CN115677638B - 红花黄色素及其在制备治疗心脑血管疾病药物中的应用 - Google Patents
红花黄色素及其在制备治疗心脑血管疾病药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种红花黄色素及其在制备疗心脑血管等血液循环障碍疾病药物中的应用,所述新型红花黄色素为下式所示,其中,R1为β‑D‑葡萄糖基或α‑D‑葡萄糖基;R2、R3分别独立的为羟基、氢或β‑D‑葡萄糖基或α‑D‑葡萄糖基;R4为氢、羟基;R5为氢、羟基;R6为羟基。本发明的新型红花黄色素具有显著的自由基清除和抗血小板聚集的药理作用,并且这种药理作用优于临床药物羟基红花黄色素A或者相当,对于开发治疗效果更强、毒性更低、适应症更广的抗心血管疾病药物具有重要意义。
Description
本发明为申请号为:2018115868871,发明名称为:红花黄色素及其在制备治疗心脑血管疾病药物中的应用的分案申请。
技术领域
本发明属于药学领域,具体涉及一种新型红花黄色素及其在制备治疗心脑血管疾病药物中的应用。
背景技术
红花黄色素是菊科植物红花的主要有效成分之一,由多种查耳酮类化合物组成。水溶性羟基红花黄色素A是红花黄色素中含量最高的成分,已经被成功开发为临床用药--注射用红花黄色素,具有活血化瘀、通脉止痛的功效,用于心血瘀阻引起的Ⅰ、Ⅱ、Ⅲ级的稳定型劳累性心绞痛的治疗。
红花黄色素具有抑制血小板聚集及血栓形成、改善心肌供血、抗氧化、降血压、抗炎镇痛等作用,在心血管疾病的治疗和病情改善中起到重要作用。抗氧化和抗血小板聚集是红花黄色素两大重要药理功能。一方面,红花黄色素能够清除冠心病缺血再灌注损伤及炎症反应过程中产生的大量自由基,抑制脂质过氧化,从而保护心肌和神经免受损伤。另一方面,红花黄色素是血小板活化因子(PAF)的拮抗剂,能够抑制PAF诱导的血小板聚集与炎性反应,红花黄色素同时还能抑制二磷酸腺苷钠盐(ADP)诱导的血小板聚集,显著延长凝血时间和凝血酶原时间,降低纤维蛋白原含量,从而抑制血栓形成。
目前对于红花黄色素在心血管疾病防治中的研究主要集中在羟基红花黄色素A上,其他类型的红花黄色素鲜有报道。但是心血管疾病的复杂性和现有药物的弊端也为心血管疾病的防治带来了新的挑战,因此,急需开发新的治疗药物。
发明内容
本发明提供了一种新型红花黄色素及其在制备治疗心脑血管疾病药物中的应用,本发明研究了新型红花黄色素在抗氧化和抗血小板聚集方面的药理作用。
一种红花黄色素,具有如下结构中的一种或多种:
其中,R1为β-D-葡萄糖基或α-D-葡萄糖基;R2、R3分别独立的为羟基、氢或β-D-葡萄糖基或α-D-葡萄糖基;R4为氢、羟基;R5为氢、羟基;R6为羟基。
一种红花黄色素,具有如下结构中的一种或多种:
包括:
一种新型红花黄色素,所述红花黄色素为如下化合物中的一种或多种:
4-β-D-葡萄糖-2,2,4,5-四羟基-6-[(2E)-3-(4-羟基苯基)-1-酮-2-丙烯-1-基]-5-环己烯-1,3-二酮(I-1);
2,4-二-β-D-葡萄糖-3,4,5-三羟基-6-[(2E)-3-(3,4-二羟基苯基)-1-酮-2-丙烯-1-基]-2,5-环己二烯-1-酮(I-2);
4-β-D-葡萄糖-4,5-二羟基-6-[(2E)-3-(4-羟基苯基)-1-酮-2-丙烯-1-基]-5-环己烯-1,3-二酮(I-3)。
结构式如下:
一种新型红花黄色素在制备治疗心脑血管疾病药物中的应用,其特征在于,所述新型红花黄色素为如下化合物中的一种或多种:
4-β-D-葡萄糖-2,2,4,5-四羟基-6-[(2E)-3-(4-羟基苯基)-1-酮-2-丙烯-1-基]-5-环己烯-1,3-二酮(I-1);
