JPH05339283A - 5-bromo-4-chloroindo-3-yl-2-sialic acid - Google Patents

5-bromo-4-chloroindo-3-yl-2-sialic acid

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JPH05339283A
JPH05339283A JP15327592A JP15327592A JPH05339283A JP H05339283 A JPH05339283 A JP H05339283A JP 15327592 A JP15327592 A JP 15327592A JP 15327592 A JP15327592 A JP 15327592A JP H05339283 A JPH05339283 A JP H05339283A
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compound
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sialidase
bromo
sialic acid
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JP2904647B2 (en
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Ikuo Fujii
郁雄 藤井
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Tanpaku Kogaku Kenkyusho:Kk
株式会社蛋白工学研究所
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Abstract

PURPOSE: To provide a new compound giving a chromogenic substrate useful for the retrieval of new sialidase-like enzyme.
CONSTITUTION: The compound of formula I. The compound can be produced e.g. by reacting a compound of formula II with acetic anhydride in pyridine, chlorinating the 2-acetyl group of the resultant compound of formula III in a saturated HCl/acetyl chloride solution, reacting the product with a compound of formula IV in formamide in the presence of sodium hydride and treating the produced compound of formula V with 28% sodium methoxide and 1N sodium hydroxide in methanol.
COPYRIGHT: (C)1993,JPO&Japio

Description

【発明の詳細な説明】 DETAILED DESCRIPTION OF THE INVENTION

【0001】 [0001]

【産業上の利用分野】本発明は、酵素の検索、スクリーニングに有用な、新規な発色性基質に関する。 The present invention relates to a search of the enzyme, screening useful, it relates to a novel chromogenic substrate. この新規な発色性基質は特に、組み換えDNA技術や菌株のスクリーニングによる新規シアリダーゼ様酵素の検索に極めて有用である。 The novel chromogenic substrate, in particular, is very useful in the search of new sialidase-like enzymes by screening of recombinant DNA technology and strains.

【0002】 [0002]

【従来の技術と発明が解決しようとする課題】細胞表層にはシアル酸を含む糖脂質や糖タンパク質が存在し、細胞の分化、増殖、ガン化、免疫などの基本的な生命現象に深くかかわっている。 The cell surface Background of the invention is to provide a present glycolipids and glycoproteins, including sialic acid, deeply involved in cell differentiation, proliferation, cancerous, the basic life phenomena such as immune ing. また、それらの糖鎖部分がウィルスや毒素のレセプターとして機能したり、細胞認識にも関与していることが次第に明らかにされてきている。 Also, or their carbohydrate portion functions as a receptor for viruses and toxins, to be involved in cell recognition have been increasingly clear.
現在までに200種を超える糖鎖構造の異なる糖脂質分子種の存在が知られており、もし糖脂質糖鎖を選択的に加水分解することができればそれぞれの糖脂質の生理的意義を明確にすることができる。 And the presence of different glycolipid species of sugar chain structure more than 200 species so far known, if clear physiological significance of each glycolipid if it is possible to selectively hydrolyze glycolipids sugar chain can do. 以上のような観点から、今日糖脂質の糖鎖配列に特異的に作用する未知の糖加水分解酵素(グリコシダーゼ)の検索が様々な方法によって試みられている。 In view of the above, a search for an unknown sugar hydrolases which act specifically (glycosidases) in a sugar chain sequence today glycolipid has been attempted by a variety of methods.

【0003】その代表的な例として、ウシ脳から単離したガングリオシドを唯一の炭素源とする合成培地に生育する菌株から、糖脂質の糖鎖配列に選択的に作用するグリコシダーゼの検索が行なわれている。 [0003] As a typical example, a strain growing in synthetic medium isolated gangliosides from bovine brain as the only carbon source, search glycosidase is performed selectively acting sugar chain sequence of glycolipids ing. また組み換えD The recombinant D
NA技術により新しい活性をもつ酵素の発現が検討されているが、いずれの場合も酵素の精製及びその活性測定に多大な労力が費やされており、簡便なスクリーニング法の開発が強く望まれている。 The expression of enzymes with new activity by NA technology has been studied, in either case have been expended great effort in purifying and activity measurement of enzymes, it is strongly desired to develop a simple screening method there. 特に、特定の糖鎖構造の末端に位置するシアル酸を特異的に切断する酵素(以下、この酵素をシアリダーゼ様酵素という)を培地上で効率良くスクリーニングする方法が開発されたならば、 In particular, an enzyme that specifically cleaves the sialic acid located at the terminus of a particular sugar chain structure (hereinafter, the enzyme that sialidase-like enzyme) If a method of efficiently screening on a medium has been developed,
その技術は医療分野はもとより、糖脂質(ガングリオシド)の生理学的役割の研究等、様々な分野に大いに貢献し得ると考えられる。 The technology is the medical field, as well as research, etc. of the physiological role of the glycolipid (ganglioside), it is considered to be capable of contributing greatly to the various fields.

