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Structure-Activity Relationships for Bergenin Analogues As Β-Secretase

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Structure-Activity Relationships for Bergenin Analogues As Β-Secretase Journal of Oleo Science Copyright ©2013 by Japan Oil Chemists’ Society J. Oleo Sci. 62, (6) 391-401 (2013) Structure-activity Relationships for Bergenin Analogues as β-Secretase (BACE1) Inhibitors Yusei Kashima and Mitsuo Miyazawa＊ Department of Applied Chemistry, Faculty of Science and Engineering, Kinki University (3-4-1, Kowakae, Higashiosaka-shi, Osaka 577-8502, JAPAN) Abstract: Here we evaluated the inhibitory effects of bergenin analogues (2-10), prepared from naturally occurring bergenin, (1) on β-secretase (BACE1) activity. All the bergenin analogues that were analyzed inhibited BACE1 in a dose-dependent manner. 11-O-protocatechuoylbergenin (5) was the most potent inhibitor, with an IC50 value of 0.6 ± 0.07 mM. The other bergenin analogues, in particular, 11-O-3′,4′- dimethoxybenzoyl)-bergenin (6), 11-O-vanilloylbergenin (7), and 11-O-isovanilloylbergenin (8), inhibited BACE1 activity with IC50 values of <10.0 mM. BACE1 inhibitory activity was influenced by the substituents of the benzoic acid moiety. To the best of our knowledge, this is the first report on the structure-activity relationships (SAR) in the BACE1 inhibitory activities of bergenin analogues. These bergenin analogues may be useful in studying the mechanisms of Alzheimer’s disease. Key words: bergenin, bergenin analogues, β-secretase, antioxidant activity, structure-activity relationships 1 INTRODUCTION in adult mice was without any significant effect on brain Alzheimer’s diseas（e AD）is a neurodegenerative disorder, neuregulin processing9）, indicating that BACE1 inhibitors with symptoms such as memory loss and disruption in could be established as therapeutic targets for AD. judging, reasoning, and emotional stability. AD is pathologi- Oxidative stress also a cause of AD has been proposed to cally characterized by the accumulation of senile plaques, contribute to Aβ generation and the formation of NFT10）. neurofibrillary tangle（s NFT）, synaptic loss, and neuronal The β-amyloid peptide（Aβ）generates free radicals in a death. Much of AD research has been focused on the metal-catalyzed reaction, inducing neuronal cell death by amyloid cascade hypothesis, which states that β-amyloid reactive oxygen specie（s ROS）, which peroxidize mem- peptide（Aβ）, a proteolytic derivative of the large trans- brane lipids and oxidize proteins, producing drastic cellular membrane protein amyloid precursor protein（APP）, plays damages. Upregulation of lipid peroxidation leads to amy- an early role in the pathogenesis of AD1）. Aβ peptides, the loidogenesis through increased expression and activity of major constituent of senile plaques found in the brain of BACE111, 12）. Expression of BACE1 increases in conditions patients with AD, are generated from the cleavage of APP of oxidative stress caused by the lipid peroxidation product by β-secretas（e BACE1: β-site APP cleaving enzyme-1）and 4-hydroxynonena（l HNE）and hydrogen peroxide, indicat- γ-secretase. β-Secretase cleavage results in the production ing a correlation between BACE1 activity and oxidative of soluble APPβ and a membrane-associated C-terminal stress marker in AD brain13, 14）. In addition, microglia acti- fragment, C99 2, 3）. After the β-secretase cleavage, vated by oxidative damage release proinflammatory and γ-secretase cleaves C99 within its transmembrane domain free radicals, leading to various inflammatory reactions that to generate Aβ peptides. Thus, these secretases have been cause damage to neurons. Enhanced inflammation induces recognized as the key enzymes that commit APP catabo- the generation of ROS in ambient neurons, which contrib- lism to the amyloidogenic pathway4－6）. However, inhibition ute to Aβ generation15）. It is generally accepted that oxida- of γ-secretase may elicit unwanted side effects as it is in- tive damage in cellular structures precedes the phenome- volved in Notch processing7, 8）. Therefore, β-secretase is non of other pathological hallmarks of AD, and therefore, considered a better target than γ-secretase for the develop- oxidative stress as well as Aβ is an early causative event in ment of anti-AD agents with less severe side effects. More- the pathogenesis and progression of AD. On the basis of over, a recent report showed that inhibition of β-secretase these data, it can be concluded that drugs specifically scav- ＊Correspondence to: Mitsuo Miyazawa, Department of Applied Chemistry, Faculty of Science and Engineering, Kinki University, 3-4-1, Kowakae, Higashiosaka-shi, Osaka 577-8502, JAPAN E-mail: [email protected] Accepted February 5, 2013 (received for review December 1, 2012) Journal of Oleo Science ISSN 1345-8957 print / ISSN 1347-3352 online http://www.jstage.jst.go.jp/browse/jos/ http://mc.manusriptcentral.com/jjocs 391 Y. Kashima and M. Miyazawa enging oxygen radicals could be useful for either the pre- tentially active. Furthermore, its esterified analogues occur