CN1583758A - 麦拓莱霉素的用途 - Google Patents
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Abstract
本发明公开一种麦拓莱霉素的用途,所述用途是在制备抗病毒药物中的用途,所述病毒是柯萨奇B6病毒或人类免疫缺陷病毒,本发明的实验结果显示,麦拓莱霉素对柯萨奇B6病毒具有很好的抑制作用,其抑制效果优于现代临床中常用的病毒唑,安全指数亦高于病毒唑,因此,抗柯萨奇病毒是麦拓莱霉素具有的重要用途之一,麦拓莱霉素抗人类免疫缺陷病毒蛋白酶的作用亦具有一定的活性,有希望成为抗人类免疫缺陷病毒类药物之一。
Description
技术领域
本发明属于医药领域,具体地说,是涉及一种大环内酯类抗生素在制备抗病毒药物中的用途。
背景技术
大环内酯类抗生素是临床中常使用的一类抗生素,它们被普遍地应用于制备抗细菌的的药物,并以其抗菌谱广,抗菌效果明显,疗效确定而广为使用,中国专利公开号1488633公开了“一种大环内酯类抗生素及其制备方法”,在该项专利申请中,公开了被命名为麦拓莱霉素的一种大环内酯化合物的结构及制备方法,以及通过实验证明对多种细菌有较强的抑制作用,对红霉素耐药的金葡菌亦有作用。
病毒是引起人体多种疾病的微生物,由于形态结构不同于细菌,因此,用抗生素作为制备抗病毒的药物,很少有报道。
柯萨奇病毒Coxsackievirus属肠道病毒,人是柯萨奇病毒唯一的天然宿主,通过呼吸道和消化道传染,接触是其主要的感染方式。病毒进入人的口腔后,首先在口咽部或胃肠道细胞内繁殖,然后进入局部淋巴结或血循环,再进入其他组织引起相应的疾病。该病毒进入中枢神经系统后,在脑膜和/或脑组织造成炎症性损害、血管病变。该病毒还可抑制体液免疫及细胞免疫,以后者明显。柯萨奇病毒致病后临床表现轻重不一,这与病毒的致病力及不同的机体的免疫功能有关。轻者症状轻微,类似感冒,如发热、上呼吸道感染等,重者表现为脑膜炎、流行性肌痛、疲劳综合征、头晕、呼吸道感染、肺炎及腹泻等多脏器损害,病死率高。凡急性发热患者伴有多脏器损害时,均应疑似柯萨奇病毒感染。有些病人第一次感染痊愈后又会有第二次感染,说明本病毒并非终生免疫,可交叉其它类型感染,治疗的手段则以抗病毒为主。
关于病毒感染可导致心肌炎这一观点.已经动物实验得到证实,特别是柯萨奇病毒B组病毒是引起病毒性心肌炎的重要病原体,有文献报道:我国长春地区病毒性心肌炎有半数以上是由柯萨奇B组病毒引起,大量资料已证实这点。
由于认识不足,柯萨奇B组病毒引起病毒脑炎或脊髓炎、脑膜脑炎报道较少,往往将头痛、头晕、乏力、视力下降当作其它病因引起的症状而误诊或忽略,更没有意识到柯萨奇病毒感染是一种全身性疾病,其症状复杂,可表现为多系统损害,并非单纯心肌损害,如不及时确诊出并给予治疗,有些病人可能会双目失明或致残。
艾滋病全名为获得性免疫缺陷综合症(Acquired Immune Deficiency Syndrome,简称AIDS),是由人类免疫缺陷病毒(Human immunodeficiency Virus,简称HIV)侵入人体后自身复制而繁殖,主要侵袭辅助T淋巴细胞,破坏免疫系统,最终使患者免疫功能衰竭而死亡。因此在过去20多年中,受到世界各国科学家们比其它任何感染介质更密切的关注,对其研究已取得了突破性进展。人们对HIV复制循环过程也基本搞清,同时,还了解到HIV如何感染正常细胞并复制本身产生新的感染性病毒粒子的详细过程。研究发现HIV的复制过程是一个由细胞和病毒编码蛋白质之间相互作用和高度调节的过程。这些蛋白质调节的许多过程对HIV来讲可能是独特的。由于全球HIV感染人数已近6000万之多,故世界抗病毒药物需求呈现前所未有的坚挺。近年来世界抗病毒药物市场的年增长率超过1%,其中绝大部分为抗HIV/AIDS药物。
以病毒繁殖过程所需的特异性酶作为靶点,通过改变底物的结构,选择性抑制这些特异性酶或作为特异性酶的底物掺入病毒复制的基因组,使病毒RNA链终止延伸,可以达到抗病毒的目的。
发明内容
本发明的目的是提供麦拓莱霉素的用途。
本发明的技术方案概述如下:
麦拓莱霉素
的用途,所述用途是在制备抗病毒药物中的用途。
所述病毒是柯萨奇B6病毒。
所述病毒是人类免疫缺陷病毒。
临床中由于对病毒类疾病缺乏有针对性的药物,为了能够抑制病毒的复制,常常加大广谱抗病毒类药物的剂量,这又导致病毒的变种,更加难以有效控制。另外。随着对艾滋病病毒传播途径和治疗的深入研究,发现HIV蛋白酶是艾滋病病毒传播中的一个关键的步骤,因此具有抗HIV蛋白酶的化合物,就能够有效的抑制艾滋病病毒复制,从而达到治疗的作用。本发明的实验结果显示,麦拓莱霉素对柯萨奇B6病毒具有很好的抑制作用,其抑制效果优于现代临床中常用的病毒唑,安全指数亦高于病毒唑,因此,抗柯萨奇病毒是麦拓莱霉素具有的重要用途之一。其抗HIV蛋白酶的作用亦具有一定的活性,有希望成为抗HIV病毒类药物之一。
具体实施方式
下面结合具体实施例对本发明作进一步的说明。
实施例1
化合物(I)的制备
(1)菌种培养发酵:
