CN110279689B - 一种α-倒捻子素衍生物在制备抗治疗性前列腺增生药物中的应用 - Google Patents
一种α-倒捻子素衍生物在制备抗治疗性前列腺增生药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种α‑倒捻子素衍生物在制备抗良性前列腺增生药物中的应用,及一种抗良性前列腺增生药物组合物,所述抗良性前列腺增生药物组合物的有效成分为α‑倒捻子素衍生物。本发明中α‑倒捻子素衍生物能被前列腺组织所吸收并且仍旧具有抗炎活性,可以提高SOD活力降低MDA含量,减轻前列腺腺体膨大,因此可以用于治疗前列腺增生,在制备治疗前列腺增生药物中具有广阔的应用前景。
Description
技术领域
本发明属于医药技术领域,具体涉及一种α-倒捻子素衍生物在制备抗治疗性前列腺增生药物中的应用
背景技术
良性前列腺增生(benign prostatic hyperplasia,BPH)是以前列腺间质和上皮细胞增生为其特征,是最为常见的一种老年男性的多发性疾病。主要表现是排尿困难,是前列腺腺体进行性肥大对尿道形成压迫,导致前列腺周围组织平滑肌张力上升,使膀胱出口发生梗阻(Bladder outlet obstruction,BOO)和下尿路症状(Lower urinary tractsymptoms,LUTS),主要表现为储尿期症状:夜尿增多、尿频尿急、尿失禁等;排尿期症状:排尿困难、射程变短、排尿等待、间断排尿、排尿时间延长等;排尿后症状:尿不尽、尿潴留等。治疗主要以康复疗养结合中药复方药物治疗为主:如公开号为CN105535042A的中国专利文献公开了一种治疗良性前列腺增生的药物组合物及其制备方法,本发明药物组合物是以野火绳、狼萁草、鳞叶甘草素C、仙鹤草内酯为原料药,配比而成,可按常规制剂工艺制成各种剂型,治疗良性前列腺增生疗效显著;如公开号为CN105497119A的中国专利文献公开了一种治疗良性前列腺增生的药物组合物及其制备方法,该发明药物组合物是以白果黄素、梳篦叶、浙江铃子香为原料药,配比而成,可按常规制剂工艺制成各种剂型,治疗良性前列腺增生疗效显著。
α-倒捻子素是由山竹外果皮中分离得到的一种活性成分,其活性成分见式I。报道称α-倒捻子素在人巨噬细胞和脂肪脂肪细胞中能够抑制脂多糖LPS所诱导的炎症。在某种程度上,α-倒捻子素还降低了肿瘤坏死因子TNF-α和白介素IL-6基因的表达,但是确切机制还尚不清楚。
其中,α-倒捻子素化学名称1,3,6-三羟基-7-甲氧基-2,8-(3-甲基-2-丁烯基)9H-氧杂蒽-9-酮。
但迄今,尚未见α-倒捻子素在良性前列腺增生中的应用,其原因很可能是α-倒捻子素很难被前列腺组织所吸收。
发明内容
本发明的目的在于提供一种α-倒捻子素衍生物在制备抗良性前列腺增生药物中的应用,可以减轻前列腺腺体膨大,因此可以用于治疗前列腺增生,在制备治疗前列腺增生药物中具有广阔的应用前景。
本发明提供如下技术方案:
一种α-倒捻子素衍生物在制备抗良性前列腺增生药物中的应用,所述α-倒捻子素衍生物具有如下结构:
所述良性前列腺增生为膀胱出口梗阻或下尿路症状。
本发明还提供一种抗良性前列腺增生药物组合物,所述抗良性前列腺增生药物组合物的有效成分为权利要求1所述的α-倒捻子素衍生物。
所述药物组合物包括α-倒捻子素衍生物、药学上可接受的赋形剂。
所述药物组合物为口服给药或注射给药的剂型。
所述口服给药的剂型选自水剂、片剂、胶囊剂或颗粒剂。
本发明提供的α-倒捻子素衍生物是对进行α-倒捻子素结构修饰后的衍生物,能被前列腺组织所吸收并且仍旧具有抗炎活性,可以提高SOD活力降低MDA含量,减轻前列腺腺体膨大,因此可以用于治疗前列腺增生,在制备治疗前列腺增生药物中具有广阔的应用前景。
附图说明
图1为α-倒捻子素衍生物对前列腺增生大鼠前列腺指数的测定。
图2为该α-倒捻子素衍生给药对良性前列腺增生大鼠前列腺细胞MDA含量的影响;
图3为该α-倒捻子素衍生给药对良性前列腺增生大鼠前列腺细胞SOD含量的影响;
图4为HE染色正常对照组前列腺腺体组织图;
图5为HE染色良性前列腺增生模型组前列腺腺体组织图;
图6为HE染色α-倒捻子素衍生高剂量组前列腺腺体组织图;
图7为HE染色α-倒捻子素衍生中剂量组前列腺腺体组织图。
具体实施方式
为使本发明的目的、技术方案及优点更加清楚明白,以下结合附图及实施例对本发明进行进一步的详细说明。应当理解,此处所描述的具体实施方式仅仅用以解释本发明,并不限定本发明的保护范围。
在本发明中,α-倒捻子素衍生物通过以下方法制备:
