CN107698652A - 一种含丹参酮类化合物的吲哚胺2,3‑双加氧酶抑制剂 - Google Patents
一种含丹参酮类化合物的吲哚胺2,3‑双加氧酶抑制剂 Download PDFInfo
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Abstract
本发明涉及吲哚胺2,3‑双加氧酶抑制剂技术领域,具体为一种以丹参酮类化合物为活性物质的吲哚胺2,3‑双加氧酶抑制剂。经IDO抑制活性检测,本发明所述结构的丹参酮类化合物或其药学上可接受的盐对于IDO具有抑制作用,其可对IDO在疾病发生发展中的促进作用进行阻碍和/或破坏,从而为治疗IDO介导的色氨酸代谢途径的病理学特征的疾病提供良好的前景。
Description
技术领域
本发明涉及吲哚胺2,3-双加氧酶抑制剂技术领域,尤其涉及一种以丹参酮类化合物为活性物质的吲哚胺2,3-双加氧酶抑制剂。
背景技术
吲哚胺2,3-双加氧酶(Indoleamine 2,3-dioxygenase,IDO)是一种细胞内含亚铁血红素的二聚体酶,控制着色氨酸沿犬尿氨酸代谢途径的关键限速步骤。在多种组织和细胞中均有表达,包括胎盘、肺、大肠、小肠、结肠、脾脏、肝脏、肾脏、胃、脑、肿瘤细胞、树突状细胞和巨噬细胞等。
IDO与众多疾病联系密切,在感染性疾病、癌症、神经相关类疾病以及白内障等疾病中,IDO的表达存在上调。在感染性疾病和癌症中,当出现炎症反应,一些生物因子,例如IFN-γ、NF-κB会诱导IDO基因的高表达,消耗更多的色氨酸,而T细胞对色氨酸缺乏的微环境较为敏感,在IDO诱导出的免疫抑制型抗原提呈细胞的影响下,T细胞停止增殖,并转变为抑制型调节T细胞,免疫反应受到抑制;色氨酸沿犬尿氨酸代谢的代谢终产物会对神经系统产生损伤,与阿尔茨海默病、帕金森病、亨廷顿舞蹈症等疾病联系密切;色氨酸也是五羟色胺的合成原料,五羟色胺的缺乏对抑郁症的产生至关重要;色氨酸降解的紫外线滤器化合物存在于人晶状体中,这些紫外线滤器化合物的量随年龄而增加,并且会导致与年龄相关的核性白内障的晶状体逐渐浑浊。IDO被认为是上述疾病的重要靶标,其抑制剂的发展具有广阔的应用前景。
目前尚未有批准上市的IDO抑制剂药物,IDO抑制剂的研发多处于实验室阶段,仅有三个抑制剂进入了临床试验。专利文献CN201610419113.4公开了如下结构的丹参酮IIA或其磺酸盐作为吲哚胺2,3-双加氧酶-1抑制剂的用途。
然而,由于化合物中的部分基团会显著影响其物理性质、化学性质及生物活性,即使骨架相似的化合物,其物理性质、化学性质及生物活性也可能存在巨大的差异。实验表明,丹参酮类化合物含6,7,8,9碳位的六元环与五元环上不同的取代基或双键对抑制吲哚胺2,3-双加氧酶的活性有显著影响,具体构效关系有待进一步研究。
丹参为唇形科鼠尾草属植物,为常用活血化瘀的中药。丹参酮为从丹参根部提取的脂溶性药用成分,临床上主要用于治疗冠心病、痤疮、痛经、失眠等病症。
发明内容
本发明的目的在于针对IDO被认为是许多疾病的重要靶标,而目前IDO抑制剂药物匮缺的问题,提供一种以丹参酮类化合物为活性物质的吲哚胺2,3-双加氧酶抑制剂,用于治疗或预防由吲哚胺2,3-双加氧酶介导的色氨酸代谢途径的病理学特征疾病。
为实现上述目的,本发明采用以下技术方案。
一种含丹参酮类化合物的吲哚胺2,3-双加氧酶抑制剂,所述抑制剂含有丹参酮类化合物和/或其药学上可接受的盐;所述丹参酮类化合物的结构式如下结构式A-G所示:
且当所述丹参酮类化合物的结构为结构式F时,R1不包括H,R2不包括H和SO3 -,R3不包括CH3。
优选的,上述结构的化合物中,R1为H、CH3、F、Cl、Br、I、OH、OCH3、NH2、NO2、CN、CHO、COOH、SH、SO3H或SO2H。
优选的,上述结构的化合物中,R2为H、R、F、Cl、Br、I、OH、OR、NH2、NHR、NR2、NO2、CN、CHO、COOH、COOR、COO-、SH、SR、SO3H、SO2R、SO3 -、SO2 -、SO2H或SO3R,其中的R是任意取代的饱和或不饱和的直链、支链或环状烃基基团或任意取代的芳基基团。
优选的,上述结构的化合物中,R3为H、CH3、F、Cl、Br、I、OH、OCH3、NH2、NO2、CN、CHO、COOH、SH、SO3H或SO2H。
更优选的,所述丹参酮类化合物为如下结构的化合物J1-J13:
