CN1171790A - 新的氨基寡糖衍生物及其制备方法 - Google Patents
新的氨基寡糖衍生物及其制备方法 Download PDFInfo
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- CN1171790A CN1171790A CN95197214A CN95197214A CN1171790A CN 1171790 A CN1171790 A CN 1171790A CN 95197214 A CN95197214 A CN 95197214A CN 95197214 A CN95197214 A CN 95197214A CN 1171790 A CN1171790 A CN 1171790A
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Abstract
本发明涉及新的氨基寡糖衍生物和其可药用的无毒性盐,它具有有效的糖水解酶抑制作用和抗菌活性。本发明也涉及制备上述物质的方法和含有它们作为活性组分的药用组合物。按照本发明,发明者从类型为链霉菌的土壤微生物中分离出了新的氨基寡糖衍生物并发现它能够用作糖水解的有效抑制剂以及抗菌剂。
Description
发明背景
发明领域
本发明涉及新的氨基寡糖衍生物和其可药用的无毒性盐,它具有有效的糖水解酶抑制作用和抗菌活性。本发明也涉及制备上述物质的方法和含有该物质作为活性组分的药用组合物。
现有技术的描述
已知糖水解酶如淀粉酶和蔗糖酶的抑制剂可以应用于糖尿病、高脂蛋白血、血脂过高、肥胖或其它由此造成的第二症状的治疗或防治。
在这点上,已报道了做为糖水解酶的有效抑制剂的几种氨基寡糖衍生物,例如由链霉菌A2396(见:日本专利申请公开(Sho)54-92909)产生的A-2396,由Streptomyces myxogenes(见J.Antibiotics,34:1424-1433(1981))提供的寡聚抑制素,由产黄色链霉菌(见:日本专利申请公开(Hei)3-19239)产生的脂解素(见:J.Antibiotics,35:1234-1236(1982))和NS复合物。
按照本发明,发明者从类型为链霉菌的土壤微生物中分离出了新的氨基寡糖衍生物,并发现它能够用作糖水解的有效抑制剂以及抗菌剂。
发明概述
m是0或1的整数;
n是1到4的整数;
m+n是1到5的整数;
R1是低级烷基羟化物;和
R2是氢或低级烷基。
本发明的另一目的是提供氨基寡糖衍生物做为糖水解酶的抑制剂和抗菌剂的应用。
本发明的另一目的是提供从链霉菌CK-4416制备氨基寡糖的方法。
附图的简单描述
从下列结合附图所给出的描述中,本发明的上述和其它目的以及特点会变得明显。
图1是本发明CK-4416材料的IR谱;
图2是CK-4416的1H-NMR谱;
图3是CK-4426的13C-NMR谱;和
图4是CK-4416的FAB-MS/MS谱。
本发明的详细描述
本发明者筛选了土壤微生物并分离了一种产生本发明的氨基寡糖衍生物的细菌。如此分离的该细菌鉴定为链霉菌属的一种并命名为链霉菌CK-4416。另外,由此产生的氨基寡糖衍生物测定为是新的并命名为CK-4416。
CK-4416产生自采用搅动培养或需氧旋转培养的需氧条件下,在含有碳和氮源的培养基中培养的链霉菌CK-4416。做为碳源,可采用购得的葡萄糖、甘油、麦芽糖、淀粉、蔗糖、糖蜜和糊精;做为氮源,可使用购得的大豆粉、玉米浸泡液、牛肉提取物、棉籽粉、胨、麦胚、鱼肉、无机铵盐和NaNO3;以及CaCO3、NaCl、MgSO4和磷酸盐可用作无机盐。如果需要,培养链霉菌CK-4416的培养基可以进一步含有一些微量的金属离子如Fe、Mn和Zn,以及消泡剂如植物油,包括十八烷醇的高级醇和硅酮化合物。培养基也可以含有使链霉菌CK-4416产生高收率CK-4416材料的培养简便的其它任意化合物。
