CN109651332B - 多巴胺类衍生物的制备方法及其应用 - Google Patents

多巴胺类衍生物的制备方法及其应用 Download PDF

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CN109651332B
CN109651332B CN201811175923.5A CN201811175923A CN109651332B CN 109651332 B CN109651332 B CN 109651332B CN 201811175923 A CN201811175923 A CN 201811175923A CN 109651332 B CN109651332 B CN 109651332B
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程永现
刘越飞
晏永明
向斌
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Abstract

本发明提供了一类具有促进伤口愈合的多巴胺类衍生物,其结构分别为Aspongopusamide A、Aspongopusamide B、7,8‑dehydro‑N‑acetyldopamine、7,8‑erythro‑8‑methoxy‑3,4,7‑trihydroxy‑N‑acetyldopamine。本发明还提供了一种含有该类化合物的药物组合物、所述化合物的提取分离方法,通过实验表明该类化合物具有促进创面愈合作用。

Description

多巴胺类衍生物的制备方法及其应用
技术领域
本发明属于化学药物领域,涉及一类多巴胺类衍生物及其在治疗包括溃疡在内的创面愈合中的应用。
背景技术
创伤包括溃疡在内的成因、危害及治疗在以往申请专利CN105434450A中已经述及。创伤的组织重建过程至少包括细胞的增殖、迁移和血管形成,目前HUVEC(人脐静脉内皮细胞)已经成为研究促创伤愈合的重要模型。本发明采用HUVEC测试发现具有促进创面修复的活性成分。
美洲大蠊(Periplaneta americana)为昆虫纲有翅亚纲蜚蠊目蜚蠊科大蠊属昆虫,由其制备的康复新液临床上治疗各种创伤包括溃疡效果肯定,从中发现促进创面修复成分或药物是可能的。
发明内容
本发明提供了一类促进创面修复的多巴胺类衍生物,其化合物的结构为Aspongopusamide A、Aspongopusamide B、7,8-dehydro-N-acetyldopamine或7,8-erythro-8-methoxy-3,4,7-trihydroxy-N-acetyldopamine中的任意一种,机构式:
Figure BDA0001822329690000011
7,8-erythro-8-methoxy-3,4,7-trihydroxy-N-acetyldopamine。
进一步,所述化合物包括Aspongopusamide A、Aspongopusamide B、7,8-dehydro-N-acetyldopamine或7,8-erythro-8-methoxy-3,4,7-trihydroxy-N-acetyldopamine中的任意一种,或其药学上可接受的衍生物及其盐类。
进一步,所述的化合物为药物制剂,其是由Aspongopusamide A、AspongopusamideB、7,8-dehydro-N-acetyldopamine或7,8-erythro-8-methoxy-3,4,7-trihydroxy-N-acetyldopamine的任意一种,或其药学上可接受的衍生物及其盐类作为活性成分和药学上可接受的赋形剂组成。
其中固体制剂包括:片剂、胶囊剂、丸剂、颗粒剂等;半固体制剂包括软膏剂、栓剂等;液体制剂包括:溶液剂、注射剂、喷雾剂等;眼用制剂包括:滴眼剂、眼用凝胶剂等。
本发明还公布了所述的多巴胺类衍生物的制备方法为:
美洲大蠊,粉碎,80%乙醇回流提取3次,合并乙醇提取液,浓缩得浸膏;该浸膏用水混悬后采用石油醚,乙酸乙酯各萃取3次,得乙酸乙酯部分,乙酸乙酯萃取物经MCI gelCHP 20P柱,流动相为:甲醇-水,0%~100%进行梯度洗脱,得6个组分,依次为F1~F6;F4经Sephadex LH-20凝胶得4个组分,依次为F4.1~F4.4;F4.2经MCI gel CHP 20P色谱柱,流动相为甲醇-水,10%~70%梯度洗脱得8个组分,依次为F4.2.1~F4.2.8;F4.2.3经RP-18柱,流动相为甲醇-水,15%~50%梯度洗脱得6个组分,依次为F4.2.3.1~F4.2.3.6;F4.2.3.3经半制备HPLC,流动相为甲醇:水=25%:75%,得化合物7,8-erythro-8-methoxy-3,4,7-trihydroxy-N-acetyldopamine;F4.2.5经RP-18柱,流动相为甲醇-水,15%~50%进行梯度洗脱得5个组分,依次为F4.2.5.1~F4.2.5.5;F4.2.5.4经半制备HPLC,流动相为甲醇:水=35%:65%,得化合物Aspongopusamide A和Aspongopusamide B;F4.2.5.5经半制备HPLC,流动相为甲醇:水=30%:70%,得化合物7,8-dehydro-N-acetyldo-pamine。