vention and treatment of AD16）. widely in several plants, especially those used in traditional To have therapeutic potential, inhibitors should be able medicines36－39）, and are commonly found in plant extracts40－43）. to penetrate the blood-brain barrier and thus have molecu- In the present study, bergenin analogue（s 2-10）were pre- lar weights below 700 Da16）. Therefore, large peptide-based pared from naturally occurring bergenin（1）（Fig. 1）and in- inhibitors are not proper drug candidates, but the second- vestigated for their inhibitory effects against BACE1 activi- ary metabolites of plants, which have relatively low molecu- ty. To the best of our knowledge, this is the first report on lar weights and high lipophilicity, may be potential drugs the correlation between BACE1 inhibition and the struc- against AD. Polyphenols are a group of phytochemicals tures of bergenin and its analogues. that exhibit a wide range of physiological and therapeutic properties. Phenolic compounds could be a major determi- nant of the potential of food as a source of natural antioxi- dants17）. Phenolic compounds might be good candidates for 2 EXPERIMENTAL PROCEDURES BACE1 inhibitors; however, natural product inhibitors have 2.1 Materials rarely been reported18－23）. Here, we focused on the analysis Thin layer chromatograph（y TLC）was performed on pre- of these antioxidant substances. coated plate（s silica gel 60 F254, 0.25 mm, Merck, Darmstadt, Bergenin, a unique phenolic compound, has been isolat- Germany）. Column chromatography was carried out using ed from the Bergenia species, roots of Caesalpinia 70-230 mesh silica ge（l Kieselgel 60, Merck, Germany）. digyna, bark of Corylopsis spicata, and bark of Mallotus Melting point（s m.p）were measured on an MP-5000D philippinensis24－27）. It exhibits various biological activi- melting point apparatus and were uncorrected. Optical ro- ties, such as antioxidant27, 28）, anti-inflammatory29）, anti-ar- tations were measured on a LTDDIP-1000 polarimeter thritis30）, hypolipidemic31）, anti-HIV32）, antiarrhythmic33）, （Japan Spectroscopic Co.）. 1H and 13C NMR data were all hepatoprotective34）, and antinociceptive effects35）. Bergenin obtained with a JEOL ECA-400（400 MHz）spectrometer in contains 5 hydroxyl groups, which are considered to be po- DMSO-d6 or CDCl3 with tetramethylsilan（e TMS）as internal Fig. 1 Structure of bergenin and its analogues (1-10). 392 J. Oleo Sci. 62, (6) 391-401 (2013) BERGENIN ANALOGUES AS β-SECRETASE INHIBITOR standard（chemical shift in δ, ppm）. J values were reported in hertz. Infrared（IR）spectra were obtained with a Jasco FT/IR-470 plus Fourier transform infrared spectrometer. Electron ionization mass spectrometry（EI-MS）spectra were obtained on a JEOL JMS-700 Tandem MS station （Japan Electron Optics Laboratory Co., Ltd.）. The absor- bance or fluorescence was measured with an MTP-800Lab microplate reader. A BACE1（recombinant human BACE1） assay kit was purchased from PanVera Co（. USA）. 1,1-Di- phenyl-2-picrylhydrazy（l DPPH）, dibutylhydroxytoluene （BHT）, benzoic acid, p-hydroxybenzoic acid, p-anisic acid, protocatechuic acid, 3,4-dimethoxy benzoic acid, vanillic acid, isovanillic acid, 3,5-dimethoxy benzoic acid, syringic acid, diisopropyl azodicarboxylate（DIAD）, tetraki（s triphe- nyl phosphine）palladium［Pd（PPh3）4］, triphenylphosphine （Ph3P）, sodium iodid（e NaI）, morpholine, and allyl bromide were purchased from Tokyo Kasei Kogyo. All solvents were purchased from Kanto Chemical. 2.2 Isolation of bergenin The bark（5.0 kg）of Bergenia ligulata was extracted once with MeOH at room temperature. The solution was evaporated until it dried in vacuo to obtain a MeOH Fig. 2 Isolation scheme of bergenin (1) from Bergenia extrac（t 480 g）. The residue was re-extracted successively ligurata. with n-hexane, CH2Cl2, EtOAc, n-BuOH, and water. Each fraction was concentrated to dryness in vacuo to give n- hexane extrac（t 12.5 g）, CH2Cl2 extrac（t 40.5 g）, EtOAc 10.8, 1.8 Hz, 2×＝CHa）, 5.40（2H, dd, J＝17.2 Hz, 1.8, 2× extrac（t 88.2 g）, n-BuOH extrac（t 98.1 g）, and water ＝CHb）, 5.97-6.12（2H, m, 2×－CH＝）, 7.34（1H, s, H-7）. fraction（240.7 g）. The n-BuOH extract was fractionated to fractions 1-3 by silica gel column chromatography with 2.4 Synthesis of bergenin derivatives（2-4, 6-10） CH2Cl2-MeOH（9:1, 8:2, 7:3, v/v）as eluents. Fraction 2 was First, various benzoic acids and Ph3P（2 equiv.）were dis- recrystallized from CH2Cl2-MeOH（12:1, v/v）, and bergenin solved in a solution of 1a in anhydrous tetrahydrofuran （1）（3.7 g）was isolated（Fig. 2）. The structure of 1 was （THF）（2 ml/mmol）. DIAD（1.7 equiv.）was added dropwise identified by the comparison of its physical and spectral at 0℃. The mixture was stirred under nitrogen for 2 h and data with those described in the literature44）. then concentrated in vacuo. The residue was chromato- graphed on silica gel to afford benzoic acid ester of 1a 2.3 Synthesis of 8,10-diallyloxy-bergenin（1a） （yield 79-92％）as a white powder. The phenolic hydroxy groups in bergenin（1）（700 mg, Next, the allyl protected esters and Pd（PPh3）（4 1 mol％, 2.13 mmol）were selectively allylated.
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