【0004】 [0004]

【課題を解決するための手段】本発明者らは、菌株や組み換えDNA技術による培地上でのシアリダーゼ様酵素の検索・スクリーニングを簡便化し得る発色性基質について鋭意検討を重ねた結果、下記式で示される5−ブロム−4−クロロインド−3−イル−2−シアル酸がその目的を達成し得ることを見い出し本発明を完成するに至った。 The present inventors Means for Solving the Problems] As a result of intensive study for chromogenic substrate that can simplify the search and screening of sialidase-like enzyme on media by strains and recombinant DNA techniques, the following formula 5-bromo-4-chloro India 3-yl-2-sialic acid represented has led to the completion of the present invention found that it is possible to achieve the purpose.

【0005】 [0005]

【化2】 ## STR2 ##

【0006】本発明に係る発色性基質(1)は、下記反応式1 [0006] chromogenic substrate according to the present invention (1) is represented by the following reaction formula 1

【化3】 [Formula 3] に示すように、シアリダーゼの認識部位(A)と発色性部位(B)を兼ね備えており、シアリダーゼ様酵素の存在下、グリコシル結合が加水分解され、それと同時に遊離されたインドール型発色部位(B)がすみやかに空気酸化され、インディゴ化合物(2)を生成する。 As shown in the recognition site of sialidase (A) and has both chromogenic site (B), the presence of sialidase-like enzyme, the glycosyl bond is hydrolyzed, and at the same time liberated indole coloration site (B) is quickly be air oxidized to produce indigo compound (2). インディゴ化合物(2)は青色を呈し、この青色を指標として新規シアリダーゼ様酵素の検索が可能となる。 Indigo compounds (2) exhibits a blue Find new sialidase-like enzyme can be achieved with this blue as an indicator.

【0007】本発明の発色性基質(1)は、下記反応式2 [0007] chromogenic substrate of the present invention (1) is represented by the following reaction formula 2

【化4】 [Of 4] に示す合成経路に従って合成することができる。 It can be synthesized according to the synthetic route shown in. 即ち、 In other words,
シアル酸(3)をピリジン中無水酢酸と反応させ水酸基とアセチル基として保護した後ジアゾメタンによりカルボキシル基をエステルとした化合物(4)を得、次に飽和塩化水素/塩化アセチル溶液中で化合物(4)の2位のアセチル基をクロル基とし、これを、別途3−アセトキシ− Sialic acid (3) a compound in which the carboxyl group and an ester by diazomethane was protected as hydroxyl group and an acetyl group is reacted with pyridine in acetic anhydride (4), which then saturated hydrogen chloride / compound with acetyl chloride solution (4 the 2-position acetyl group) as a chloro group, which, separately 3-acetoxy -
1−アセチル−5−ブロム−4−クロロ−インドール 1-acetyl-5-bromo-4-chloro - indole
(5)の加水分解より得られる1−アセチル−5−ブロム−4−クロロ−インドール(6)と水素化ナトリウム存在下、ホルムアミド中で反応させて縮合体(7)を得る。 (5) obtained from hydrolysis of 1-acetyl-5-bromo-4-chloro - obtaining indole and (6) the presence of sodium hydride, condensate reacted in formamide (7). その後、縮合体(7)をメタノール中、28%ナトリウムメトキシド及び1N水酸化ナトリウムで処理し、その全アセチル基を加水分解する。 Thereafter, a methanol condensate (7), and treated with 28% sodium methoxide and 1N sodium hydroxide, hydrolyzes the entire acetyl group. 反応残査を高速液体クロマトグラフィーにより精製し、発色性基質(1)を得ることができる。 The reaction residue 査 was purified by high performance liquid chromatography to obtain a chromogenic substrate (1).

