CN109467563B - 一种喜树碱衍生物及其在制备抗炎症药物中的应用 - Google Patents
一种喜树碱衍生物及其在制备抗炎症药物中的应用 Download PDFInfo
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- CN109467563B CN109467563B CN201810585208.2A CN201810585208A CN109467563B CN 109467563 B CN109467563 B CN 109467563B CN 201810585208 A CN201810585208 A CN 201810585208A CN 109467563 B CN109467563 B CN 109467563B
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- acid
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- camptothecin derivative
- camptothecin
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Abstract
本发明公开了一种喜树碱衍生物及其在制备抗炎症药物中的应用，属于药物技术领域。所述的喜树碱衍生物由对10‑羟基喜树碱结构式的9、10、20位上进行结构修饰得到，相较于未修饰的喜树碱，该衍生物的稳定性、水溶性、生物活性进一步提高，生物毒性降低，在急性炎症小鼠模型中显著降低血液中前炎症细胞因子浓度，降低小鼠的死亡率，其体内抗炎症效果显著，为抗炎症药物的研制提供研究基础。
Description
技术领域
本发明涉及药物技术领域，具体涉及一种新型喜树碱衍生物及其在制备抗炎症药物中的应用。
背景技术
炎症是免疫系统对病原威胁的正常反应，涉及各种化学信号的产生和免疫细胞的激活，中性粒细胞是最早反应的重要炎症效应细胞之一。炎症对控制细菌等病原体具有重要作用，但是炎症也会对身体自身细胞产生危害，严重炎症可以造成血容量不足，导致器官功能衰竭，危害健康甚至生命。科学家推测，1918-1919年的世界流感大爆发，导致4千万人死亡，之所以如此恐怖是因为当时没有控制严重炎症的手段。过度炎症反应往往是机体免疫系统对感染的过度反应，发生后数小时可导致重要器官严重伤害，但治疗的手段又非常有限，临床上一直缺乏特异性治疗药物。
脓毒症是由致病微生物感染引发的全身炎症反应综合征(SIRS)，合并血压降低且经快速液体复苏后血压仍不能恢复正常者称为脓毒性休克(Septic shock)，其中一部分患者发展为多器官功能障碍综合症(MODS)。脓毒症病死率居高不下，每10万人口中约50-300人会发生严重脓毒症，其短期死亡率达20％-25％，当发展为脓毒性休克时其死亡率达50％。整合消灭致病微生物、阻断炎症介质和处理MODS等措施的“集束化”治疗并未显著降低脓毒症患者的病死率。脓毒症的早期治疗关键在于阻断炎症介质的级联反应，糖皮质激素具有抗炎作用，这就使得其被引入脓毒性休克的治疗，但与此同时发生的一些急性并发症如高钠血症、心律失常、高血糖、消化道出血等使得糖皮质激素在严重脓毒症及脓毒性休克中的应用一直饱受争议。因此诸多的临床研究对糖皮质激素疗效的评价褒贬不一，糖皮质激素是否有利于脓毒症的转归一直饱受争议。
