CN113304138B - Vitisinol D在制备黄嘌呤氧化酶抑制药物中的应用 - Google Patents
Vitisinol D在制备黄嘌呤氧化酶抑制药物中的应用 Download PDFInfo
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Abstract
本发明属于中药材有效成分应用的技术领域，具体涉及Vitisinol D在制备黄嘌呤氧化酶抑制药物中的应用，所述黄嘌呤氧化酶抑制药物由以Vitisinol D为有效成分和其他药物赋形剂或载体制成，所述Vitisinol D的分子式为C28H22O6，本发明的Vitisinol D是一种从金雀花根中分离得到的单体化合物，具有高安全性和强烈的黄嘌呤氧化酶抑制作用。
Description
技术领域
本发明属于中药材有效成分应用的技术领域，具体涉及Vitisinol D在制备黄嘌呤氧化酶抑制药物中的应用。
背景技术
目前，痛风患病率逐年升高，发病率仅次于糖尿病发病率，成为第二大代谢类疾病；痛风是由于体内长期的嘌呤生物代谢增加，尿酸产生过多或排泄不良而致血中尿酸升高，尿酸盐结晶沉积在关节等处，而引起的一组临床综合症状，持续的血中高尿酸水平是引发痛风的必不可少的条件。尿酸是嘌呤类物质在体内代谢的最终产物，高尿酸血症是因体内尿酸浓度超出正常范围而诱发的，进而会引发痛风发作。
黄嘌呤氧化酶(Xanthine Oxidase,简称XO)是一种复合黄素酶，是生物体内重要的核苷酸代谢酶，它可催化体内的嘌呤类化合物以及脂肪族、芳香族的醛类化合物，最终氧化形成尿酸。黄嘌呤氧化酶活性的升高会导致尿酸代谢紊乱，且可能同时加重糖代谢的紊乱。黄嘌呤氧化酶抑制药物是通过抑制黄嘌呤氧化酶的活性，阻碍次黄嘌呤和黄嘌呤代谢为尿酸，从而减少体内尿酸的生成，起到治疗痛风的作用，其中别嘌呤醇抑制尿酸生成疗效明显、作用机理明确，被常用于降低尿酸含量，但其会出现超敏反应综合征、史蒂文斯约翰逊综合征和肾毒性等副作用。2009年XO选择性抑制剂非布司他通过美国FDA审核获批上市，其抑制XO活性进一步提升，效果优于别嘌呤醇，但是其仍旧出现了胃疼、腹泻、肝损伤和肌肉疼痛等不良反应。
因此，找寻一种有效抑制黄嘌呤氧化酶活性且无不良副作用的物质成为开发抗痛风药物的关键任务。
发明内容
本发明针对现有技术的不足，提出了Vitisinol D在制备黄嘌呤氧化酶抑制药物中的应用。
具体是通过以下技术方案来实现的：
Vitisinol D在制备黄嘌呤氧化酶抑制药物方面的应用，所述黄嘌呤氧化酶抑制表现为通过抑制黄嘌呤氧化酶的活性，减少体内尿酸的生成，进行高尿酸血症、痛风、糖尿病肾病、心血管疾病等与黄嘌呤氧化酶活性相关的疾病的防治。
所述Vitisinol D的结构式如下：
所述Vitisinol D的分子式为C28H22O6，化学名为(+)-(1R,5S,6S,7S)-6-(3,5-Dihydroxyphenyl)-7-(4-hydroxyphenyl)-4-[(1E)-2-(4-hydroxyphenyl)ethenyl]bicyclo[3.2.1]oct-3-ene-2,8-dione。
所述黄嘌呤氧化酶抑制药物由以Vitisinol D为有效成分和其他药物赋形剂或载体制成。
所述黄嘌呤氧化酶抑制药物为口服剂或注射剂。
所述口服剂为颗粒剂、胶囊剂、片剂、散剂、滴丸剂、缓释剂中任意一种或多种。
有益效果：
本发明的Vitisinol D是一种从金雀花根中分离得到的单体化合物，是中药金雀花根抗痛风作用的有效成分，未见相关毒副作用报道，具有强烈的黄嘌呤氧化酶抑制作用，其IC50(19.8μmol/L)明显优于临床用药别嘌呤醇(IC50:71.7μmol/L)，Vitisinol D是中药金雀花根抗痛风作用的有效成分，与临床用药别嘌呤醇相比，具有更好的黄嘌呤氧化酶抑制活性。
以Vitisinol D为有效成分制成的药物，不仅能够有效抑制黄嘌呤氧化酶活性，还能避免了胃疼、腹泻、肝损伤和肌肉疼痛等不良反应的出现。
Vitisinol D的药理作用明确，药效显著，其药理作用与别嘌呤醇、非布司他类似，有望开发成为别嘌呤醇、非布司他替代品而用于临床。
附图说明
图1为不同浓度的Vitisinol D对黄嘌呤氧化酶的抑制作用。
具体实施方式
下面对本发明的具体实施方式作进一步详细的说明，但本发明并不局限于这些实施方式，任何在本实施例基本精神上的改进或代替，仍属于本发明权利要求所要求保护的范围。
实施例1
