Discovery and Identification of 2-Phenylethyl 2,6-Dihydroxybenzoate as a Natural Lipid-Lowering Lead

Abstract

Guided by lipid-lowering assays, a new compound (1, 2-phenylethyl 2,6-dihydroxybenzoate) was isolated from the ethanolic extract of Geophila herbacea. The structure of 1 was determined unambiguously by spectral data interpretation and confirmed by X-ray crystallographic analysis. Preliminary dose-dependency of 1 verified its lipid-lowering bioactivity in vitro. A facile chemical synthesis for 1 was performed to provide a practical approach for further studies on structure-activity relationship.

Key words

Lipid-lowering - benzoate - Geophila herbacea - Rubiaceae - LDLR-Luc reporter gene system

References

• 1 Catapano A L. Perspectives on low-density lipoprotein cholesterol goal achievement.  Curr Med Res Opin. 2009;  25 431-477
• 2 LaRosa J C. Low-density lipoprotein cholesterol reduction: the end is more important than the means.  Am J Cardiol. 2007;  100 240-242
• 3 Issandou M. Pharmacological regulation of low density lipoprotein receptor expression: current status and future developments.  Pharmacol Ther. 2006;  111 424-433
• 4 Grand-Perret T, Bouillot A, Perrot A, Commans S, Walker M, Issandou M. SCAP ligands are potent new lipid-lowering drugs.  Nat Med. 2001;  7 1332-1338
• 5 WHO Media centre .Cardiovascular diseases (CVDs). Available at http://www.who.int/mediacentre/factsheets/fs317/en/index.html Accessed January 3, 2011
• 6 Robinson J G. Simvastatin: present and future perspectives.  Expert Opin Pharmacol. 2007;  8 2159-2172
• 7 Kong W, Liu J, Jiang J. Human low-density lipoprotein receptor gene and its regulation.  J Mol Med. 2006;  84 29-36
• 8 Ren G, Rudenko G, Ludtke S J, Deisenhofer J, Chiu W, Pownall H J. Model of human low-density lipoprotein and bound receptor based on CryoEM.  Proc Natl Acad Sci USA. 2010;  107 1059-1064
• 9 Lewis S J. Prevention and treatment of atherosclerosis: a practitioner's guide for 2008.  Am J Med. 2009;  122 S38-S50
• 10 El Harchaoui K, Akdim F, Stroes E S, Trip M D, Kastelein J J. Current and future pharmacologic options for the management of patients unable to achieve low-density lipoprotein-cholesterol goals with statins.  Am J Cardiovasc Drugs. 2008;  8 233-242
• 11 Paragh G, Fülöp P. Impact of lipid lowering therapy on liver function.  Orv Hetil. 2009;  150 1205-1212
• 12 Pedersen T R. Lipid-lowering drugs and risk for cancer.  Curr Atheroscler Rep. 2009;  11 350-357
• 13 Bhutani K K, Birari R, Kapat K. Potential anti-obesity and lipid lowering natural products: a review.  Nat Prod Commun. 2007;  2 331-348
• 14 Bensch W R, Gadski R A, Bean J S, Beavers L S, Schmidt R J, Perry D N, Murphy A T, McClure D B, Eacho P I, Breau A P, Archer R A, Kauffman R F. Effects of LY295427, a low-density lipoprotein (LDL) receptor up-regulator, on LDL receptor gene transcription and cholesterol metabolism in normal and hypercholesterolemic hamsters.  J Pharmacol Exp Ther. 1999;  289 85-92
• 15 Kuhn D J, Burns A C, Kazi A, Dou Q P. Direct inhibition of the ubiquitin-proteasome pathway by ester bond-containing green tea polyphenols is associated with increased expression of sterol regulatory element-binding protein 2 and LDL receptor.  Biochim Biophys Acta. 2004;  1682 1-10
• 16 Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, Wang Y, Wang Z, Si S, Pan H, Wang S, Wu J, Wang Y, Li Z, Liu J, Jiang J. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins.  Nat Med. 2004;  10 1344-1351
• 17 Holy E W, Akhmedov A, Lüscher T F, Tanner F C. Berberine, a natural lipid-lowering drug, exerts prothrombotic effects on vascular cells.  J Mol Cell Cardiol. 2009;  46 234-240
• 18 Mehta K D, Chang R X, Underwood J, Wise J, Kumar A. Identification of a novel cis-acting element participating in maximal induction of the human low density lipoprotein receptor gene transcription in response to low cellular cholesterol levels.  J Biol Chem. 1996;  271 33616-33622
• 19 Tang J, Gao X, Zhang Y. Construction of LDLR-Luc reporter system and screening of cholesterol-lowering drug from Traditional Chinese Medicine.  Nat Prod Res Dev. 2005;  17 316-319
• 20 Ma W, Anderson J E, McLaughlin J L. Bioactive benzyl benzoates from the roots of Endlicheria dysodantha.  Int J Pharmacognosy. 1991;  29 237-239
• 21 Anjaneyulu A S R, Narayana Rao M. Elaeodendrol and elaeodendradiol, new nor-triterpenes from Elaeodendron glaucum.  Phytochemistry. 1980;  19 1163-1169
• 22 Razdan T K, Qadri B, Harkar S, Waight E S. Chromones and coumarins from Skimmia laureola.  Phytochemistry. 1987;  26 2063-2069
• 23 CCDC 795099 contains the supplementary crystallographic data for this compound. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [e-mail], or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK, Fax: + 44 12 23 33 60 33
• 24 Appendino G, Minassi A, Daddario N, Bianchi F, Tron G C. Chemoselective esterification of phenolic acids and alcohols.  Org Lett. 2002;  4 3839-3841
• 25 Node M, Nishide K, Fuji K, Fujita E. Hard acid and soft nucleophile system. 2. Demethylation of methyl ethers of alcohol and phenol with an aluminum halide-thiol system.  J Org Chem. 1980;  45 4275-4277
• 26 Horie T, Tsukayama M, Kawamura Y, Seno M. Studies of the selective O-alkylation and dealkylation of flavonoids. 10. Selective demethylation of 7-hydroxy-3,5,8-trimethoxyflavones with anhydrous aluminum halide in acetonitrile or ether.  J Org Chem. 1987;  52 4702-4709