CN115177605B - 化合物(r)-stu104在制备防治急性胰腺炎相关疾病药物中的应用 - Google Patents
化合物(r)-stu104在制备防治急性胰腺炎相关疾病药物中的应用 Download PDFInfo
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Abstract
本发明属医药技术领域,涉及化合物(R)‑STU104新的药用用途,具体涉及化合物(R)‑STU104在制备防治急性胰腺炎相关疾病药物中的用途。经实验证实,本发明的化合物(R)‑STU104在体内具有显著的抑制急性胰腺炎引起的血清淀粉酶、血清胰脂肪酶的水平升高和胰腺组织髓过氧化物酶活性升高,同时还显著改善急性胰腺炎引起的胰腺组织水肿及胰腺炎症浸润程度;所述化合物(R)‑STU104可用于制备防治急性胰腺炎相关疾病的药物。
Description
技术领域
本发明属医药技术领域,涉及天然来源白藜芦醇倍半萜(±)-Isopaucifloral F的结构优化衍生物(R)-STU104新的药用用途。具体涉及化合物(R)-STU104在急性胰腺炎发病过程中可发挥关键的调控作用,进一步用于制备防治急性胰腺炎相关疾病的药物。
背景技术
现有技术公开了急性胰腺炎(Actue pancreatitis,AP)是一种常见的临床急性腹部疾病,由多种病因如饮酒过多、胆管结石等导致胰酶在胰腺内被异常激活,引起胰腺组织水肿和自身消化,严重时会造成多器官功能性障碍,从而导致较高的死亡率。据统计,约20%-30%的急性胰腺炎患者发展为以导致重症急性胰腺炎,并伴随胰腺脓肿、胰腺假性囊肿、休克、脏器功能衰竭等多种并发症,病情重者可继发腹腔、呼吸道、泌尿道等感染,感染扩散可引起败血症,无疑给患者及家属带来精神、肉体和经济上的巨大负担。鉴于临床实践中对其发病机制仍未完全阐明,目前临床上缺乏有效的手段阻止胰腺组织坏死及炎症反应由局部向全身的扩散和恶化,因此建立与人类发病机制最为接近的动物模型,认识和探讨发病机理,验证治疗手段,开发防治急性胰腺炎的新药物或保健食品显得尤为重要。
化合物(R)-STU104是以天然产物白藜芦醇倍半萜(±)-Isopaucifloral F为原料合成的带有3-芳基茚满酮的结构优化衍生物,该化合物的合成路径已有文献报道(Chem.Eur.J.2016,22,14535-14539)。
化合物(R)-STU104的结构式如下:
(R)-4,6-二甲氧基-3-(4-甲氧基苯基)-2,3-二氢-1H-茚满酮分子量:298;
旋光值:
迄今为止。国内外尚未将有关(R)-STU104治疗急性胰腺炎的报道。
基于现有技术的现状本申请的发明人拟提供化合物(R)-STU104在制备防治急性胰腺炎相关疾病药物中新的药物用途
发明内容
本发明的目的在于基于现有技术的现状,提供化合物(R)-STU104新的药用用途,具体涉及化合物(R)-STU104在急性胰腺炎发病过程中发挥关键的调控作用,可进一步用于制备防治急性胰腺炎相关疾病的药物中的用途。
本发明的化合物(R)-STU104的结构式如下:
(R)-4,6-二甲氧基-3-(4-甲氧基苯基)-2,3-二氢-1H-茚满酮分子量:298;
旋光值:
本发明式(1)所示化合物(R)-STU104还包括其药学上可接受的盐。
本发明进行了动物实验,其中,在体内研究结果表明:化合物(R)-STU104可显著降低血清淀粉酶、血清胰脂肪酶的水平和胰腺组织髓过氧化物酶活性,表明本发明化合物(R)-STU104可用于制备胰腺炎发病过程中降低血清淀粉酶、血清胰脂肪酶的水平和胰腺组织髓过氧化物酶活性的药物。
本发明在动物体内实验研究表明,化合物(R)-STU104可显著缓解小鼠急性胰腺炎组织水肿及胰腺炎症浸润程度,结果表明,所述化合物(R)-STU104可用于制备胰腺炎发病过程中降低胰腺水肿和胰腺炎症的药物。
本发明化合物(R)-STU104由于具有降低血清淀粉酶、血清胰脂肪酶的水平和胰腺组织髓过氧化物酶和减轻胰腺水肿和胰腺炎症,证明它在急性胰腺炎发病过程中可发挥关键调控作用,进一步,本发明化合物(R)-STU104可用于制备缓解/治疗急性胰腺炎的药物。
