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Pistagremic acid, a novel β-secretase enzyme (BACE1) inhibitor from Pistacia integerrima Stewart a
a
b
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Abdur Rauf , Ghias Uddin , Ajmal Khan , Bina S. Siddiqui , a
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Mohammad Arfan , Kourosh Dalvandi & Taibi Ben Hadda
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Institute of Chemical Sciences, University of Peshawar, Peshawar 25120, KPK, Pakistan b
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H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan c
Dr. Panjwani Centre for Molecular Medicine and Drug Research, International Centre for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan d
Laboratoire Chimie Matériaux, FSO, Université Mohammed Premier, Oujda 60000, Morocco Published online: 15 Jan 2015.
To cite this article: Abdur Rauf, Ghias Uddin, Ajmal Khan, Bina S. Siddiqui, Mohammad Arfan, Kourosh Dalvandi & Taibi Ben Hadda (2015): Pistagremic acid, a novel β-secretase enzyme (BACE1) inhibitor from Pistacia integerrima Stewart, Natural Product Research: Formerly Natural Product Letters, DOI: 10.1080/14786419.2014.997231 To link to this article: http://dx.doi.org/10.1080/14786419.2014.997231
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Natural Product Research, 2015 http://dx.doi.org/10.1080/14786419.2014.997231
SHORT COMMUNICATION Pistagremic acid, a novel b-secretase enzyme (BACE1) inhibitor from Pistacia integerrima Stewart Abdur Raufa*, Ghias Uddina, Ajmal Khanb, Bina S. Siddiquib, Mohammad Arfana, Kourosh Dalvandic and Taibi Ben Haddad
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a
Institute of Chemical Sciences, University of Peshawar, Peshawar 25120, KPK, Pakistan; bH.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; cDr. Panjwani Centre for Molecular Medicine and Drug Research, International Centre for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; dLaboratoire Chimie Mate´riaux, FSO, Universite´ Mohammed Premier, Oujda 60000, Morocco (Received 31 October 2014; final version received 6 December 2014)
HOOC
O Pistacia integerrima J. L. Stewart
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Novel Betasecretase enzyme inhibitor
Pistagremic acid
Graphical abstract illustrating the chemical structure of pistagremic acid isolated from P. integerrima; pistagremic acid exhibited significantly active against b-secretase enzyme (BACE1).
A new triterpenic compound named pistagremic acid (PA) was once again isolated from Pistacia integerrima. The b-secretase inhibition study was carried out. Compound PA was found significantly active against b-secretase enzyme (BACE1) with IC50 value of 350 ^ 2 nM in comparison to the standard inhibitors [Asn670, Sta671, Val672]-amyloid-b/A4 precursor protein 770 fragment 662 – 675 (IC50 ¼ 290.71 ^ 1 nM). The selectivity of this compound was also evaluated against the acetylcholinesterase and butyrylcholinesterase enzymes. Interestingly compound PA was found to be inactive against them and showed selectivity towards b-secretase enzyme (BACE1). Keywords: Pistacia integerrima; pistagremic acid; triterpenoid; b-secretase; selectivity; acetylcholinesterase and butyrylcholinesterase
1. Introduction Alzheimer’s disease (AD) is a nerve degenerative disease characterised by formation of senile plaques and neurofibrillary tangles together with degeneration and disappearance of nerve cells. The senile plaques that is most characteristic of AD are deposits consisting primarily of b-amyloid protein (also referred to hereinafter as Ab) in the brain (Glenner & Wong 1984). Ab consisting of 40 or 42 amino acids (hereinafter abbreviated as Ab1-40 and Ab1-42, respectively) is known to be toxic to nerve cells (Vassar et al. 1999; Miyamoto et al. 2005).