进一步,所述的多巴胺类衍生物活性是通过从美洲大蠊中提取获得或通过人工合成获得。
进一步,所述的多巴胺类衍生物在促进创面愈合方面的应用。
本发明的有益效果:
1.本发明首次公开了从美洲大蠊中提取分离所述的一类多巴胺类衍生物的方法。
2.本发明所述的多巴胺类衍生物是首次从美洲大蠊中分离鉴定得到的。
3.本发明所述的一类多巴胺类衍生物具有显著促进HUVEC细胞迁移和血管生成的功效。
附图说明
图1~图5为化合物促进HUVECs迁移。
图6和图7为血管生成活性试验结果(n=3),*p<0.05,**p<0.01,***p<0.001。
具体实施方式
下面结合实施例对本发明作进一步描述。
实施例1本发明所述多巴胺类衍生物的提取分离及结构鉴定
美洲大蠊30kg,粉碎,80%乙醇回流提取3次,合并乙醇提取液,浓缩得浸膏。该浸膏用水混悬后采用石油醚,乙酸乙酯各萃取3次,得乙酸乙酯部分230g,乙酸乙酯萃取物经MCI gel CHP 20P柱梯度洗脱(甲醇/水,0%~100%)得6个组分,分别为F1~F6。F4经Sephadex LH-20凝胶(甲醇)得4个组分(F4.1~F4.4)。F4.2经MCI gel CHP 20P色谱柱(甲醇-水,10%~70%)梯度洗脱得8个组分(F4.2.1~F4.2.8)。F4.2.3经RP-18柱(甲醇-水,15%~50%)得6个组分(F4.2.3.1~F4.2.3.6)。F4.2.3.3经半制备HPLC(甲醇-水,25%)得化合物7,8-erythro-8-methoxy-3,4,7-trihydroxy-N-acetyldopamine(3.0mg,tR=14.5min)。F4.2.5经RP-18柱(甲醇-水,15%~50%)得5个组分(F4.2.5.1~F4.2.5.5)。F4.2.5.4经半制备HPLC(甲醇-水,35%)得化合物Aspongopusamide A(13.0mg,tR=14.5min)和Aspongopusamide B(15.5mg,tR=17.2min)。F4.2.5.5经半制备HPLC(甲醇-水,30%)得化合物7,8-dehydro-N-acetyldopamine(14.2mg,tR=18.4min)。化合物结果鉴定如下:
化合物Aspongopusamide A,淡黄色固体,ESI-MS m/z:407[M+Na]+,1H NMR(600MHz,acetone-d6)δ:8.92(1H,d,J=9.6Hz,NH),8.16(1H,d,J=9.7Hz,NH),6.95(1H,d,J=2.0Hz,H-2′),6.93(1H,d,J=2.0Hz,H-2),6.86(1H,dd,J=8.3,2.0Hz,H-6),6.84(1H,d,J=8.1Hz,H-5′),6.83(1H,dd,J=8.1,2.0Hz,H-6′),6.82(1H,dd,J=10.0,9.6Hz,H-8),6.82(1H,d,J=8.3Hz,H-5),5.80(1H,dd,J=9.7,7.2Hz,H-8′),5.54(1H,d,J=10.0Hz,H-7),4.80(1H,d,J=7.2Hz,H-7′),2.03(3H,s,H-10),1.83(3H,s,H-10′);13C NMR(150MHz,acetone-d6)δ:170.0(C-9′),168.7(C-9),146.7(C-4′),146.0(C-3′),144.0(C-3),142.1(C-4),130.5(C-1),128.6(C-1′),122.9(C-6),122.2(C-8),120.4(C-6′),117.8(C-5),117.0(C-2),116.0(C-5′),115.7(C-2′),109.0(C-7),77.8(C-7′),77.8(C-8′),22.9(C-10),22.9(C-10′)。