制备路线如下:称取三光气(100mg,0.33mmol)于50ml单口瓶中,加入新蒸干燥无水的二氯甲烷,搅拌溶解,25mL恒压滴液漏斗内缓慢加入1.0摩尔当量N-甲基苯胺衍生物或N-乙基苯胺,三乙胺(200μL,0.27mmol),10mL无水二氯甲烷稀释,于冰盐浴下缓慢滴加,滴毕撤去冰盐浴,常温搅拌反应8h。
取α-倒捻子素(50mg,0.12mmol)溶解于8mL二氯甲烷中,并加入催化量DMAP搅拌溶解,将混合液转移至恒压漏斗内,于冰盐浴条件下缓慢滴加,滴加完毕,撤去冰盐浴,常温搅拌反应,TLC检测反应进程。反应完全后,减压除去溶剂,并用乙酸乙酯萃取2次,合并有机相,饱和食盐水洗涤一次,无水硫酸钠干燥、过滤,减压浓缩得黄色胶状物。用柱层析(石油醚:乙酸乙酯=20:1)纯化,减压蒸馏除去洗脱剂,得到黄色固体,为本发明所述的α-倒捻子素衍生物,产率在85%-95%之间。重结晶得到目标纯度99.7%。
Control组是正常对照组,也可以理解为空白对照;M为模型组,Y为阳性药组,G为高剂量组,Z为中剂量组。良性前列腺模型指用丙酸睾酮皮下注射21天后的大鼠前列腺组织,可认为是良性前列腺增生。实施例中的实验数据分析采用Graphpad软件计算得到,并自动生成所有附图。
实施例1 α-倒捻子素衍生给药对前列腺增生大鼠前列腺指数的影响。
1.动物设组:SD大鼠(200-220g,每组6只),随机分组。分组如表1.1。
表1.1实施例1所需动物及设组情况
2.给药及剂量:将纯度99%以上该α-倒捻子素衍生物溶于DMA:PEG400:EtOH=30:40:30(V:V:V),动物经尾静脉注射给药,剂量为:1mg/kg,0.5mg/kg;阳性药前列康灌喂给药:20mg/kg,作为阳性对照;模型组与正常对照组均同等方式给予等量溶剂。每日11:00给药,造模后连续给药七日。
3.手术过程:动物麻醉后,切开下腹部部皮肤,暴露左右睾丸,分别于左右睾丸连接处各打一死结并从中剪断,摘除睾丸,缝合。放回鼠笼休息3天。
如图1所示,实验结果显示,在前列腺指数测定中,模型组前列腺指数相比正常组显著增加(P<0.001),阳性药组可显著减少其前列腺指数(P<0.05),高剂量给药组前列腺指数显著降低(P<0.05),中剂量组前列腺指数显著降低(P<0.01)。
实施例2 α-倒捻子素衍生物给药对良性前列腺增生大鼠前列腺指数和前列腺组织中MDA及SOD含量测试的影响。
鼠水合氯醛麻醉后,取出前列腺组织,用分析天平测定其质量做出相关前列腺指数,取同质量同部位组织用组织匀浆机做出组织匀浆,按南京生物建成公司的MDA,SOD试剂盒说明书操作测定组织中MDA和SOD的含量。
如图2所示,在MDA含量测定中,模型组相比正常组有显著差异(P<0.01),高剂量组与模型组有显著性差异(P<0.05)。如图3所示,在SOD含量测定中,模型组相比正常组有显著性差异(P<0.05),阳性药组与模型组大鼠有显著性差异,高剂量组与模型组有显著性差异(P<0.05)。
因此,α-倒捻子素衍生物给药可以改善良性前列腺增生模型大鼠的前列腺组织增生。
实施例3α-倒捻子素衍生物给药对前列腺增生大鼠前列腺腺体细胞染色观察的影响。
大鼠水合氯醛麻醉后,4%的多聚甲醛(0.1M磷酸盐缓冲液,PH=7.4)分离前列腺组织,浸入4%的多聚甲醛中,4℃避光保存24h,再浸入30%蔗糖溶液3天,冰冻切片机切片。冰冻切片晾干后滴入无水酒精5-10min,75%酒精3min
滴入染液,95%酒精两次,二甲苯两次每次5min,最后以中性树胶封片,自然晾干,细胞呈现斑驳的蓝紫色染色,显微镜拍照。
如图4所示,正常组腺体组织形状完好,腺体大小较小,腺体上皮稍有折叠,腺体上皮细胞成立方状排列未见增生,未见明显炎细胞浸润。如图5所示,模型组腺体大小较大,腺体上皮较厚折叠较多成乳头状增生,上皮细胞成长方状或高柱状,腺体周围炎细胞浸润较多。如图6所示,高剂量组腺体上皮较薄,折叠较少,上皮细胞成立方状排列,未见明显炎细胞浸润,但腺体大小不一,有的较大但相比模型组有较大改善。如图7所示给中剂量组腺体较小,腺体上皮有折叠,有的腺体上皮较厚部分上皮细胞成高柱状排列,有少量炎细胞浸润但相比模型组有改善。
以上所述的具体实施方式对本发明的技术方案和有益效果进行了详细说明,应理解的是以上所述仅为本发明的最优选实施例,并不用于限制本发明,凡在本发明的原则范围内所做的任何修改、补充和等同替换等,均应包含在本发明的保护范围之内。
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