本发明提供了化合物(R)-STU104在制备防治急性胰腺炎相关疾病药物中的用途。实验证实,本发明的化合物(R)-STU104在体内具有显著的抑制急性胰腺炎引起的血清淀粉酶、血清胰脂肪酶的水平升高和胰腺组织髓过氧化物酶活性升高,同时还显著改善急性胰腺炎引起的胰腺组织水肿及胰腺炎症浸润程度;所述化合物(R)-STU104可用于制备防治急性胰腺炎相关疾病的药物。
附图说明
图1,(R)-STU104对急性胰腺炎引起的胰腺水肿的影响,
其中,通过比较新鲜的胰腺样品重量(湿重)和烘干的胰腺样品重量(干重)对胰腺组织水肿程度进行评估,*:P<0.05,**:P<0.01,***:P<0.001,结果显示(R)-STU104能显著改善急性胰腺炎引起的胰腺水肿。
图2,(R)-STU104对急性胰腺炎引起的血清淀粉酶水平的影响,
其中,采用血清淀粉酶试剂盒测定小鼠血清中淀粉酶水平,*:P<0.05,**:P<0.01,***:P<0.001,结果显示,(R)-STU104能显著降低急性胰腺炎引起的血清淀粉酶升高。
图3,(R)-STU104对急性胰腺炎引起的血清脂肪酶水平的影响,
其中,采用脂肪酶试剂盒测定小鼠血清脂肪酶水平,
其中,*:P<0.05,**:P<0.01,***:P<0.001,结果显示,(R)-STU104能显著降低急性胰腺炎引起的血清脂肪酶升高。
图4,(R)-STU104对急性胰腺炎引起的胰腺组织髓过氧化物酶活性的影响采用髓过氧化物酶试剂盒测定小鼠胰腺组织髓过氧化物酶的活性,
其中,*:P<0.05,**:P<0.01,***:P<0.001,结果显示,(R)-STU104能显著降低急性胰腺炎引起的胰腺组织髓过氧化物酶活性的升高。
图5,(R)-STU104对急性胰腺炎引起的胰腺组织形态学改变和炎症细胞浸润的影响用H&E染色的方法观察胰腺组织的病理变化,结果显示,(R)-STU104能显著降低急性胰腺炎引起的胰腺组织形态学改变和炎症细胞浸润。
具体实施方式
下面实施例对本发明作进一步阐述,由于篇幅原因,实验过程的描述无法做到非常详细,凡是实验中未详细描述的部分均为本领域技术人员熟知的常规操作,但实施例绝不是对本发明的任何限制。
下列实施例中所用方法如无特别说明,均为本领域常规方法,以下实施中所需的试剂,如无特殊说明均为市场购得
实例中的数据分析均采用Graphpad Prism 8.0统计分析软件进行One-Way ANOVA多组比较。
实施例1、建立急性胰腺炎模型
将8周龄雌性Balb/c小鼠随机分成对照组(CON)、白藜芦醇衍生物(R)-STU104单处理组(STU+CON)、急性胰腺炎组(AP)、白藜芦醇衍生物(R)-STU104治疗组(STU+AP)和白藜芦醇治疗组(Res+AP),采用腹腔注射的方式分别给AP组、STU+AP组和Res+AP小鼠注射雨蛙素(50μg/kg);每小时注射一次,连续注射8次。CON及STU+CON组腹腔注射等体积生理盐水(0.90%)。STU+CON和STU+AP组在第一次注射2h前腹腔注射20mg/kg白藜芦醇衍生物(R)-STU104溶液,Res+AP组在第一次注射2h前腹腔注射20mg/kg白藜芦醇(Resveratrol)溶液。最后一针雨蛙素注射完毕后1小时,向小鼠注射致死剂量的戊巴比妥钠后取血、解剖小鼠取出胰腺组织进行生化指标和组织学分析。
实施例2、(R)-STU104降低急性胰腺炎发生时胰腺水肿程度实验
胰腺水肿是急性胰腺炎发生时胰腺最直观的变化之一,水肿程度可以反应急性胰腺炎的严重程度,其诱因主要是急性胰腺炎发生时胰腺中大量免疫细胞的募集和浸润。在这些大量浸润的免疫细胞中,中性粒细胞的活化在急性胰腺炎病理过程中发挥着重要作用,通常以湿重和干重的质量差与湿重的比值来衡量胰腺的水肿程度。
如图1结果显示,STU+CON组仅使用白藜芦醇衍生物(R)-STU104对正常小鼠处理后,对胰腺水肿程度无影响。AP组的胰腺水肿程度(4.80)较CON组(3.37)明显上升(P<0.001),白藜芦醇衍生物预处理后STU+AP组较AP组下降至3.57(P<0.001),而作为对照的白藜芦醇预处理后的Res+AP仅下降至4.03。由此可得,经白藜芦醇衍生物处理后急性胰腺炎小鼠显著改善了胰腺的水肿程度,从而改善急性胰腺炎。