链霉菌CK-4416按照本领域常规的方法培养,它包括固态和液态培养。液体培养优选采用固定培养,旋动培养,摇动培养和充气培养,更优选的是摇动培养和浸没通气培养。温育在pH6到8的中性条件于20℃到37℃的温度范围,更优选地是25到30℃,进行24到192小时,更优选地是48到120小时。
按照本领域的常规纯化方法,采用离子交换、吸附、分配和凝胶过滤色谱,从链霉菌CK-4416培养物中获得CK-4416。CK-4416也可以用高效液相色谱(HPLC)或薄层层析(TLC)分离。
CK-4416可用于治疗或预防胰岛素依赖的糖尿病,血脂过高造成的高脂蛋白血和肥胖,或做为免疫降低的恢复剂,它也能用做抗菌剂。
本发明进一步在下列实施例中解释,它不意味着对本发明范围的限制。实施例1:链霉菌CK-4416的分离和鉴定
进行土壤微生物的筛选以分离标题微生物,并且它是从收集自Chochun-Eup,BukKun,Cheju-Do,Korea地区森林地带的土壤中分离的。分离的微生物特性表示如下:1.生长特性
分离的微生物在各种生长培养基的生长特性概括在下列表1中。表1:链霉菌CK-4416在各种琼脂培养基的生长特性(28℃温育14天)
2.形态特性
酵母-麦芽提取物琼脂(ISP No.2)生长:中等气生菌丝体:白色,好营养菌丝体:黄白色可溶色素:无 | 燕麦粉琼脂(ISP No.3)生长:好气生菌丝体:灰黄色,好营养菌丝体:黄白色可溶色素:无 |
无机盐-淀粉琼脂(ISP No.4)生长:少-中等气生菌丝体:少营养菌丝体:少,黄白色可溶色素:无 | 甘油-天冬酰胺琼脂(ISP No.5)生长:中等气生菌丝体:中等,黄白色营养菌丝体:少,黄白色可溶色素:无 |
胨-酵母铁琼脂(ISP No.6)生长:少气生菌丝体:无营养菌丝体:少可溶色素:无 | 酪氨酸琼脂(ISP No.7)生长:好气生菌丝体:好营养菌丝体:少可溶色素:无 |
蔗糖-硝酸盐琼脂(Waksman No.1)生长:少-中等气生菌丝体:无营养菌丝体:中等,黄白色可溶色素:无 | 葡萄糖-天冬酰胺琼脂(Waksman No.2)生长:好气生菌丝体:灰白色,好营养菌丝体:少,灰棕色可溶色素:无 |
营养琼脂(Waksman No.14)生长:少气生菌丝体:无营养菌丝体:少,黄白色可溶色素:无 | Emerson琼脂(Waksman No.28)生长:少-中等气生菌丝体:少营养菌丝体:中等,折叠,黄白色可溶色素:无 |
链霉菌CK-4416的显微鉴定显示:从气生菌丝体的末端生长的每条链可见多于20个芽孢的1-3个螺旋,没有观察到轮生菌丝体和断裂。可见表面光滑、大小为(0.6-0.7)×(0.5-1.0)μm的椭圆形芽孢,未见特殊细胞器如菌核和孢子束。3.生长温度的影响(燕麦粉琼脂温育14天)
4℃:不生长
15℃:少量生长,无气生菌丝体
20℃:少量生长,差的气生菌丝体
28℃:中等生长,好的气生菌丝体
37℃:中等生长,好的气生菌丝体
45℃:中等生长,中等气生菌丝体
55℃:不生长4.生理学特性
(1)淀粉水解(淀粉-无机盐琼脂):(+)
(2)黑色素色素产生:(-)5.碳源可同化性质
链霉菌CK-4416在各自含有示于下列表2的糖的Pridham-Gottlieb gar培养基(ISP No.9)中,于28℃温度培养14天,测定糖的碳源可同化性质。表2:链霉菌CK-4416的碳源可同化性质
* -:无生长 ±:少量生长+:中等生长 ++:好的生长6.细胞壁组成
糖 | 可同化性质* |
无碳源D-葡萄糖L-阿拉伯糖山梨糖醇D(+)-棉籽糖肌醇D-木糖β-D(-)-果糖D(+)-甘露糖L(-)-山梨糖蔗糖α-L-鼠李糖 | ±+++±++±++++-++- |
在链霉菌CK-4416细胞壁部分检测到LL-二氨基庚二酸和甘氨酸。
从对本发明分离的微生物的生长、生态学、生理学和碳源可同化性质的研究,该微生物最终鉴定为本领域未报道的链霉菌属。因此,该新的微生物命名为链霉菌CK-4416,并存放在位于KRIBB,KIST,PO Box 115,Yusong-Ku,Taejon,305-600,韩国的国际保藏机构(IDA)--韩国典型培养物保藏中心(KCTC),登记号为No.KCTC 0131 BP。实施例2:链霉菌CK-4416的培养