2,4-二-β-D-葡萄糖-3,4,5-三羟基-6-[(2E)-3-(3,4-二羟基苯基)-1-酮-2-丙烯-1-基]-2,5-环己二烯-1-酮(I-2);
4-β-D-葡萄糖-4,5-二羟基-6-[(2E)-3-(4-羟基苯基)-1-酮-2-丙烯-1-基]-5-环己烯-1,3-二酮(I-3)。
结构式如下:
作为优选,所述新型红花黄色素为2,4-二-β-D-葡萄糖-3,4,5-三羟基-6-[(2E)-3-(3,4-二羟基苯基)-1-酮-2-丙烯-1-基]-2,5-环己二烯-1-酮(I-2),4-β-D-葡萄糖-4,5-二羟基-6-[(2E)-3-(4-羟基苯基)-1-酮-2-丙烯-1-基]-5-环己烯-1,3-二酮(I-3)中的一种或多种。
作为优选,所述抗心血管疾病药物用于治疗的疾病为自由基氧化和血小板聚集导致的心血管疾病。
作为优选,所述抗心血管疾病药物用于治疗的疾病包括冠心病、血栓病、心绞痛、肺源性心脏病、动脉粥样硬化、高血压、高血脂、高血糖中的一种或多种。
本发明所述的化合物可以先通过水提法浓缩富集,再通过大孔树脂柱层析、凝胶柱层析、ODS反向柱层析等步骤制备得到。
自由基DPPH清除实验、自由基ABTS清除实验表明,本发明所述的新型红花黄色素能有效清除自由基;ADP诱发的血小板聚集的抑制实验、PAF诱发的血小板聚集的抑制实验表明,本发明所述的新型红花黄色素能有效抑制血小板聚集。
本发明的有益效果在于,本发明所述的红花黄色素是首次报道的结构新颖的天然活性化合物,具有显著的自由基清除和抗血小板聚集的药理作用,并且这种药理作用优于临床用药羟基红花黄色素A或者相当,对于开发治疗效果更强、毒性更低、适应症更广的抗心血管疾病药物具有重要意义。
具体实施方式
下面通过实施例进一步说明本发明,应该理解的是,本发明的实施例仅仅是用于说明本发明,而不是对本发明的限制。
实施例1:新型红花黄色素的制备方法和结构表征
新型红花黄色素的制备参考了专利文献(CN106496172A、CN102657691A)和文献(金鸣,高子淳,李金荣,等.大孔树脂柱色谱法制备红花黄色素和羟基红花黄色素A.中草药,2004,35(1):25-28)的方法,先通过水提法从中药材红花中提取粗品红花黄色素,再通过大孔树脂柱层析、凝胶柱层析、ODS反向柱层析等手段分离纯化得到新型红花黄色素。
制备得到的新型红花黄色素的结构表征数据如下:
4-β-D-葡萄糖-2,2,4,5-四羟基-6-[(2E)-3-(4-羟基苯基)-1-酮-2-丙烯-1-基]-5-环己烯-1,3-二酮(I-1)
FTIR(KBr)νmax cm-1:3384,2931,1750,1683,1597,1513,1423,1260,1079,1008,942,832;
1H NMR(500MHz,DMSO-d6)δ9.86(s,1H),7.90(d,J=16.0Hz,1H),7.44(d,J=8.5Hz,2H),7.38(d,J=16.0Hz,1H),6.81(d,J=9.0Hz,2H),5.99(s,1H),5.54(s,2H),5.24(s,1H),4.78(s,1H),3.73(m,2H),3.49(d,J=10.5Hz,1H),3.38(m,2H),3.20(m,1H),2.95(t,J=9.0Hz,1H);
13C NMR(500MHz,DMSO-d6)δ195.82,192.27,183.97,171.43,159.40,138.92,129.98,127.24,124.84,116.25,110.89,81.36,81.02,80.91,79.60,75.73,75.23,70.46,61.54;HRMS(ESI):m/z calcd for C21H22O13[M+H-H2O]+:465.1028,found:465.1031.
