et al. A role of the fast ATP-gated P2X1 cation channel in trombosis of small arteries in vivo // J. Exp. Med. - 2003. - Vol. 198. - P. 661-667.

[11] Hechler B., Mangenat S., Zighetti M.L. et al. Inhibition of platelet functions and thrombosis through selective or nonselective inhibition of the platelet P2 receptors with increasing doses of NF449 [4,4’,4’’,4’’’-carbonylbis(imino5,1,3-benzenetriylbis-(carbonylimino))]tetrakis-benzene-1,3disulfonicacidoctasodium salt // J. Pharmacol. Exp. Ther. - 2006. - Vol. 314. - P. 232-243.

[12] Oury C., Toth-Zsamboki E., Thys C et al. The ATPgated P2X1 ion channel acts a positive regulator of platelet responses to collagen // Thromb. Haemost. - 2001. - Vol. 86. - P. 1264-1271.

[13] Oury C., Kuijpers M.J., Toth-Zsamboki E. et al. Overex pression of the platelet P2X1 ion channel in transgenic mice generates a novel prothrombotic phenotype // Blood. - 2003. - Vol. 101. - P. 3969-3976.

[14] Rolf M.G., Mahaut-Swith M.P. Effects of enhanced P2X1 receptor Ca2+ signals functional responses in human platelets // Thromb. Haemost. - 2002. - Vol. 88. - P. 495-502.

RIGHTS & PERMISSIONS

Kiselev S.V., Nikitina L.E., Vorontsova M.M., Turaev R.G.