喜树碱具有控制过度炎症的作用，在多种动物模型中表现出良好的治疗效果，有望成为治疗脓毒症的药物。喜树碱是一种植物抗癌药物，从中国中南、西南分布的喜树中提取得到。喜树碱发挥抗癌作用的分子基础是阻断拓扑异构酶I型(topoisomerase I)。在闭环状双链DNA的拓扑学转变中，要暂时将DNA的一个链或两个链切断，根据异构体化的方式而分为二个型，切断一个链而改变拓扑结构的称为拓扑异构酶Ⅰ型，通过切断二个链来进行的称为拓扑异构酶Ⅱ型(topoisomerase II)。研究显示，拓扑异构酶Ⅰ型是协助免疫系统对病原体发动攻击的关键分子。因此，喜树碱有望成为一种挽救导致数百万患者死亡的潜在药物。
此外，现有的喜树碱衍生物存在水溶解性、稳定性较差，难以成药的问题，限制了其应用。
发明内容
本发明的目的在于提供一种新型的喜树碱衍生物，以解决现有的喜树碱衍生物稳定性差、水溶解性差等问题。
为实现上述目的，本发明采用如下技术方案：
本发明通过在喜树碱的9、10、20位上进行结构修饰，得到新型的喜树碱衍生物，其结构式如式(Ⅰ)所示，
其中，R1选自H或HOOC-(CH2)2-CO-NH-CH2-CO-；
R2取代基团选自H、(CH3)2-CH-、CH3-(CH2)3-、(CH3)2-CH-CH2-或吡啶基。
与未修饰的喜树碱相比，本发明提供的喜树碱衍生物在保持稳定性的前提下，其生物活性提高，水溶性增加，毒性降低。
作为优选，所述的喜树碱衍生物结构式选自式(Ⅱ)-(Ⅷ)：
所述喜树碱衍生物还可以为由上述结构式所述的化合物经化学修饰得到的药学上可接受的酯、醚、盐、酰胺类衍生物。
作为优选，R1为HOOC-(CH2)2-CO-NH-CH2-CO-时，喜树碱衍生物还包括其药学上可接受的盐、酯、酰胺。
喜树碱衍生物药学上可接受的盐为其钠、钾、钙、铁、锌盐，或乙酸、2,2-二氯乙酸、已二酸、藻酸、抗坏血酸(如L-抗坏血酸)、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、丁酸、(+)樟脑酸、樟脑-磺酸、(+)-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟乙基磺酸、甲酸、富马酸、半乳糖酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、葡萄糖醛酸(如D-葡萄糖醛酸)、谷氨酸(如L-谷氨酸)、α-酮戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、羟乙磺酸、(+)-L-乳酸、(±)-DL-乳酸、乳糖酸、马来酸、苹果酸、(-)-L-苹果酸、丙二酸、(±)-DL-扁桃酸、甲基磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、帕莫酸、磷酸、丙酸、L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、丁二酸、硫酸、单宁酸、(+)-L-酒石酸、硫氰酸、p-甲苯磺酸、十一碳烯酸和戊酸，以及酰化氨基酸盐。
喜树碱衍生物药学上可接受的酯为其C1～C6的链酯。
喜树碱衍生物药学上可接受的酰胺为其与药学上可接受的胺形成的酰胺。
本发明还提供了所述的喜树碱衍生物的制备方法，包括以下步骤：
(1)在10-羟基喜树碱的醋酸溶液中加入硝酸溶液，室温下反应过夜，过滤取固体过滤物，分离获得化合物A；
