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Arisugacins Aand B, Novel and Selective Acetylcholinesterase

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Arisugacins Aand B, Novel and Selective Acetylcholinesterase 742 THE JOURNAL OF ANTIBIOTICS AUG. 1996 Arisugacins A and B, Novel and Selective Acetylcholinesterase Inhibitors from Penicillium sp. FO-4259 I. Screening, Taxonomy, Fermentation, Isolation and Biological Activity Fumiyoshi Kuno, Kazuhiko Otoguro, Kazuro Shiomi, Yuzuru Iwai and Satoshi Omura* Research Center for Biological Function, The Kitasato Institute, Minato-ku, Tokyo 108, Japan (Received for publication February 29, 1996) Anin vitro screening method for selective acetylcholinesterase (AChE) inhibitors was established. Inhibitory activity of AChEand butyrylcholinesterase (BuChE) was measured and the culture broths of microorganisms that showedselective inhibition against AChEwere characterized. Byusing this method, a strain producing the novel and selective inhibitors of AChE, arisugacins A and B, was picked out amongover seven thousand microorganisms tested. Arisugacins were obtained as white powders from the culture broth together with three knowncompounds, territrems B and C and cyclopenin that also showed selective inhibition against AChE. Arisugacins and territrems are members of the meroterpenoid compounds. They showed potent inhibitory activities against AChEwith IC50 values in range of 1.0~25.8 nM. Furthermore, they showed greater than 2,000-fold more potent inhibition against AChEthan BuChE. Alzheimer's Disease (AD) is a degenerative disorder dated with peripheral side effects3). of the central nervous system characterized clinically by The standard assay for AChEwas performed by the the loss of memory, intellect and cognitive functions. method of Ellman et aL4). Recently, a qualitative assay The etiology and the pathophysiology of ADare still using silica gel TLCplates was reported by Kiely et al.5\ unknown. Currently, clinical study with an acetylcholin- Doctor et al. applied the method of Ellman et al. to a esterase (AChE) inhibitor, tacrine, has demonstrated a 96-well microtiter plate for the assay of large numbers significant improvement of cognitive function in patients of samples6). Weestablished a rapid method to screen ofAD1}. Tacrine has been approved by the FDAas the for selective AChEinhibitors from a large number of first agent for the treatment of AD, although it suffers culture broths by comparing inhibitory activities against from dose-limiting side effects2). Clinical data of selective both AChE and BuChE. By using the method, we and nonselective AChE inhibitors suggested that the discovered the novel and selective AChE inhibitors, butyrylcholinesterase (BuChE) inhibition may be asso- arisugacins A (previously reported as arisugacin7)) and Fig. 1. Structures of arisugacins A and B, territrems B and C, cyclopenin and cyclophostin. VOL.49 NO.8 THE JOURNAL OF ANTIBIOTICS 743 B (Fig. 1) from the culture broth of fungal strain FO- Results and Discussion 4259. Inhibition of AChEand BuChEActivities by In this paper, wedescribe the details of the discovery, taxonomy of the producing strain, fermentation, iso- Various Cholinesterase Inhibitors Cholinesterases (ChEs) may be classified as AChE lation and biological activities of arisugacins A and B. Structure elucidation including their relative configura- and BuChEon the basis of differential specificity of ACh tion will be reported separately8). and BuCh hydrolysis. The AChEis primarily associated with nerve and muscle, localizing typically at synaptic contacts, while BuChE is synthesized in liver with Materials and Methods substantial amounts appearing in serum. Several ChE Chemicals inhibitors have been shown to be selective for one of the AChE (E.C. 3.1.1.7) from human erythrocytes, BuChE two enzymes as reported by Taylor10). (E.C. 3.1.1.8) from horse serum, BW284C51 and tetra- In our assay, ChEinhibitors were classified into 4 types isopropylprophosphoramide (iso-OMPA) were purchas- by their IC50 values (concentrations required for ed from Sigma Chemicals Co. Ltd. Acetylcholine-HCl inhibition of control enzyme activity by 50%) against was purchased from Daiichi Pharmaceutical Co., Ltd. AChEand BuChE as shown in Table 1. The type A Tacrine and physostigmine were purchased from Re- search Biochemical Co., Ltd. Butyrylcholine-HCl was ChE inhibitor, BW284C51, exerted 920 times more purchased from Nacalai Tesque Co., Ltd. Substrate- potent effect on AChEthan on BuChE. The type B ChE enzyme (Cholinesterase B test Kit) was purchased from inhibitors, physostigmine and diazinon acted equally Wako Pure Chemical Industries, Ltd. Diazinon and on both AChEand BuChE. Diazinon is a synthetic cyclophostin were kindly supplied by Nippon Kayaku organophosphate and used as an insecticide. The type C Co., Ltd. Other chemicals were analytical grade. ChE inhibitor, tacrine, exerted 17 times more potent Assay methods of Cholinesterase effect on BuChE than on AChE. The type D ChE The inhibitory activities against AChEwere measured inhibitor, iso-OMPA, exerted 850 times more potent by the method of Okabe et al9) with modifications as effect on BuChE than on AChE. Except for