向四个500ml Erlenmeyer瓶中加入含有葡萄糖1(W/V)%、糊精1(W/V)%、NZ-胺(A型)0.5(W/V)%、酵母提取物0.5(W/V)%和碳酸钙0.1(W/V)%的100ml用于接种培养的培养基(pH6.5),并在120℃灭菌15分钟。将从传代培养物中获得的链霉菌CK-4416的1铂环斜面培养物接种到四个瓶中,并在27℃摇动培养3天。然后,将100ml含有可溶淀粉3(W/V)%、大豆粉1.5(W/V)%、玉米浸泡液1.5(W/V)%、多胨0.2(W/V)%、Na2S2O30.1(W/V)%、碳酸铵0.5(W/V)%、氯化钴0.0001(W/V)%的培养介质(pH6.5)加入到500ml Erlenmeyer瓶中至200ml,并在120℃灭菌30分钟。2(V/V)%的接种培养物被接种到培养基中并在27℃、240rmp摇动培养3天。采用测试有机体Comamonas terrigena(ATCC 8461),按照常规纸圆盘法,通过抗菌活性的测定对CK-4426进行定量分析。培养3天后,测定的pH和产量分别为7.2和0.6mg/ml。实施例3:CK-4416物质(I)的分离
18L从实施例2得到的培养物离心除去细胞沉淀,收集14L上清液,调节上清液酸度至pH3.1,以50ml/min流速上样到以活化碳(Wako Junyaku,Japan)做为吸附树脂的6cm×30cm柱,用5L蒸馏水洗,用50(V/V)%甲醇洗脱。洗脱液按每份400ml收集,CK-4416在第3到第6份洗脱出。合并这些流份,减压浓缩给出14g黄色油状物。此油状物溶于50ml蒸馏水并调其酸度至pH3.1。产物以20ml/min流速上到用购自Sigma化学公司之Sp-Sephadex(H+)填装的6cm×30cm柱上,用5L蒸馏水洗,用1N氨水洗脱。洗脱液按每份400ml收集,含CK-4416化合物的组份在第3-4份洗脱出。合并这些流份,减压浓缩并干燥,得到1g黄色粉末。然后将该粉末溶于30ml蒸馏水。产物的酸度调至pH3.1,产物以5ml/min流速上到用购自美国Sigma化学公司之Dowex 50 W-8X(吡啶盐)填装的柱(3cm×40cm)上,用2L蒸馏水洗,用3L吡啶-甲酸缓冲液(pH3.1)以0到0.2M梯度洗脱。洗脱液按每份15ml收集,物质A从第79-120份洗脱出,物质B从第129-159份洗脱出。每个洗脱组份减压浓缩分别给出浓黄色粉末500mg物质A和90mg物质B。实施例4:CK-4416物质的分离(II)
从实施例3得到的A物质溶于4ml蒸馏水中,上样到用购自美国Sigma化学公司之Sephadex G-10填装的3cm×50cm柱,并用水洗脱。洗脱物按每份5ml收集,活性物质在第39-45组份洗脱下来。这些组份经浓缩、干燥,得到390mg白色粉末。实施例3得到的B物质类似处理得到50mg白色粉末。实施例5:CK-4416物质的分离(III)
从实施例4得到的60mg A物质上样到购自日本岛津的制备型高压液相色谱柱(柱:Tosoh,Amide-80,溶剂:60(V/V)%乙腈)。由通式(I)表示的物质中,其中m=1,n=2,R1=羟甲基及R2=氢的一种通式(I)物质;其中m=0,n=4,R1=羟甲基及R2=氢的一种通式(I)物质;以及其中m=1,n=3,R1=羟甲基及R2=氢的一种通式(I)物质被相继洗脱下来。这三种洗脱物被分别减压浓缩、冷冻干燥,得到5mg,45mg和3mg白色粉末。
从实施例4得到的30mg B物质在相同条件下以相同方式处理。在通式(I)表示的物质中,其中m=0,n=2,R1=羟甲基及R2=氢的一种通式(I)物质10mg;其中m=1,n=1,R1=羟甲基及R2=氢的一种通式(I)物质7mg;和其中m=0,n=3,R1=羟甲基及R2=氢的一种通式(I)物质8mg分别被得到。实施例6:化合物CK-4416的鉴定