(2)将化合物A与含有Pd/C的甲醇悬浊液在氢气气体环境下搅拌，待反应完全后，将溶剂移除，剩余物溶于四氢呋喃溶剂，分别加入甲醛、异丁醛、正戊醛、异戊醛、2-吡啶甲醛，搅拌反应，再加入二氯二氰基苯醌(DDQ)混合，继续反应，待反应完全后，将溶剂移除，剩余物经分离获得化合物1、化合物2、化合物3、化合物4、化合物5，其结构式如(Ⅱ)、(Ⅲ)、(Ⅳ)、(Ⅴ)、(Ⅵ)；
(3)将化合物1或化合物2、Sc(OTf)3与4-二甲氨基吡啶(DMAP)溶于二氯甲烷溶剂中，搅拌后加入Boc-甘氨酸，搅拌后加入N,N'-二环己基碳酰亚胺(DCC)，搅拌过夜，利用硅藻土过滤，从滤液中分离获得化合物B或化合物C；
将化合物B或化合物C溶于二氯甲烷，再加入TFA，搅拌后移除反应溶剂，剩余物溶于N,N-二甲基甲酰胺(DMF)，然后加入丁二酸酐和4-甲基吡啶，混合搅拌过夜，移除反应溶剂，剩余物经分离获得化合物6或化合物7，其结构式如(Ⅶ)或(Ⅷ)。
本发明还提供了所述的喜树碱衍生物在制备抗炎症药物中的应用。研究表明，本发明提供的喜树碱衍生物在小鼠急性炎症模型中表现出优良的体内活性，可以显著降低脓毒症小鼠血液中的IL-6和TNF-α浓度，显著降低小鼠死亡率。
所述的炎症为细菌或病毒引起的急性炎症，包括但不限于，如败血症、脓毒症、关节炎、肺炎、肠炎。
本发明还提供了一种抗炎症药物组合物，包括有效剂量的所述的喜树碱衍生物。
所述有效剂量是指使被治疗的对象症状好转的充分剂量，所述好转是指在治疗中降低或减轻患病状态所带来的负面效应。
作为优选，药物组合物还包括药学上可接受的载体、赋形剂或稀释剂。
作为优选，所述抗炎症药物组合物的剂型为口服给药的片剂、含片、颗粒、粉末、乳液、胶囊剂、糖浆。
本发明具备的有益效果：
本发明通过对10-羟基喜树碱结构式的9、10、20位上进行结构修饰，获得新型喜树碱衍生物，相较于未修饰的喜树碱，该衍生物的稳定性、水溶性、生物活性进一步提高，生物毒性降低，在急性炎症小鼠模型中显著降低血液中前炎症细胞因子浓度，降低小鼠的死亡率，其体内抗炎症效果显著，为抗炎症药物的研制提供研究基础。
附图说明
图1是化合物1的核磁氢谱。
图2是化合物1的碳谱。
图3是化合物2的核磁氢谱。
图4是化合物2的碳谱。
图5是化合物3的核磁氢谱。
图6是化合物3的碳谱。
图7是化合物4的核磁氢谱。
图8是化合物4的碳谱。
图9是化合物5的核磁氢谱。
图10是化合物6的核磁氢谱。
图11是化合物6的碳谱。
图12是化合物7的核磁氢谱。
图13是化合物7的碳谱。
图14是各组脓毒症小鼠中血液中IL-6浓度的柱形图，其中纵坐标的单位为(pg/mL)。
图15是各组脓毒症小鼠中血液中TNF-α浓度的柱形图，其中纵坐标的单位为(ng/L)。
具体实施方式
相关定义：
1、药学上可接受的盐
所述的“药学上可接受的”指在化合物如盐或赋形剂中缺少不能接受的毒性。碱性化合物能够与各种酸形成不同形式的盐，这些酸被用以制备药学上可接受的盐，这些盐的无机阴离子，包括但并不限于，硫酸根、硫酸氢根，亚硫酸根、硝酸根、亚硝酸根、氯离子、溴离子、碘离子、磷酸根、磷酸(一、二)氢根、异烟酸等；有机阴离子包括醋酸根、乳酸根、草酸根、马来酸根、枸橼酸根、水杨酸根、肉桂酸根、油酸根、富马酸根、酒石(氢)酸根、丙酮酸根、丹宁酸根、三氟醋酸盐、丙酸根、柠檬酸根、泛酸根、抗坏血酸盐、琥珀酸盐、延胡索酸盐、葡糖酸盐、葡萄糖醛酸根、蔗糖盐、甲酸盐、苯酸盐、谷氨酸盐、甲基磺酸根、乙烷磺酸根、苯磺酸根、甲基苯磺酸根、双羟萘酸根等。