化合物Aspongopusamide B,淡黄色固体,ESI-MS m/z:407[M+Na]+,1H NMR(600MHz,acetone-d6)δ:8.98(1H,d,J=10.8Hz,NH),8.19(1H,d,J=9.8Hz,NH),6.95(1H,d,J=1.8Hz,H-2′),6.90(1H,d,J=1.8Hz,H-2),6.86(1H,dd,J=7.8,1.8Hz,H-6′),6.84(1H,dd,J=8.0,1.8Hz,H-6),6.82(1H,d,J=7.8Hz,H-5′),6.82(1H,overlap,H-8),6.80(1H,d,J=8.0Hz,H-5),5.79(1H,dd,J=9.8,7.2Hz,H-8′),5.53(1H,d,J=10.0Hz,H-7),4.81(1H,d,J=7.2Hz,H-7′),2.03(3H,s,H-10),1.79(3H,s,H-10′);13C NMR(150MHz,acetone-d6)δ:170.1(C-9′),168.8(C-9),146.7(C-4′),146.0(C-3′),143.3(C-3),142.7(C-4),130.8(C-1),128.7(C-1′),122.8(C-6),122.2(C-8),120.4(C-6′),117.8(C-5),117.1(C-2),116.0(C-5′),115.6(C-2′),109.0(C-7),77.8(C-7′),77.8(C-8′),23.0(C-10),22.9(C-10′)。
化合物7,8-dehydro-N-acetyldopamine,黄色固体,ESI-MS m/z:216[M+Na]+,1HNMR(500MHz,CD3OD)δ:7.18(1H,d,J=14.6Hz,H-8),6.75(1H,d,J=1.8Hz,H-2),6.65(1H,d,J=8.0Hz,H-5),6.59(1H,dd,J=8.0,1.8Hz,H-6),6.01(1H,d,J=14.6Hz,H-7),1.98(3H,s,H-10)。
化合物7,8-erythro-8-methoxy-3,4,7-trihydroxy-N-acetyldopamine,淡黄色固体,ESI-MS m/z:264[M+Na]+,1H NMR(600MHz,CD3OD)δ:6.83(1H,d,J=2.0Hz,H-2),6.71(1H,d,J=8.0Hz,H-5),6.69(1H,dd,J=8.0,2.0Hz,H-6),4.53(1H,d,J=4.8Hz,H-7),5.05(1H,d,J=4.8Hz,H-8),1.98(3H,s,H-10);13C NMR(methanol-d4,150MHz)δc 173.6(C-9),146.0(C-4),145.9(C-3),133.5(C-1),119.5(C-6),115.8(C-5),115.1(C-2),85.4(C-8),75.2(C-7),22.7(C-10)。
实施例2多巴胺类衍生物促HUVECs迁移实验方法
人脐静脉内皮细胞(HUVECs)来自深圳大学医学部,由刘宝华教授研究组馈赠。M199培养基和胎牛血清购自Gibco公司。收集对数期HUVECs细胞,接种于24孔培养板中,每孔14×104个细胞。置于37℃、5%CO2条件下培养24h待细胞贴壁后,用1×PBS清洗3次,然后用含0.5%FBS的M199培养基饥饿6小时。饥饿结束后,用P10枪头进行划痕,实验组加入溶有不同药物(终浓度20μM)的M199培养基,空白组加入新鲜的M199培养基,并进行拍照。在37℃、5%CO2条件下孵育6h后,用1×PBS清洗3次,加入新鲜的M199培养基,并进行拍照。划痕面积计算用Image pro plus6进行。
迁移面积%=(实验组0h划痕面积-实验组6h划痕面积/空白对照组0h划痕面积-空白组6h划痕面积)×100%
实施例3多巴胺类衍生物促HUVECs血管生成活性测试
人脐静脉内皮细胞(HUVECs)来自深圳大学医学部,由刘宝华教授研究组馈赠;M199培养基和胎牛血清购自Gibco公司;Matrigel胶购自Corning公司。将Matrigel胶均匀铺于预冷的96孔板中,每孔50μL,37℃孵育40min,待Matrigel胶凝固后,每孔加入1×104HUVECs细胞,实验组加入待测化合物(终浓度20μM)处理(其中化合物对应的编号依次为:Aspongopusamide A(yzl-52)、Aspongopusamide B(yzl-57)、7,8-dehydro-N-acetyldopamine(yzl-62)、7,8-erythro-8-methoxy-3,4,7-trihydroxy-N-acetyldopamine(yzl-101)),对照组不含药物。在37℃、5%CO2条件下,培养6h后,于显微镜下观察拍照,图片分析用Image J软件进行,每个实验重复3次。
血管生成率(%)=药物处理组成管长度/对照组成管长度×100%
由图可知,所述多巴胺类衍生物分别在人脐静脉内皮细胞迁移(图1~图5)、血管形成(图6和图7)方面显示明显的促进作用,表明具有促进创面愈合作用。