以上所述的含丹参酮类化合物的吲哚胺2,3-双加氧酶抑制剂在制备治疗由吲哚胺2,3-双加氧酶介导的色氨酸代谢途径的病理学特征的疾病的药物中的应用,即可用于治疗由吲哚胺2,3-双加氧酶介导的色氨酸代谢途径的病理学特征的疾病。
所述由吲哚胺2,3-双加氧酶介导的色氨酸代谢途径的病理学特征的疾病包括癌症、阿尔茨海默病、帕金森病、亨廷顿舞蹈症、白内障、抑郁症和感染性疾病。
所述癌症包括卵巢癌、结直肠癌、肺癌、肝癌、肾癌、淋巴癌、胃癌、脑肿瘤和白血病。
所述感染性疾病包括细菌感染、真菌感染和寄生虫感染。
与现有技术相比,本发明的有益效果是:经IDO抑制活性检测,本发明所述结构的丹参酮类化合物或其药学上可接受的盐对于IDO具有抑制作用,其可对IDO在疾病发生发展中的促进作用进行阻碍和/或破坏,从而为治疗IDO介导的色氨酸代谢途径的病理学特征的疾病提供良好的前景。
具体实施方式
为了更充分的理解本发明的技术内容,下面结合具体实施例对本发明的技术方案作进一步介绍和说明。
分别测试评价丹参酮类化合物J1-J13及化合物K1-K7对吲哚胺2,3-双加氧酶的抑制活性。化合物K1-K7的结构分别如下所示。
化合物J1-J13及化合物K1-K7对吲哚胺2,3-双加氧酶的抑制活性的测试评价方法如下:
IDO酶学抑制试验
将90mL反应液加入96孔黑板,包括0.5M磷酸钾缓冲液10μL(pH6.5)、0.2M抗坏血酸10μL、0.5mM亚甲基蓝2μL、5mg/mL过氧化氢酶2μL、4mM L-色氨酸5μL、56μL超纯水以及不同浓度的待测化合物(化合物J1-J13,K1-K7)5μL。λex 360nm,λem 480nm条件下测量荧光值。反应液加入10μL 20μg/mL的IDO蛋白,37℃孵育1小时。20μL 1M NaOH溶液用以停止反应,60℃孵育15分钟。置于室温下冷却约1.5小时后同样条件下测量荧光值。阴性组和空白组以含1%DMSO的超纯水代替待测化合物溶液,空白组以0.05M磷酸钾缓冲液代替IDO蛋白溶液。不同抑制剂浓度下3次平行实验计算出IC50值。
抑制百分比=100-(A/B×100),A:有抑制剂条件下的IDO活性B:无抑制剂条件下的IDO活性。
化合物对吲哚胺2,3-双加氧酶的抑制活性的测试评价结果如下表1所示。
表1丹参酮类化合物在酶学抑制试验中的IC50值
从上表所示的测试结果可见,丹参酮类化合物含6,7,8,9碳位的六元环与五元环上不同的取代基或双键对抑制吲哚胺2,3-双加氧酶的活性有显著影响。当含6,7,8,9碳位的六元环上有双键或取代基时,可以显著提高丹参酮类化合物对IDO的抑制作用,如化合物J5、J6;五元环上的双键虽然不利于活性的提高,如化合物J1,但是其上的吸电子取代基对活性有提升作用,如化合物J8、J10;当五元环上的取代基为六元环甚至更大体积的基团时,其结构对活性影响较难预测,如化合物J12、J13、K6、K7。值得注意的是,本测试结果显示,化合物J1-J13的IDO抑制活性明显好于化合物K1(丹参酮IIA)的IDO抑制活性,化合物K1不具有良好的IDO抑制活性。
以下为部分化合物的结构表征:
化合物J12:HNMRδ:8.12-8.17(m,2H),7.76-7.79(m,2H),7.63(d,J=8.1Hz,1H),7.56(m,J=8.1Hz,1H),3.21(t,J=6Hz,2H),2.25(s,3H),2.23(s,3H),1.76-1.85(m,2H),1.65-1.70(m,2H),1.33(s,6H);MS m/z:467[M+1]+。
化合物J13:HNMRδ:8.14(m,2H),7.78(m,2H),7.63(d,J=8.1Hz,1H),7.56(d,J=8.1Hz,1H),3.21(t,J=6.3Hz,2H),2.25(s,3H),2.23(s,3H),1.78-1.83(m,2H),1.61-1.66(m,2H),1.33(s,6H);MS m/z:463[M-1]-。
化合物K4:HNMRδ:9.23(s,1H),8.97(s,1H),7.70(d,J=8.1Hz,1H),7.45(d,J=8.4Hz,1H),6.87(s,1H),6.83(d,J=3.3Hz,1H),6.42(d,J=3.3Hz,1H),2.22(s,3H),3.10(t,J=6.3Hz,2H),1.78-1.83(m,2H),1.66-1.70(m,2H),1.29(s,6H);CNMRδ:183.3,175.4,160.0,150.3,149.6,148.3,143.6,133.8,127.6,126.7,124.9,121.3,120.3,117.9,117.4,116.9,116.3,38.1,34.7,31.5,30.1,19.4,9.7;MS m/z:403[M+1]+。