通过采用物理和化学的分析方法测定通式(I)的寡糖衍生物,其是m=,n=4,R1=羟甲基及R2=氢的化合物,对化合物CK-4416的理化性质进行鉴定。1.颜色和类型白色粉末2.元素分析(%)
碳 氢 氮
(分析值) 44.31 6.32 1.36
(计算值) 44.35 6.33 1.393.分子式
C37H63NO304.分子量
1,001.9
FAB-MS/MS(M+H)+1002(见:图4)5.熔点
162℃6.比旋光度
[α]D=+146°(c 0.1,水溶液)7.UV吸收谱
(溶剂:水,浓度=0.1mg/ml):
观察到终吸收8.IR谱
IR谱由KBr方法测定(见:图1)
主波长(cm-1):3,400;2,900;1,630;1,410;1,390;和1,0509.1H-NMR谱
1H-NMR谱在D2O中测定(见:图2)10.13H-NMR谱
13H-NMR谱在D2O中测定(见:图3)11.溶解度
溶解于水和甲醇
不溶于苯和正己烷12.颜色反应
硝酸银-氢氧化钠,Somoginelson,和高锰酸盐反应呈阳性;水合印三酮和Sakaguchi反应呈阴性。13.酸性、中性或碱性性质
弱碱性14.TLC
Rf:0.14;
[Tokyo Kasei K.K.,硅胶f(S201),日本]
展开剂∶乙酸乙酯-甲醇-水=5∶3∶2(v/v/v)
此外,还鉴定了m=0,n=2,R1=羟甲基及R2=氢的式(I)化合物分子式为C25H43NO20,分子量为677.6111;m=1,n=1,R1=羟甲基及R2=氢的式(I)化合物分子式为C25H43NO20,分子量为677.6111;m=0,n=3,R1=羟甲基及R2=氢的式(I)化合物分子式为C31H53NO25,分子量为839.7514;m=1,n=2,R1=羟甲基及R2=氢的式(I)化合物分子式为C31H53NO25,分子量为839.7514;和m=1,n=3,R1=羟甲基及R2=氢的式(I)化合物分子式为C37H63NO30,分子量为1,001.8934。
从上面的分析结果确定本发明的氨基寡糖衍生物是新的化合物。实施例7:CK-416的生物活性
用通式(I)表示的氨基寡糖化合物,其中m=0,n=4,R1=甲氧基及R2=氢测定了CK-4416的生物活性。实施例7-1:抗菌活性
采用纸圆盘法测定了1mg/ml CK-4416样品对革兰氏阳性和阴性菌株的抗菌活性。从结果可见对革兰氏阳性菌无活性,而对革兰氏阴性菌,即Comamonas terrigena(ATCC 8461)显示24.8mm的抑制区带。实施例7-2:对淀粉酶活性的抑制作用
分别制备含有溶于0.25M磷酸缓冲液(pH7.0)的淀粉酶的酶溶液(此后称作‘溶液A’),0.25M磷酸缓冲液(pH7.0)(此后称作‘溶液B’)和0.04(W/V)%淀粉溶液(此后称作‘溶液C’)。然后将含有溶于溶液B的CK-4416的0.05ml溶液B,0.1ml溶液B和0.05ml溶液B混合于37℃温育5分钟,加入0.5ml溶液C后再温育30min。温育后在660nm处测定CK-4416样品(T)和不含样品的对照(C)的吸光度。最后按下式计算得到对淀粉酶活性的半数(50%)抑制浓度为1.6×10-6M。
抑制率=(C-T)/C×100实施例7-3:降低血液中的糖水平
给两组5只禁食12小时的雄性SD大鼠口服1.5g/kg淀粉,同时给予40mg/kg和80mg/kg样品。给药后1小时从大鼠取血,用葡萄糖氧化酶法测定血中葡萄糖水平,并与未给CK-4416样品的对照组进行比较。结果见下面表3。从表3可见,明显确定本发明的CK-4416能够降低血中的糖水平;好于先前文献报道的其它氨基寡糖化合物如NS-复合物。表3:降低血糖水平
实施例7-4:毒性
血中葡萄糖水平 | |
对照CK-4416 40mg/kg80mg/kg | 124.6±10.297.5±14.387.5±11.3 |