*Corresponding author. Emails:
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It is generally recognised that an excess level of Ab in the brain over a long time period is a leading factor in the pathogenesis of Alzheimer’s disease (AD) (Citron 2002). Logically, clinical intervention to reduce Ab levels in the brain has been an attractive therapeutics approach for this disease. The homeostasis level Ab in the brain is a consequence of its production, efflux out of the brain, degradation and possibly formation of insoluble aggregates in AD brains. Clinically, each of these factors can be manipulated to achieve a reduction of Ab level. The inhibition of Ab production is much more appealing. Ab is generated in neurons from amyloid precursor protein (APP) by the activities of two aspartic proteases, b-secretase (memapsin 2, BACE1) and g-secretase (Ghosh et al. 2012). g-Secretase inhibitor drugs have been actively pursued over the years and several compounds have been brought to human trials. A major obstacle of g-secretase inhibitors is their toxicity (Wolfe, 2008). Some of the toxicity of g-secretase inhibitors may have come from the lack of compensatory pathways for these important physiological functions. At present, it is not clear if the function of g-secretase in Ab production can be specifically inhibited without interfering with other important functions of this protease. The development of b-secretase inhibitor drugs, however, presented a different set of problems. b-Secretase (memapsin 2; BACE1) is the first protease involved in processing of APP leading to the production of Ab in the brain. It is believed that high levels of Ab in the brain are responsible for the pathogenesis of AD. Therefore, b-secretase is a major therapeutic target for the development of inhibitor drugs (Ghosh et al. 2012). Pistacia integerrima belongs to family Anacardiacea. It is commonly known as kakar singhi. It is distributed in the eastern Himalayan range from Indus to Kumaon (Anonymous 1998) at a height of 12,000 to 8000 feet. P. integerrima is a medium sized deciduous tree that can achieve a height of 40 ft. P. integerrima is a significant medicinal plant and is used as an antiinflammatory, antidiabetic agent, a blood cleanser, a tonic for gastrointestinal disorders and as cough expectorant (Rauf et al. 2014). In Pakistan, galls of P. integerrima are used for treatment of hepatitis and other liver disorders (Ahmad et al. 2010). It has also been reported to possess CNS depressant activity (Ansari et al. 1994). Recently, we have isolated pistagremic acid (PA) from P. integerrima (Rauf, Uddin, Latif, et al. 2014; Rauf, Uddin, Siddiqui, et al. 2014). The single X-ray crystallography of PA was published with Reference: BQ2281 (Arfan et al. 2011). The present invention relates to the discovery PA a novel inhibitor of the aspartyl protease BACE (beta-secretase) isolated from P. integerrima and can be use for treating diseases caused by Ab peptide depositions such as AD. 2. Results and discussions Shade-dried and crushed bark of P. integerrima was repeatedly extracted with MeOH (X5) at room temperature. The extracts were suspended in water and successively partitioned with various organic solvents to obtain CHCl3 and EtOAc fractions. The EtOAc fraction (30 g) was subjected to repeated chromatography using silica gel and further purified by the recrystallisation process. To obtain pure and larger crystals, these crystals were re-grown from a mixture of n-hexane – acetone and chloroform (70:20:10) and thus obtained a compound named PA (50 mg). b-Secretase, (BACE 1), processing of b-APP is the first step in the pathway leading to the production of Ab, thus it is a major target for the development of a drug for the treatment of AD. Although there are distinctive advantages of this protease as a drug target, the development of drug-like b-secretase inhibitors has been somewhat slow since the cloning of the protease 7 years ago. The beta secretase enzyme (BACE1) is essential for formation of Ab. It has been shown that BACE1 levels are elevated in AD, therefore, study on BACE1 inhibition can help to develop AD therapies. However, recent studies indicate that block BACE1 may be
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associated with AD signs and symptoms to recent data detailing the apparent dysregulation of BACE1 in AD (3). Keeping the importance of b-secretase (BACE 1) inhibition in mind, the compound PA was isolated from P. integerrima and evaluated for in vitro b-secretase, (BACE 1) inhibition studies. The compound PA was found significantly active in nano-molar range against b-secretase, (BACE 1) enzyme with IC50 value of 350 ^ 2 nM in comparison to the standard inhibitors [Asn670, Sta671, Val672]-Ab/A4 precursor protein 770 fragment 662 – 675 (IC50 ¼ 290.71 ^ 1 nM). The activity of this may be due to the carboxyl group of this compound. In order to check the selectivity of compound PA for b-secretase, compound PA was also evaluated against acetylcholinesterase and butyrylcholinesterase enzymes. Compound PA was found to be inactive against both enzymes and shows selectivity towards b-secretase enzyme (BACE1).
3. Conclusion Natural compounds can provide a good pharmacophore template for new drugs associated with various diseases. The high levels of brain Ab are responsible for the pathogenesis of AD, and b-secretase is a major enzyme responsible for production and is a therapeutic target for the development of inhibitor drugs. In this study, the natural compound PA inhibits bsecretase significantly and can be used as a good template compound for drugs used in the AD.
Supplementary material Experimental details related to this article along with chemical structure and crystallographic image are available online (see supplementary data online only).
Funding The authors are grateful for the financial supported by Higher Education Commission of Pakistan and Institute of Chemical Sciences, University of Peshawar, Peshawar, Pakistan.
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