Isolation, Identification and Molecular Docking Studies of a New Isolated Compound, from Onopordon acanthium: A Novel Angiotensin Converting Enzyme (ACE) inhibitor
Graphical abstract
Introduction
Hypertension is one of the greatest public health problems worldwide. It is predicted that by 2025, 60% of the world population will suffer hypertension (Kearney et al., 2005). Since hypertension, results in an increasing risk of developing cardiovascular diseases, kidney diseases (Johnson et al., 2007) and stroke (Stokes et al., 1987), developing new therapeutic approaches is critical (Carretero and Oparil, 2000). It has been accepted that angiotensin converting enzyme (ACE) plays an important role in blood pressure management (Skeggs et al., 1956). ACE (EC 3.4.15.1), a zinc metallopeptidase, cleaves the dipeptide His-Leu residue from the C-terminal of inactive decapeptide angiotensin I (Ang I) and converts it to the potent vasoconstrictor angiotensin II (Ang II). ACE also affects kallikrein–kinin system, by promoting the degradation of bradykinin, which is a potent vasodilator peptide involve in blood pressure management and inflammation (Campbell, 2003). ACE is expressed in two forms, somatic and germinal. Somatic ACE is composed of two catalytic domains (N- and C- domains) with 60% identity in sequence. Each domain consists of a functional active site and distinct functional properties. Germinal ACE exhibits only one domain which is identical to the C-domain of somatic ACE (Kim et al., 2003). Despite the structural identity of the two domains, there are some variations between the active sites, that results in a specific affinity for substrates and designing precise inhibitors. Lack of adequate C-domain specificity for ACE inhibitors, leads to bradykinin accumulation (Van Esch et al., 2005), which result in several adverse side effects associated, such as dry cough and angioedema (Morimoto et al., 2004). On the other hand, in hypotensive patients nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation is induced by Ang II that ends up in oxidative stress, an important factor in cardiovascular diseases and hypertension. So there is a superiority for an antihypertensive drug to possess antioxidant activity.
Medicinal plants are potential sources to discover new drugs. Therefore, searching for natural and selective ACE inhibitors as alternatives to synthetic ones, is of great interest. In our recent report (submit for publication), we have used an in vitro ACE assay to identify plants with ACE inhibition activity. We have found six medicinal plants with promising activities against ACE, including Scotch thistle (Onopordon acanthium L. family Asteraceae) with high antioxidant activity in comparison with butylated hydroxytoluene (BHT) and 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox) as positive controls. O. acanthium mostly grows in Europe, western and central Asia. The plant is up to 1.5 m tall, with hairy leaves, purple flowers and annual life cycle. O. acanthium also grows in Iran, mostly in Azarbayejan province (its local name is khaje bashi). The plant petals are used as a yellow food coloring and flavoring agent. The seeds are a good source for high quality edible oil, the stems are used as a vegetable, and the receptacle is eaten like an artichoke. O. acanthium is used in traditional medicine as an antibacterial, hemostatic, and hypotensive agent (Maugini, 1994, Mariani et al., 2009).
In this study, the active compound with ACE inhibition activity was isolated from O. acanthium, ACE-C and N domain affinity was predicted by molecular docking studies, and the antioxidant activity was determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay.
Section snippets
Chemical reagents
Angiotensin converting enzyme (ACE) from rabbit lung, hippuryl-L-histidyl-L-leucine (HHL) and 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffer were purchased from Sigma-Aldrich Co. (England). 2,2-diphenyl-1-picrylhydrazyl (DPPH), butylated hydroxytoluene (BHT), 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), 2-aminoethyl diphenyl borate (natural product reagent), hydrochloric acid, potassium hydrogen phosphate, sodium chloride, dimethyl solfoxide (DMSO),
Identification of the new isolated compound from O. acanthium
Compound 1 (Fig. 1) was isolated from O. acanthium extract as a yellow crystal structure. This compound has been identified by IR, 1H NMR, 13C NMR and MASS analysis.
Compound 1: C18H14O6; mp 136–139 °C; IR (KBr) νmax cm−1 3463, 3409, 3318, 2928, 1647, 1623, 1575, 1531, 1245, 1200, 975 and 812 cm−1; 1H NMR (500 MHz, DMSO-d6): 2.77 (2 H, t, J=7.6 Hz, H4- isochromen), 3.41 (2 H, m, H3- isochromen), 6.33 (1 H, d, J=15.7 Hz, Hα-vinyl), 6.58 (1 H, dd, J=8.5 & 2.3 Hz, H6- phenyl), 6.74 (1 H, d, J=8.0 Hz, H5-
Discussion
It is accepted that using ACE inhibitors have some benefits in the treatment of heart failure, hypertension, and myocardial infarction. These days most of ACE inhibitors on the market have some adverse side effects. Specific ACE inhibition activity for C-domain, has resulted in developing new ACE inhibitors with fewer side effects. On the other hand, production of reactive oxygen species (ROS) that leads to oxidative stress, plays an important role in cardiovascular disease. Therefore,
Acknowledgements
The authors would like to acknowledge Ms. K. Bagherzadeh for kindly revising the manuscript. The financial supports of the Research Council of the Tehran University of Medical Sciences, is gratefully acknowledged.
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