【0008】この様にして得られる発色性基質(1)は、 [0008] The chromogenic substrate obtained in this way (1),
天然型シアリダーゼ(EC3.2.1.18)と反応させると反応はすみやかに進行しインディゴ化合物特有の青色 Reaction is reacted with native sialidase (EC 3.2.1.18) proceeded rapidly indigo compound specific blue
(吸収極大625nm)を呈する。 Exhibit (absorption maximum 625nm). この実験事実より、本発明化合物の2位の立体化学(COOH:β配位、インドール部:α配位)が決定された。 From this experiment fact, 2-position stereochemistry of the present compounds (COOH: beta coordination, indole unit: alpha coordination) was determined.

【0009】 [0009]

【発明の作用および効果】本発明の発色性基質(1)の反応性及び基質特異性が検討された。 Reactivity and substrate specificity of a chromogenic substrate of the effects of the invention and advantages of the present invention (1) has been studied. 基質(1)は天然型シアリダーゼ(Sialidase;EC3.2.1.18)によりすみやかに分解され、青色を呈した。 Substrate (1) of the natural sialidase; degraded rapidly by (SIALIDASE EC 3.2.1.18), exhibited a blue color. この反応は吸光光度法 This reaction is absorptiometry
(625nm)により追跡され、本基質のシアリダーゼに対する速度論量を決定した(Km=1.62×10 -3 M)。 Are tracked by (625 nm), it was determined kinetics amount for sialidase of the present substrate (Km = 1.62 × 10 -3 M ). また本基質(1)は天然型β−ガラクトシダーゼ(β−Gala The present substrate (1) of the natural β- galactosidase (beta-Gala
ctosidase;EC3.2.1.23)との反応では分解されないことが判明し、本基質のシアリダーゼに対する基質特異性が証明された。 Ctosidase; The reaction with EC3.2.1.23) was found to not be degraded, substrate specificity for sialidase of the present substrate was demonstrated.

【0010】以上のことから、本基質(1)は、組み換えDNA技術による新規シアリダーゼ様酵素の検索あるいは菌株からの検索のために効果的なスクリーニング法として利用できる。 [0010] From the above, the substrate (1) can be utilized as an effective screening method for searching from the search or strain of the novel sialidase-like enzyme by recombinant DNA techniques. さらに医療分野においては天然型シアリダーゼの体内活性の測定のために臨床検査試薬としての応用性が期待できる。 It can be expected applicability as clinical diagnostic reagents for the measurement of body activity of native sialidases in further medical field. 以下に実施例を挙げ、本発明をさらに詳しく説明する。 EXAMPLES Hereinafter, the present invention will be described in more detail. 尚、実施例中の化合物番号は、反応式2で示した化合物番号と一致している。 The compound numbers in the examples are consistent with the compound numbers shown in Scheme 2.

【0011】 実施例1アセチル体(4)の合成 シアル酸(3)(2.05g,6.63mmol)をピリジン(2 [0011] Example 1 Synthesis of sialic acid acetyl form (4) (3) (2.05g , 6.63mmol) in pyridine (2
5ml)に懸濁し、氷冷下無水酢酸(30ml)を加え1時間後室温にもどし一夜攪拌した。 Was suspended in 5 ml), it was stirred overnight back to 1 hour at room temperature after addition of ice-cold acetic anhydride (30 ml). 減圧濃縮した後残渣にトルエンを加え減圧濃縮した。 Was concentrated under reduced pressure with toluene to the residue was concentrated under reduced pressure. トルエンを加え減圧濃縮する操作を3回繰り返した。 Operation was repeated three times and concentrated under reduced pressure with toluene. 残渣をメタノール(20ml)に溶解し、ジアゾメタンのエーテル溶液を反応溶液が黄色になるまで加え5分間放置した。 The residue was dissolved in methanol (20 ml), the ether solution of diazomethane reaction solution was left for 5 minutes in addition to a yellow. 酢酸を加えて過剰のジアゾメタンを分解した後減圧濃縮した。 And concentrated under reduced pressure after decomposing the excess diazomethane with acetic acid. 残渣をシリカゲルカラムクロマトにより精製した(シリカゲル:50g,溶出溶液:トルエン−酢酸エチル(1:1)〜酢酸エチル)。 The residue was purified by silica gel column chromatography (silica gel: 50 g, elution solution: toluene - ethyl acetate (1: 1) to ethyl acetate).
目的物の分画を減圧濃縮し油状物を得た。 The fractions containing the end product were concentrated under reduced pressure to obtain an oil. 収量:3.2 Yield: 3.2
8g(92.7%)。 8g (92.7%).