CK-4416的急性毒性试验给5只ICR小鼠口服1g/kg CK-4416并观察14天。结果显示所有小鼠存活。
用常规技术包括通式(I)化合物与碱(Na,K)和碱土(Ca,Ba,Zn,Mn)金属碱,优选碱金属碱如氢氧化钠和碳酸钾稀溶液反应形成药用盐。也可以用常规技术包括与胺如三乙胺、二苯胺、三乙醇胺、乙醇胺、N,N-二苯基乙二胺,普鲁卡因和等同氨反应形成药用盐。
本发明的化合物可通过任何已知的适当方法用药用载体以及需要的话用佐剂配制。例如对于口服,本发明的化合物可制成固体制剂如片剂、丸、粒剂、粉末、胶囊等,液体制剂如溶剂、悬液、乳剂等。当该制剂用于胃肠外给药,可制成注射制剂和静脉滴注液等。对于注射制剂,该化合物优选溶于蒸馏水或盐的水溶液如氯化钠。对于静脉滴注液制剂,该化合物可溶于合适的治疗液如生理盐水,葡萄糖-氯化钠溶液等。
活性成分即本发明,特殊化合物的效能,需要的温度进行大范围调节。一般地,活性成分的量占组合物重量的0.5%-90%。
本发明化合物的有效剂量可能依病人的生理条件而不同。总之,为了获得预期结果,已显示每m2体表面积服用活性化合物50-1000mg的量较好。
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KR1019940039755A KR960022566A (ko) | 1994-12-30 | 1994-12-30 | 신규한 아미노올리고당 유도체 및 그의 제조방법 |
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US20190300945A1 (en) | 2010-04-05 | 2019-10-03 | Prognosys Biosciences, Inc. | Spatially Encoded Biological Assays |
PT2556171E (pt) | 2010-04-05 | 2015-12-21 | Prognosys Biosciences Inc | Ensaios biológicos codificados espacialmente |
US10787701B2 (en) | 2010-04-05 | 2020-09-29 | Prognosys Biosciences, Inc. | Spatially encoded biological assays |
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CN105849275B (zh) | 2013-06-25 | 2020-03-17 | 普罗格诺西斯生物科学公司 | 检测样品中生物靶标的空间分布的方法和系统 |
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DE69527445D1 (de) | 2002-08-22 |
CA2208707A1 (en) | 1996-07-11 |
KR100230961B1 (ko) | 1999-12-01 |
CN1051559C (zh) | 2000-04-19 |
CA2208707C (en) | 2000-02-22 |
JP2863637B2 (ja) | 1999-03-03 |
EP0871638A1 (en) | 1998-10-21 |
RU2134694C1 (ru) | 1999-08-20 |
DE69527445T2 (de) | 2002-10-31 |
JPH10508033A (ja) | 1998-08-04 |
EP0871638B1 (en) | 2002-07-17 |
KR960022566A (ko) | 1996-07-18 |
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