diazinon, follows; 100//I of AChEsolution containing 0.65unit the above results approximately coincided with the activity/ml in 0.1 m potassium phosphate buffer (pH 7.6) results ofThOsem et al.3) obtained by using a radiometric and 10/d of a cultured broth or 50%ethanol solution assay against AChE from human erythrocytes and of purified material was added to each well of a 96-well plate. After incubation for 15minutes at 37°C, 100/A of BuChEfrom human plasma, suggesting that the culture substrate-enzyme solution (17.5 nmole of benzoylcho- broths showing type Ainhibition may contain the selec- line, 14.75nmole of 4-aminoantipilin, 0.0425unit of tive inhibitors of AChE. cholineoxidase, 0.015 unit of peroxidase and 5.25 /imole Screening of the Selective Inhibitors of AChE of phenol in 0.1 m potassium phosphate buffer, pH 7.6) and 10 jA of acetylcholine solution (1 mg/ml) were added and Discovery of Arisugacins to each well. The reaction was carried out at 37°C for The culture broths showing over 50% inhibition of 30minutes, and the formation of red quinone was AChEwere picked up in primary screening. In second- measured with a Titertek microplate reader (Dainippon ary screening, the broths that showed more potent Pharmaceutical Co., Ltd.) at 492nm. Values for per- centages of inhibition were calculated relative to a inhibition against AChEcompared with that against control sample. The inhibitory activities against BuChE BuChEwere picked out. Tertiary screening was done to were measured as described above for AChEby sub- choose lipophilic substances by extraction test using stituting BuChE (0.125 units activity/ml) and butyryl- ethyl acetate. Lipophilic and low molecular substances choline (1 mg/ml) for enzyme and substrate, respectively. The AChE and BuChE activities are inhibited by in- hibitors of choline oxidase or peroxidase in these assays, Table 1. Effects of various cholinesterase inhibitors. because the enzymesare used for coupling reaction to form red quinone. These inhibitors were eliminated by IC50 (uU) Inhibitor testing the inhibitory activities against these enzymes AChE BuChE using lOjul of 10mMcholine chloride or 0.3% hydrogen 0.10 92.0 peroxide instead of the substrate solutions. 0.03 0.03 0.01 0.01 0.20 0.012 340 0.40 744 THE JOURNAL OF ANTIBIOTICS AUG. 1996 mayhave higher permeability to across the blood-brain were abundantly produced on various agar media. barrier. Morphological observation was done under a micro- By using the above method, culture broths of actino- scope (Olympus Vanox-S AH-2). When strain FO-4259 mycetes and fungi isolated mainly from soil samples was grown on CYAat 25°C for 7days, the conidio- were subjected to the screening. Table 2 shows the phores were born from substrate hyphae, and penicillia results. Amongover seven thousand microorganisms, were mainly biverticillate as shown in Fig. 2. Phialides only two culture broths were picked out as candidates were ampulliform and 7.5~10.0x2.5~3.0/im. The with active principles showing selective inhibition to conidia were globe to subglobe in shape and 2.5~3.0/mi AChE and lipophilic properties. An actinomycete in diameter, and its surface was rough. WK-4164 was found to produce a known organophos- From the above characteristics, strain FO-4259was phate, cyclophostin (Fig. 1), which has been isolated identified as Penicillium sp. and named Penicillium sp. from Sireptomyces Mvendulae and reported as an in- FO-4259. This strain was deposited at the National hibitor of AChEin screening for insecticides11}. On the Institute of Bioscience and Human Technology, Agen- other hand, a fungus FO-4259 was found to produce cy of Industrial Science and Technology Japan, as two novel compounds, arisugacins A7) and B and three Penicillium sp. FO-4259 with the accession number known compounds, territrems B and C7) and cyclopenin FERM P-14680. (Fig. 1). Territrems B and C were reported as tremori- Fermentation genic metabolites of Aspergillus terreus 1 2t l 3\ Cyclopenin was reported as an alkaloid of Penicillium cyclopium and The production of arisugacins A and B were carried Penicillium viridicatum 1 ^. out as follows. Aloopful ofmycelia from a slant culture of Penicillium sp. FO-4259 was inoculated into a 500-ml Though only 7%of actinomycetes strains passed the Erlenmeyer flask containing 100ml of a seed medium secondary screening, 35%of fungus strains passed. This consisting of glucose 2.0%, Polypepton 0.5%, yeast may be due to physostigmine like substances produced by actinomycetes. Physostigmine and its related com- extract 0.2%, agar 0.1%, KH2PO4 0.1% and MgSO4- pounds are type B ChE inhibitors and are produced 7H2O 0.05% (adjusted to pH 6.0 before sterilization). by plants and actinomycetes15'16). After incubation at 27°C for 72 hours on a rotary shaker, one per cent of the seed culture was inoculated into each Taxonomyof the Arisugacins-producing Organism of fifty 1000-ml Roux flasks containing 200ml of a Strain FO-4259was originally isolated from a soil producing medium consisting of soluble starch 3.0%, sample collected in Arisugawa-no-miya park at Minato- glycerol 1.0%, soybean meal 2.0%, dry yeast 0.3%, ku, Tokyo, Japan.
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