【0012】 実施例2インドール誘導体(6)の合成 3−アセトキシ−1−アセチル−5−ブロモ−4−クロロ−インドール(1.00g,3.03mmol)をアルゴン置換した後、氷水下に80%硫酸(5ml)を加え、その後室温で50分攪拌した。 [0012] Synthesis of 3-acetoxy-1-acetyl-5-bromo-4-chloro Example 2 indole derivative (6) - indole (1.00 g, 3.03 mmol) and then was purged with argon, 80% ice water addition of sulfuric acid (5 ml), and then stirred at room temperature for 50 minutes. 氷を加えて溶液を約80mlにした後、析出した結晶を濾取した。 After the solution to about 80ml by the addition of ice, and the precipitated crystals were collected by filtration. 収量:844mg(96.5 Yield: 844mg (96.5
%)。 %).

【0013】 実施例3縮合体(7)の合成 アセチル体(4)(533mg,1.00mmol)を塩化アセチル [0013] Example 3 Synthesis acetyl form of condensate (7) (4) (533mg , 1.00mmol) and acetyl chloride
(10ml)に溶解し、氷冷下に飽和塩化水素−塩化アセチル溶液(5ml)を加えて室温で一夜攪拌した。 Was dissolved in (10 ml), saturated hydrogen chloride under ice-cooling - was stirred overnight at room temperature was added acetyl chloride solution (5 ml). 減圧濃縮し残渣にトルエンを加え濃縮した。 Toluene was added concentrated residue was concentrated under reduced pressure. この操作を3回繰り返すと結晶が得られた。 Crystal and repeat this operation three times was obtained. このようにして得られた結晶をD The thus crystals obtained by D
MF(2.5ml)に溶解した溶液を、インドール誘導体(6)(289mg,1.00mmol)をDMF(2.5ml)に溶解し氷冷下に水素化ナトリウム(24mg,1.00mmol)を加えた溶液に加え氷冷下に1時間、その後室温で一夜攪拌した。 A solution of the MF (2.5 ml), indole derivative (6) (289mg, 1.00mmol) was added sodium hydride (24 mg, 1.00 mmol) dissolved under ice cooling in DMF (2.5 ml) of was 1 hour under ice-cooling was added to the solution, followed by stirring at room temperature overnight. 減圧濃縮した後10%クエン酸水溶液と酢酸エチルを加え、酢酸エチル層を水洗した。 10% citric acid solution and ethyl acetate was concentrated under reduced pressure, and the mixture was washed with water and the ethyl acetate layer. 無水硫酸マグネシウムで乾燥し減圧濃縮した。 And concentrated under reduced pressure and dried with anhydrous magnesium sulfate. 残渣をシリカゲルカラムにより精製し、縮合体(7)を得た。 The residue was purified by silica gel column to give condensate (7). 収量:547mg Yield: 547mg
(71.8%)。 (71.8%).