实施例3、(R)-STU104降低急性胰腺炎发生时血清淀粉酶的水平实验
已有数据显示,90%以上急性胰腺炎患者的血清中淀粉酶含量会增高,因此本发明检测了血清淀粉酶含量变化。淀粉酶能水解淀粉生成葡萄糖、麦芽糖及糊精,在底物浓度已知并且过量的情况下,加入碘液与未水解的淀粉生成蓝色复合物,根据蓝色的深浅可推算出水解的淀粉量,从而计算出的活力。如图2结果显示,STU+CON组仅使用白藜芦醇衍生物(R)-STU104对正常小鼠处理后,对血清淀粉酶无影响。AP组的活力较CON组明显上升(P<0.001),白藜芦醇衍生物预处理后STU+AP组的活力较AP组显著下降(P<0.001)。由此可得,经白藜芦醇衍生物处理后急性胰腺炎小鼠的血清淀粉酶活力显著下调,从而改善急性胰腺炎。
实施例4、(R)-STU104降低急性胰腺炎发生时血清胰脂肪酶的活性实验
除急性胰腺炎以外,血清淀粉酶也可在其它疾病中升高,如胃穿孔、胰腺肿瘤等,因此单独用血清淀粉酶诊断急性胰腺炎是有局限性的。血清胰脂肪酶在急性胰腺炎发病后活性升高,也可用于急性胰腺炎的测定。通常但其特异性更高,持续时间更长,因此,对血清胰脂肪酶进行测定以验证结论的准确性。
采用生物素双抗体夹心酶联免疫吸附法(ELISA)测定小鼠胰脂肪酶水平。分别向预先包被了小鼠胰脂肪酶单克隆抗体的酶标孔中加入脂肪酶温育后,加入生物素标记抗体,再与联袂亲和素HRP结合,形成免疫复合物,再经温育和洗涤,去除未结合的酶,然后加入底物A、B,产生蓝色,并在酸的作用下转化成最终的黄色。颜色的深浅与样品中小鼠胰脂肪酶的浓度呈正相关。
如图3结果显示,TML+CON组仅使用白藜芦醇衍生物(R)-STU104对正常小鼠处理后,对血清胰脂肪酶活性无影响。AP组的血清胰脂肪酶活性(877U/L)较CON组(146U/L)激增(P<0.001),白藜芦醇衍生物预处理后STU+AP组的活性较AP组下降至591U/L(P<0.01),而作为对照的白藜芦醇预处理后的Res+AP仅下降至749U/L(P<0.05)。由此可得,经白藜芦醇衍生物处理后急性胰腺炎小鼠的血清胰脂肪酶活性显著下调,从而改善急性胰腺炎。
实施例5、(R)-STU104降低急性胰腺炎发生时胰腺组织髓过氧化物酶的表达活性实验
髓过氧化物酶是中性释放的一种重要酶类,是反映中心粒细胞活化状态的标志物之一,其酶活水平可间接反映中性粒细胞的活性及浸润情况。此外,髓过氧化物酶还可以激活细胞内的炎症信号通路,诱导炎症因子大量释放,加速炎症反应发生。研究表明髓过氧化物酶水平与急性胰腺炎的严重程度呈正相关。
如图4结果显示,STU+CON组仅使用白藜芦醇衍生物(R)-STU104对正常小鼠处理后,对胰腺组织髓过氧化物酶无影响。AP组的髓过氧化物酶的表达活性(12.23units/g)较CON组(8.85units/g)大幅度升高(P<0.001),白藜芦醇衍生物预处理后STU+AP组的活性较AP组显著下降至8.17(P<0.001),作为对照的白藜芦醇预处理后的Res+AP也下降至7.94units/g(P<0.001)。由此可得,经白藜芦醇衍生物处理后急性胰腺炎小鼠胰腺组织髓过氧化物酶表达活性显著下调,从而改善急性胰腺炎。
实施例6、(R)-STU104缓解小鼠急性胰腺炎胰腺组织水肿及炎症浸润程度实验
用H&E染色的方法,将实验组小鼠胰腺经固定、脱水、染色、脱蜡、透明和封片等主要过程,观察胰腺组织的组织完整性、胰腺水肿程度和炎症细胞浸润程度。如图5,结果显示,CON组胰腺组织结构密实,无明显裂纹。AP组小鼠胰腺组织结构疏松,有明显水肿及炎症浸润现象,而STU+AP组较AP组则有明显的改善作用,表明白藜芦醇衍生物对小鼠急性胰腺炎发挥保护作用。
Claims (3)
1.式(1)所示化合物(R)-STU104或其药学上可接受的盐在用于制备预防和治疗急性胰腺炎疾病的药物中的用途,
2.如权利要求1所述用途,其特征在于,所述的药物是降低血清淀粉酶、血清胰脂肪酶的水平和胰腺组织髓过氧化物酶活性的药物。
3.如权利要求1所述用途,其特征在于,所述的药物是缓解急性胰腺炎组织水肿及胰腺炎症浸润程度的药物。
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