2,4-二-β-D-葡萄糖-3,4,5-三羟基-6-[(2E)-3-(3,4-二羟基苯基)-1-酮-2-丙烯-1-基]-2,5-环己二烯-1-酮(I-2)
FTIR(KBr)νmax cm-1:3383,2929,1598,1442,1407,1283,1078,1007,923,889,811;
1H NMR(500MHz,DMSO-d6)δ7.37(d,J=16.0Hz,1H),7.22(d,J=16.0Hz,1H),6.97(d,J=1.5Hz,1H),6.84(dd,J=8.0,1.5Hz,1H),6.70(d,J=8.0Hz,1H),4.20(d,J=9.5Hz,1H),4.12(t,J=9.5Hz,1H),3.61(m,3H),3.38(m,1H),3.31(m,2H),3.10(m,2H),3.06(m,1H),3.03(m,1H),2.95(m,1H),2.89(m,1H);
13C NMR(500MHz,DMSO-d6)δ195.34,189.29,182.91,179.35,147.67,145.67,136.57,127.32,122.64,120.48,115.55,114.04,105.75,99.28,85.54,85.12,80.57,80.18,79.15,78.13,73.86,70.88,69.85,68.69,61.49 61.09;HRMS(ESI):m/z calcd forC27H32O17[M+H]+:629.1712,found:629.1712.
4-β-D-葡萄糖-4,5-二羟基-6-[(2E)-3-(4-羟基苯基)-1-酮-2-丙烯-1-基]-5-环己烯-1,3-二酮(I-3)
FTIR(KBr)νmax cm-1:3421,2926,1670,1627,1577,1514,1422,1262,1088,1016,990,826;
1H NMR(500MHz,DMSO-d6)δ9.83(s,1H),7.98(d,J=15.5Hz,1H),7.41(d,J=8.5Hz,2H),7.33(d,J=16.0Hz,1H),6.79(d,J=8.5Hz,2H),5.91(s,1H),5.46(d,J=4.5Hz,1H),5.04(d,J=5.0Hz,1H),4.97(d,J=5.5Hz,1H),4.53(t,J=5.5Hz,1H),4.34(d,J=9.5Hz,1H),3.65(m,1H),3.39(m,1H),3.29(m,1H),3.22(m,1H),3.12(m,1H),3.03(m,1H),2.68(d,J=17.0Hz,1H),2.09(d,J=17.0Hz,1H);
13C NMR(500MHz,DMSO-d6)δ207.58,198.50,196.93,183.21,158.58,137.64,129.22,126.90,124.55,115.63,111.33,84.30,81.62,78.02,77.62,71.20,70.06,61.15,46.16;HRMS(ESI):m/z calcd for C21H22O11[M+H]+:451.1235,found:451.1233.
实施例2:新型红花黄色素对自由基DPPH和ABTS的清除能力评价
本发明通过测定新型红花黄色素对自由基DPPH和ABTS的清除能力,从而评价受试化合物保护心血管免受自由基损伤和抗氧化的能力。本发明以羟基红花黄色素A为阳性对照,实验结果以自由基清除率为参数。
自由基DPPH清除能力评价方法:将样品用体积分数为70%的甲醇溶液(溶剂为水)溶解稀释到100μg/ml,得到样品溶液,取100μL样品溶液加入96孔酶标板中,加入100μL的DPPH溶液(0.15mmol/L,溶剂乙醇),充分混合后在室温下避光反应30min,采用酶标仪在517nm处测定其吸光度(As),以体积分数为70%的甲醇溶液代替样品的反应为空白(Ac),以体积分数为70%的甲醇溶液代替DPPH溶液的反应为样品空白(Ab),以羟基红花黄色素A为阳性对照,按式计算自由基清除率。
自由基ABTS清除能力评价方法:将样品用体积分数为70%的甲醇溶液溶解稀释到100μg/ml,得到样品溶液,取25μL样品溶液加入96孔酶标板中,加入200μL的ABTS溶液(含7mmol/L的ABTS和2.45mmol/L的过硫酸钾,溶剂为水),充分混合后在室温下避光反应6min,采用酶标仪在734nm处测定其吸光度(As),以体积分数为70%的甲醇溶液代替样品的反应为空白(Ac),以体积分数为70%的甲醇溶液代替ABTS溶液的反应为样品空白(Ab),以羟基红花黄色素A为阳性对照,按式计算自由基清除率。