Vitisinol D在制备黄嘌呤氧化酶抑制药物方面的应用，所述黄嘌呤氧化酶抑制表现为通过抑制黄嘌呤氧化酶的活性，减少体内尿酸的生成，进行高尿酸血症、痛风、糖尿病肾病、心血管疾病等与黄嘌呤氧化酶活性相关的疾病的防治。
所述Vitisinol D的分子式为C28H22O6，化学名为(+)-(1R,5S,6S,7S)-6-(3,5-Dihydroxyphenyl)-7-(4-hydroxyphenyl)-4-[(1E)-2-(4-hydroxyphenyl)ethenyl]bicyclo[3.2.1]oct-3-ene-2,8-dione，其结构式为：
所述黄嘌呤氧化酶抑制药物由以Vitisinol D为有效成分和其他药物赋形剂或载体制成；
所述黄嘌呤氧化酶抑制药物为口服剂或注射剂；其中，所述口服剂为颗粒剂、胶囊剂、片剂、散剂、滴丸剂、缓释剂中任意一种或多种；
所述Vitisinol D是从天然药物(如金雀花根)中提取而得，用于制备预防和治疗与黄嘌呤氧化酶相关的疾病药物；包括但不限于：高尿酸血症、痛风、糖尿病肾病、心血管疾病等与黄嘌呤氧化酶活性相关的疾病的药物；
为说明本发明Vitisinol D在制备黄嘌呤氧化酶抑制药物方面的应用取得良好的效果，下面结合具体实验对本发明所取得的效果做进一步说明。
实验例1XO抑制活性测试：
在25℃下，采用96孔板，反应总体积为200μL，首先加入50μL的酶溶液(反应终浓度为0.05U/mL)，50μL的样品溶液，25℃温育15min后，加入50μL黄嘌呤底物溶液(终浓度为150μmol/L)启动反应。于25℃温育20min后，加入1mol/L的盐酸溶液50μL终止反应。于290nm下检测吸光度值。取该值与温育0min时OD值的差值作为最终检测结果；同法检测空白样品(即不含受试药物，以含5％DMSO的PBS替代样品溶液，以测定酶的最大反应活性)的OD值，并按下式计算各提取物的抑制率：抑制率(％)＝(1-试验样品平均OD值/空白样品平均OD值)×100％。采用Graphpad prism6.0软件进行数据分析。计算半数黄嘌呤氧化酶被抑制时的药物浓度，即IC50。采用别嘌呤醇作为阳性药；活性结果见表1；
其中，酶溶液的制备：称取XO适量，用水1mL溶解，得浓度为100U/mL的XO贮备液；将上述贮备液以每管50μL分装至10mL EPP管中，于-80℃冰箱中保存。取上述贮备液适量，用PBS稀释，制得浓度为0.2U/mL的XO溶液。溶液配制完毕后，立即置于0℃冰箱中保存。
样品溶液的制备：精密称取Vitisinol D适量，用DMSO溶解，再用PBS稀释，制得质量浓度为1000μg/mL的样品母液。采用二倍稀释法，以含DMSO的PBS为溶剂将上述母液逐级稀释，制得质量浓度分别均为1000、500、250、125、62.5、31.3、15.6μg/mL的样品溶液，DMSO含量为1％。
别嘌呤醇对照溶液的制备：精密称取别嘌醇适量，用DMSO溶解，加PBS适量稀释，制得质量浓度为500μg/mL的别嘌醇母液，待用。采用二倍稀释法，以含DMSO的PBS为溶剂将上述母液逐级稀释，制得质量浓度分别为500、250、125、62.5、31.3、15.63、7.82、3.91μg/mL的对照溶液，DMSO含量为1％。
黄嘌呤底物溶液的制备：称取黄嘌呤适量，加入PBS，室温下用NaOH、HCl溶液调节pH至7.5，超声使溶解，制得浓度分别为1200、1000、800、600、400μmol/L的黄嘌呤底物溶液。
表1 Vitisinol D在不同浓度下对XO的抑制率及半数抑制浓度(IC50)
由表1可知：相较于阳性药别嘌呤醇的IC50(71.7μmol/L)以及低浓度下的较低抑制率(12.5和6.25μmol/L时分别为8.3％和4.2％)，本发明申请保护的Vitisinol D的IC50为19.8μmol/L，在低浓度下仍然具有较高的抑制率(12.5和6.25μmol/L时分别为38.5％和16.1％)，其对黄嘌呤氧化酶的抑制效果突出，明显优于别嘌呤醇。
Claims (1)
1.Vitisinol D在制备通过抑制黄嘌呤氧化酶活性防治高尿酸血症、痛风的 药物中的应用，其特征在于，所述Vitisinol D的结构式如下：
所述Vitisinol D的分子式为C28H22O6，化学名为(+)-(1R,5S,6S,7S)-6-(3,5-Dihydroxyphenyl)-7-(4-hydroxyphenyl)-4-[(1E)-2-(4-hydroxyphenyl)ethenyl]bicyclo[3.2.1]oct-3-ene-2,8-dione。
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