Design, synthesis and biological evaluation of novel emodin derivatives as potent antidyslipidemic and antioxidant agents

Hyperlipidemia is the presence of abnormal levels of lipids or lipoproteins in the blood, which contributes in the manifestation of atherosclerosis and other cardiovascular diseases [1]. As a part of our drug discovery program on antidyslipidemic agents, a large quantity of Emodin (1) was isolated from the roots of Rheum emodi L. (Polygonaceae) [2]. We studied antidyslipidemic activity in triton (WR-1339) induced hyerlipidemic rat model the naturally occurring anthraquinone emodin (1) and its synthetic derivatives 2-15. The administration of triton in rats induced marked hyperlipidemia by increasing the plasma levels of TC (2.11 folds), PL (2.37 folds) and TG (2.44 folds) compared to control rats. Treatment of hyperlipidemic rats with 2-15 at 100 mg/kg p.o. reversed the plasma levels of lipids. Emodin (1) caused a decrease in plasma levels of TC by 27% (133.50 ± 10.06 mg/dl), PL by 26% (150.75 ± 11.08 mg/dl) and TG by 28% (155.36 ± 11.05 mg/dl) respectively as compared to triton induced rats. Among 2-15, the C-alkylated emodin derivative 9 turned out to be most potent lipid lowering agent, causing a decrease in plasma levels of TC, PL and TG by 39%, 35% and 39%, respectively, as compared to triton induced rats whereas the marketed lipid lowering drug gemfibrozil decreased the levels of TC, PL and TG in plasma by 34%, 33% and 33%, respectively. Further compound 9 was studied for lecithin-cholesterol acyltransferase (LCAT) activity. Administration of triton in rats markedly decreased LCAT activity in liver by 38%. After treatment with compound 9, LCAT activity was significantly increased by 25% similar to standard drug gemfibrozil. The scavenging potential of 9 at 200 µg/ml was studied and a significant decrease in superoxide anions (36%) and hydroxyl radicals (31%) were observed. Furthermore, compound 9 at 200 µg/ml reduced the microsomal lipid peroxidation (35%). Altogether our results suggest that 9 could be a potential new class of therapeutic agent for dyslipidemia treatment.

Acknowledgements: Sukanya Pandeti is thankful to Council of Scientific and Industrial Research (CSIR), New Delhi for financial support and SAIF, CDRI for spectral data.

Keywords: Emodin derivatives, Rheum emodi, LCAT activity, antidyslipidemic activity, antioxidant activity, LDL oxidation.

References:

[1] Grundy M. Cholesterol and coronary heart disease a new era. JAMA 1986; 256: 2849 – 2858

[2] Agarwal K, Singh S, Verma S, Kumar S. Antifungal activity of anthraquinone derivatives from Rheum emodi. J Ethnopharmacol 2000; 72: 43 – 46