化合物K5:HNMRδ:7.68(d,J=8.1Hz,1H),7.17(d,J=8.1Hz,1H),6.43(d,J=8.7Hz,1H),6.87(s,1H),6.31(d,J=8.7Hz,1H),3.21(t,J=6.3Hz,2H),2.28(s,3H),1.78-1.85(m,2H),1.65-1.70(m,2H),1.34(s,6H);CNMRδ:186.7,184.3,182.9,175.5,162.2,151.7,145.0,137.1,136.6,133.8,131.5,126.8,126.4,122.6,121.1,116.2,38.1,35.2,32.1,30.1,19.4,11.4;MS m/z:401[M+1]+。
化合物K6:MS m/z:453[M+1]+。
化合物K7:HNMRδ:8.12-8.15(m,1H),8.07-8.10(m,1H),7.76-7.79(m,2H),7.59(d,J=8.1Hz,1H),7.65(d,J=8.1Hz,1H),7.18(s,1H),3.18(t,J=6Hz,2H),2.47(s,3H),1.77-1.83(m,2H),1.65-1.69(m,2H),1.33(s,6H);CNMRδ:184.3,182.7,182.2,175.3,162.0,151.5,145.2,144.9,137.6,134.2,133.7,132.4,131.9,127.1,126.2,121.7,121.0,38.0,35.2,32.2,30.0,19.4,11.7;MS m/z:451[M+1]+。
以上所述仅以实施例来进一步说明本发明的技术内容,以便于读者更容易理解,但不代表本发明的实施方式仅限于此,任何依本发明所做的技术延伸或再创造,均受本发明的保护。
Claims (9)
1.一种含丹参酮类化合物的吲哚胺2,3-双加氧酶抑制剂,其特征在于,所述抑制剂含有丹参酮类化合物和/或其药学上可接受的盐;所述丹参酮类化合物的结构式如以下结构式A-G:
且当所述丹参酮类化合物的结构为结构式F时,R1不包括H,R2不包括H和SO3 -,R3不包括CH3。
2.根据权利要求1所述一种含丹参酮类化合物的吲哚胺2,3-双加氧酶抑制剂,其特征在于,所述R1为H、CH3、F、Cl、Br、I、OH、OCH3、NH2、NO2、CN、CHO、COOH、SH、SO3H或SO2H。
3.根据权利要求1所述一种含丹参酮类化合物的吲哚胺2,3-双加氧酶抑制剂,其特征在于,所述R2为H、R、F、Cl、Br、I、OH、OR、NH2、NHR、NR2、NO2、CN、CHO、COOH、COOR、COO-、SH、SR、SO3H、SO2R、SO3 -、SO2 -、SO2H或SO3R,其中的R是任意取代的饱和或不饱和的直链、支链或环状烃基基团或任意取代的芳基基团。
4.根据权利要求1所述一种含丹参酮类化合物的吲哚胺2,3-双加氧酶抑制剂,其特征在于,所述R3为H、CH3、F、Cl、Br、I、OH、OCH3、NH2、NO2、CN、CHO、COOH、SH、SO3H或SO2H。
5.根据权利要求1所述一种含丹参酮类化合物的吲哚胺2,3-双加氧酶抑制剂,其特征在于,所述丹参酮类化合物的结构式如以下结构式J1-J13:
6.根据权利要求1所述一种含丹参酮类化合物的吲哚胺2,3-双加氧酶抑制剂,其特征在于,在制备治疗由吲哚胺2,3-双加氧酶介导的色氨酸代谢途径的病理学特征的疾病的药物中的应用。
7.根据权利要求6所述一种含丹参酮类化合物的吲哚胺2,3-双加氧酶抑制剂,其特征在于,所述由吲哚胺2,3-双加氧酶介导的色氨酸代谢途径的病理学特征的疾病包括癌症、阿尔茨海默病、帕金森病、亨廷顿舞蹈症、白内障、抑郁症和感染性疾病。
8.根据权利要求7所述一种含丹参酮类化合物的吲哚胺2,3-双加氧酶抑制剂,其特征在于,所述癌症包括卵巢癌、结直肠癌、肺癌、肝癌、肾癌、淋巴癌、胃癌、脑肿瘤和白血病。
9.根据权利要求7所述一种含丹参酮类化合物的吲哚胺2,3-双加氧酶抑制剂,其特征在于,所述感染性疾病包括细菌感染、真菌感染和寄生虫感染。
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