①培养基(g/l)的制备:取葡萄糖5.0g、可溶性淀粉40.0g、蛋白胨4.0g、玉米浆2.0ml g、K2HPO4 0.5g、MgSO4·7H2O 0.5g、NaCl 0.5g、加水至1000ml在pH6.0,121℃灭菌15min;②发酵:把天津市英捷科技发展有限公司出售的藤黄灰链霉菌菌株(streptomyces luteogriseus via.099)加入灭菌后的培养基中,加菌种重量为发酵培养基重量的10%,摇瓶发酵,160转/分,28℃,发酵4天;
(2)发酵液处理:①发酵液经4800转/分,离心,20分;②以等体积乙酸乙酯萃取5次,乙酸乙酯部分经2∶1体积的水反萃,去除色素杂质;③回收乙酸乙酯,得到具有活性部位的褐色油状物;④进行硅胶柱层析,以二氯甲烷∶甲醇1∶0到0∶1梯度洗脱,收集二氯甲烷∶甲醇为11∶1的活性组分,回收溶剂,得到粗品一种大环内酯类抗生素;⑤将粗品一种大环内酯类抗生素经过制备高效液相纯化,收集活性峰段,冷冻干燥,得到一种大环内酯类抗生素纯品。
每2升的发酵液可得到0.05g的目的产物。
如上所得的本发明化合物,具有下述理化及生物性质:
1.性状:淡黄色结晶或类白色粉末。
2.熔点:123±1℃(乙睛水体系为干燥前溶剂)。
3.分子量:分子量为600.3047。
4.分子式:分子式为C32H44N2O9。
5.元素分析:C 63.98%、H 7.38%、N 4.66%、O 23.97%。
6.紫外吸收光谱:UVλmax:252,337(乙醇溶剂)证明分子结构中有α,β不饱和共轭,二烯体系。
7.红外吸收光谱:(KBr)IR(3590,3421,2990,2932,1704,1622,1568,1444,1398,1297,1239,1206,982,933,750cm-1 wavelength)
证明分子结构中有羟基,羰基,酰胺基,顺式双键,反式双键,氧杂三元环,及氧杂六元环等。
1H谱、13C谱、HSQC(异核单量子相关)、HMBC(异核多键相关)、NOESY差谱、H-H COSY(同核位移相关谱)、快原子轰击高分辨质谱分析(HRFAB-MS)M+Na=623.2930。证实分子量为600.3047;分子式为C32H44N2O9
鉴定该化合物为大环内酯类抗生素,该抗生素可与多种酸成盐,如盐酸盐、硫酸盐、磷酸盐等。
实施例2
麦拓莱霉素(maituolaimycin)抗柯萨奇病毒(Coxsackievirus)B6病毒(COXB6)活性测试
以Vero(非洲绿猴肾)细胞为病毒宿主,测定样品抗柯萨奇B6病毒引起Vero细胞病变程度。病毒唑(PBV,浙江康裕药业有限公司,批号:(960501)阳性对照药,样品临用前溶于二甲基亚砜,配成适当浓度,用培养液作3倍稀释,共8个稀释度。COXB6细胞种96孔培养板,24小时后分别感染柯萨奇B6病毒由ATCC提供,1/210-4(233TCID50)的感染量,吸附2小时,弃病毒液,按以上稀释度加入样品麦拓莱霉素,同时设细胞对照孔和病毒对照孔,36小时观察细胞病变程度(CPE),用Reed-Muench法分别计算麦拓莱霉素对柯萨奇B6病毒的半数抑制浓度(IC50)。结果显示麦拓莱霉素(maituolaimycin)具有很强的抗病毒作用,IC50为231.1μg/ml,抗病毒活性明显高于阳性对照药病毒唑,IC50为569.3。而且其安全指数SI为2.88,也高于对照药物病毒唑,病毒唑的SI为1.75(见表1)。(上海国家新药筛选中心测试)
表1:麦拓莱霉素抗Coxsackievirus B6病毒(COXB6)活性筛选
样品编号 TC50(μg/ml) 实验初始浓度(μg/ml) IC50(μg/ml) SI
maituolaimycin 666.7 1000 231.1 2.88
RBV >1000 1000 569.3 >1.75
TC50:半数有毒浓度;IC50:对病毒半数抑制浓度;SI=TC50/IC50。
实施例3
抗HIV-1蛋白酶作用测试结果
HIV-1蛋白酶在最佳反应条件和反应体系中可将荧光标记底物切开,检测酶反应产物中荧光强度来反映酶的活性。在反应体系中加入麦拓莱霉素样品可用于筛选该酶的抑制剂。选取印地那韦(indinavir)为阳性对照药(葛兰素史克公司提供)。麦拓莱霉素样品临用前溶于DMSO,配成适当浓度,2倍稀释,各5个稀释度。样品稀释后加入含有荧光标记底物的反应缓冲液中,并加入基因工程靶酶(-85℃保存的HIV-1 PR),在最佳反应条件下孵育,用FLUO star Galaxy荧光仪测定荧光值。(见表2)(上海国家新药筛选中心测试)
表2 麦拓莱霉素的体外抗HIV-1 PR活性筛选
对照 250μg/ml 50μg/ml 10μg/ml 0.4μg/ml IC50
maituolaimycin 75.8 -1.7 0.1 12.4 39.8μg/ml
a:阳性对照:Indinavir(印地那韦)95.1(nM)选自GSK(葛兰素史克公司)
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