自由基清除率=[Ac-(As-Ab)]/Ac×100%
根据受试化合物的自由基清除率大小,将受试化合物的自由基清除能力划分为4种等级,即高清除能力“+++”:自由基清除能力(%)75-100;中清除能力“++”:自由基清除能力(%)50-75;低清除能力“+”:自由基清除能力(%)25-50;无清除能力“--”:自由基清除能力(%)25以下。实验结果见表1。
表1新型红花黄色素的自由基清除能力
实验结果表明新型红花黄色素均具有一定的自由基清除能力,其中化合物I-2自由基清除能力优于羟基红花黄色素A。
实施例3:新型红花黄色素的抗血小板聚集能力评价
本发明通过测定新型红花黄色素对ADP、PAF诱发的血小板聚集的抑制能力,从而评价受试化合物延长凝血时间、抑制血栓形成、改善心肌供血的能力。本发明以羟基红花黄色素A为阳性对照,实验结果以血小板聚集抑制率为参数。
ADP诱发的血小板聚集的抑制能力评价:SD大鼠50只,适应性喂养一周,随机分成5组,每组10只,分别为正常对照组(生理盐水)、羟基红花黄色素A(60mg/kg)组与给药组(60mg/kg)。连续7d腹腔注射给药,第6天禁食过夜,第7天给药2h后用乙醚麻醉动物,腹主动脉取血,3.8%枸橼酸钠溶液,按1:9抗凝,1000rpm离心10min后取上清液既得富血小板血浆(PRP),剩余部分以3000rpm离心10min,取上清液既得贫血小板血浆(PPP),用PPP调PRP中的血小板数为(3~4)×109/L。用20μL的ADP诱导大鼠的血小板聚集,测定5min内正常对照组和给药组的血小板最大聚集率(PAGmax,%)。计算给药组对血小板聚集的抑制率(IR%)。IR%=(正常对照组PAGmax-给药组PAGmax)/正常对照组PAGmax×100%。
PAF诱发的血小板聚集的抑制能力评价:大耳白家兔于清醒状态下用利多卡因局部麻醉,分离出左侧颈总动脉,长约2~3cm,颈总动脉取血,以体积比9:l与3.8%枸橼酸钠混匀,置于塑料管中,以1000rpm离心10min后,上清部分即为富血小板血浆(PRP);剩余部分以3000rpm离心10min,取上清部分即为贫血小板血浆(PPP)。用全自动血细胞计数仪计数血小板,并用PPP调PRP至血小板终浓度为3×105/mL。根据Born法,将加入500μL检测标本的PPP放入PPP孔,加入500μL检测标本的PRP放入PRP孔,育温5min,对照组加入20μL的无水乙醇(终浓度为9.26‰),试验组加入红花黄色素20μL(终浓度为0.448g/L),阳性对照组加入羟基红花黄色素A20μL(终浓度为0.448g/L)。温育5min后每个比色杯加入20μL的PAF(终浓度为725.63μmol/mL),通过570-VS血小板聚集仪描记的聚集曲线检测血小板聚集率,并计算给药组对血小板聚集的抑制率(IR%)。IR%=(无水乙醇组聚集率-给药组聚集率)/无水乙醇组聚集率×100%。
根据受试化合物对血小板聚集的抑制能力大小,将受试化合物抑制血小板聚集的能力划分为4种等级,即高抑制能力“+++”:血小板聚集抑制率(%)75-100;中抑制能力“++”:血小板聚集抑制率(%)50-75;低抑制能力“+”:血小板聚集抑制率(%)25-50;无抑制能力“--”:血小板聚集抑制率(%)25以下。实验结果见表2。
表2新型红花黄色素的抗血小板聚集能力
实验结果表明本发明所述的新型红花黄色素均有一定的抑制血小板聚集的能力,其中化合物I-2抑制血小板聚集的能力优于羟基红花黄色素A,I-3抑制血小板聚集的能力与羟基红花黄色素A相当。
Claims (4)
1.一种红花黄色素,其特征在于,具有如下结构中的一种或多种:
。
2.一种红花黄色素在制备治疗心脑血管疾病药物中的应用,其特征在于,所述红花黄色素为权利要求1所述的红花黄色素。
3.根据权利要求2所述的红花黄色素在制备治疗心脑血管疾病药物中的应用,其特征在于,所述心血管疾病为由自由基氧化和血小板聚集导致的心血管疾病。
4.根据权利要求2所述的红花黄色素在制备治疗心脑血管疾病药物中的应用,其特征在于,所述心血管疾病包括冠心病、血栓病、心绞痛、肺源性心脏病、动脉粥样硬化、高血压、高血脂、高血糖中的一种或多种。
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