【0014】 実施例4発色性基質(1)の合成 化合物(7)(260mg,341μmol)をメタノール(15m [0014] Example 4 chromogenic synthetic compounds of substrate (1) (7) (260mg , 341μmol) in methanol (15 m
l)に溶解し28%ナトリウムメトキシド(45μl)を加えて室温で2時間反応した。 It was reacted for 2 hours at room temperature, mixed and dissolved in l) 28% sodium methoxide (45 [mu] l). アンバーリスト15を加え In addition the amber list 15
pH7にした後減圧濃縮した。 And concentrated under reduced pressure after the pH7. 残渣を水(3ml)に溶解し1M−水酸化ナトリウム(600μmol)を加えて室温で30分攪拌した。 The residue was dissolved in water (3 ml) 1M- by adding sodium hydroxide (600 [mu] mol) was stirred at room temperature for 30 minutes. アンバーリスト15を加えpH2にした後、ただちに樹脂を濾過し濾液に1M酢酸アンモニウム(pH7.0)(10ml)を加えて凍結乾燥した。 After to pH2 added Amberlyst 15 was added thereto to conduct lyophilization 1M ammonium acetate (pH7.0) (10ml) to the filtrate immediately filtered resin. 残渣をH The residue H
PLCにより精製した(コスモシール5C 18 、10×2 And purified by PLC (Cosmosil 5C 18, 10 × 2
50mm、アセトニトリル−50mmol酢酸アンモニウム緩衝溶液、グラジエント10%−40%アセトニトリル 50 mm, acetonitrile -50mmol ammonium acetate buffer solution, a gradient of 10% -40% acetonitrile
(15分)、流速3ml/分、検出254nm、保持時間1 (15 min), a flow rate of 3 ml / min, detection 254 nm, retention time 1
5.0分)。 5.0 minutes). 保持時間15.0分のピークを分取し、凍結乾燥した。 Sample was collected peak at a retention time of 15.0 minutes was lyophilized. 残渣として含まれている酢酸アンモニウムをHPLCにより除去し目的した発色性基質(1)を得た Ammonium acetate contained as a residue was removed by HPLC to give the chromogenic substrates noted object (1)
(コスモシール5C 18 、10×250mm、アセトニトリル−水、グラジエント10%−80%アセトニトリル (Cosmosil 5C 18, 10 × 250 mm, acetonitrile - water, gradient 10% -80% acetonitrile
(10分)、流速3ml/分、検出254nm)。 (10 min), a flow rate of 3 ml / min, detection 254 nm). 収量:10 Yield: 10
0mg(54.5%)。 0mg (54.5%). 融点:158〜160℃。 Melting point: 158~160 ℃. NMR NMR
(δ,ppm):1.79(dd,J=12.0,12.0H (Δ, ppm): 1.79 (dd, J = 12.0,12.0H
z,1H),1.91(s,3H),2.82(dd,J=1 z, 1H), 1.91 (s, 3H), 2.82 (dd, J = 1
2.0,4.4Hz,1H),3.46〜3.77(m,7 2.0,4.4Hz, 1H), 3.46~3.77 (m, 7
H),7.13(d,J=8.8Hz,1H),7.28 H), 7.13 (d, J = 8.8Hz, 1H), 7.28
(d,J=8.8Hz,1H)。 (D, J = 8.8Hz, 1H). NMRはD 2 O(重水)で測定した。 NMR was measured in D 2 O (deuterated water).

【0015】 実施例5速度論量の決定 天然シアリダーゼ(0.04unit)とウシ血清アルブミン [0015] Example 5 Kinetics of determining natural sialidase (0.04unit) and bovine serum albumin
(0.03%)の200mM酢酸カリウム緩衝液(pH4.6 200mM potassium acetate buffer (0.03%) (pH4.6
2)0.9mlを恒温層で25℃に保つ。 It kept 25 ° C. The 2) 0.9 ml at constant temperature layer. これに基質(1)の各種濃度(40mM,20mM,10mM,5mM,2.5mM)溶液0.1mlを加え、すばやく振盪したのち吸光光度計で吸収(625nm)の増加を、30分間追跡した。 This various concentrations of the substrate (1) (40mM, 20mM, 10mM, 5mM, 2.5mM) solution 0.1ml added, an increase in absorption (625 nm) with absorptiometer After quickly shaken, was followed for 30 minutes. 得られた結果よりシアリダーゼの本基質(1)に対するKm値を1. 1 Km value than the results obtained with respect to the substrate (1) of the sialidase.
62×10 -3 Mと決定した。 It was determined to 62 × 10 -3 M.

Claims (1)

    【特許請求の範囲】 [The claims]
  1. 【請求項1】 下記式1で表わされる化合物。 1. A compound represented by the following formula 1. 【化1】 [Formula 1]
JP15327592A 1992-06-12 1992-06-12 Method for producing a 5-bromo-4-chloro India 3-yl-2-sialic acid Expired - Lifetime JP2904647B2 (en)

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US6812332B2 (en) 1997-10-27 2004-11-02 Ibbex, Inc. Chromogenic substrates of sialidase and methods of making and using the same
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