Claims (9)

1.多巴胺类衍生物Aspongopusamide A、Aspongopusamide B或7,8-dehydro-N-acetyldopamine中的任意一种在制备促进创面修复药物中的用途;结构式:
Figure FDA0003267004240000011
2.如权利要求1所述的用途,其特征在于,所述药物为:由Aspongopusamide A、Aspongopusamide B或7,8-dehydro-N-acetyldopamine的任意一种或其盐类作为活性成分和药学上可接受的赋形剂组成。
3.多巴胺类衍生物的制备方法,其特征在于,
美洲大蠊,粉碎,80%乙醇回流提取3次,合并乙醇提取液,浓缩得浸膏;该浸膏用水混悬后采用石油醚,乙酸乙酯各萃取3次,得乙酸乙酯部分,乙酸乙酯萃取物经MCI gel CHP20P柱,流动相为:甲醇-水,0%~100%进行梯度洗脱,得6个组分,依次为F1~F6;F4经Sephadex LH-20凝胶得4个组分,依次为F4.1~F4.4;F4.2经MCI gel CHP 20P色谱柱,流动相为甲醇-水,10%~70%梯度洗脱得8个组分,依次为F4.2.1~F4.2.8;F4.2.3经RP-18柱,流动相为甲醇-水,15%~50%梯度洗脱得6个组分,依次为F4.2.3.1~F4.2.3.6;F4.2.3.3经半制备HPLC,流动相为甲醇:水=25%:75%,得化合物7,8-erythro-8-methoxy-3,4,7-trihydroxy-N-acetyldopamine;F4.2.5经RP-18柱,流动相为甲醇-水,15%~50%进行梯度洗脱得5个组分,依次为F4.2.5.1~F4.2.5.5;F4.2.5.4经半制备HPLC,流动相为甲醇:水=35%:65%,得化合物Aspongopusamide A和Aspongopusamide B;F4.2.5.5经半制备HPLC,流动相为甲醇:水=30%:70%,得化合物7,8-dehydro-N-acetyl-dopamine;
Figure FDA0003267004240000021
4.如权利要求1或2所述的用途,其特征在于,所述的多巴胺类衍生物是通过从美洲大蠊中提取获得。
5.多巴胺类衍生物,其特征在于,所述多巴胺类衍生物的结构为:7,8-erythro-8-methoxy-3,4,7-trihydroxy-N-acetyldopamine;结构式:
Figure FDA0003267004240000022
6.权利要求5所述的多巴胺类衍生物的制备方法,其特征在于,
美洲大蠊,粉碎,80%乙醇回流提取3次,合并乙醇提取液,浓缩得浸膏;该浸膏用水混悬后采用石油醚,乙酸乙酯各萃取3次,得乙酸乙酯部分,乙酸乙酯萃取物经MCI gel CHP20P柱,流动相为:甲醇-水,0%~100%进行梯度洗脱,得6个组分,依次为F1~F6;F4经Sephadex LH-20凝胶得4个组分,依次为F4.1~F4.4;F4.2经MCI gel CHP 20P色谱柱,流动相为甲醇-水,10%~70%梯度洗脱得8个组分,依次为F4.2.1~F4.2.8;F4.2.3经RP-18柱,流动相为甲醇-水,15%~50%梯度洗脱得6个组分,依次为F4.2.3.1~F4.2.3.6;F4.2.3.3经半制备HPLC,流动相为甲醇:水=25%:75%,得化合物7,8-erythro-8-methoxy-3,4,7-trihydroxy-N-acetyldopamine;F4.2.5经RP-18柱,流动相为甲醇-水,15%~50%进行梯度洗脱得5个组分,依次为F4.2.5.1~F4.2.5.5;F4.2.5.4经半制备HPLC,流动相为甲醇:水=35%:65%,得化合物Aspongopusamide A和Aspongopusamide B;F4.2.5.5经半制备HPLC,流动相为甲醇:水=30%:70%,得化合物7,8-dehydro-N-acetyl-dopamine;
Figure FDA0003267004240000031
7.权利要求5所述的多巴胺类衍生物在制备促进创面修复药物中的用途。
8.如权利要求7所述的用途,其特征在于,所述药物为:由7,8-erythro-8-methoxy-3,4,7-trihydroxy-N-acetyldopamine或其盐类作为活性成分和药学上可接受的赋形剂组成。
9.如权利要求7或8所述的用途,其特征在于,所述的多巴胺类衍生物是通过从美洲大蠊中提取获得。
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