酸式化合物在自然界也可以与药理学上可接受的阳离子形成碱式盐，这些盐包括但并不限于碱土金属、碱性金属，尤其钙离子、镁离子、钠离子、锂离子、锌离子、钾离子、铁离子等等。
2、剂型
本发明的喜树碱衍生物可以连续地或间断地与其他分子相容的方式给药，口服或不经肠道的方式吸收，包括肌肉注射、腹腔、静脉、皮下、鼻内、硬膜外、口服、舌下、脊柱内、心室内、鞘内、脑池内、囊内、阴道、透皮、直肠，通过吸入或外敷，特别是耳朵，鼻子，眼睛，或皮肤等。也可能是与另一种生物活性剂一起作用。其作用可以是全身或局部。不同的药物输送系统包括了，封装于脂质体、微粒子、微胶囊、胶囊等。
本发明也可以通过使用吸入器或喷雾器，和制成气雾剂，或通过灌注在氟碳化合物或合成的肺表面活性剂。本发明的化合物还可作为栓剂，以传统的粘合剂和载体如甘油三酯。
“药学上可接受的”是指普遍公认的药典所列在动物身上，尤其是在人类身上的载体是指稀释剂，助剂，辅料。这种载体可以诸如水和油。动物，蔬菜或合成来源，如花生油，大豆油，矿物油，香油之类的。载体亦可以为生理盐水，阿拉伯胶，明胶，淀粉糊，滑石粉，角质，胶体二氧化硅等等。此外。辅助剂，稳定剂，增稠剂，润滑剂，着色剂均可以使用。当给病人用药时，发明的化合物成分和药学上可接受载体，赋形剂或稀释剂，最好是无菌的。静脉给药时，水是本发明的化合物是首选的载体。盐、葡萄糖和甘油的溶液也可作为液态载体，特别是注射的方案中。合适的制药载体还包括诸如辅料淀粉，葡萄糖，乳糖，蔗糖，明胶，麦芽，大米，面粉，硅胶，硬脂酸钠，甘油单硬脂酸，滑石粉，氯化钠，脱脂牛奶，甘油，丙二醇，水，乙醇等。目前化合物和组成，如果有需要的话，也可以包含适量的润湿剂或乳化剂，或pH缓冲剂。
目前的化合物和组合物可以采取解决方案的形式包括，悬浮物。乳剂，片剂，丸剂，装有液体的颗粒，胶囊，粉末，长控释制剂，栓剂，乳剂。航空溶胶，喷雾剂，悬浮物，或任何其他形式适合使用。
发明的化合物和组成物口服给药形式为片剂，含片，水的形式或油性悬浮物，颗粒，粉末，乳液，胶囊剂，糖浆。化合物和组成物口服给药方式也可以制定食品和食品混合。另外在药片或药丸形式的化合物成分可延迟解体和在胃肠道吸收，从而提供持续一个较长时期的效果。时间延迟材料包括如甘油单硬脂酸酯或甘油硬脂酸。口服成分可以包括标准医药级别的载体如甘露醇，乳糖，淀粉，硬脂酸镁，糖精钠，纤维素，碳酸镁等等。
3、联合治疗
本发明提供的喜树碱衍生物可同时与一个或多个其他的治疗药物，联合用于哺乳动物，尤其人类。当结合使用其他治疗，如其他抗癌化合物，该化合物和治疗剂的加法可以充当或更好的协同作用。本发明的化合物与其他治疗药物可以是同样的组成，或是分开的组合，之前或之后的用药方式。对于许多慢性疾病治疗，其体现就在于一个综合疗法与交互组合的用药方式，例如，以尽量减少特定的药物毒性。在某些情况，当发明的组成与另一种治疗剂或试剂使用可能产生的副作用，包括，但不仅限于毒性，可以降低治疗剂剂量以低于阈值达到降低所引起的不良副作用(如血尿、尿频、尿急、白细胞下降、腹泻等)。
下面结合实施例和实验数据，进一步说明本发明的技术方案。
本发明通过在喜树碱的9、10、20位上进行结构修饰，得到新型的喜树碱衍生物，其结构式如下所示，
其中，R1选自H或HOOC-(CH2)2-CO-NH-CH2-CO-；
R2取代基团选自H、(CH3)2-CH-、CH3-(CH2)3-、(CH3)2-CH-CH2-或吡啶基。
实施例1
化合物1：
制备方法：
在10-羟基喜树碱(180mg，0.5mmol)的醋酸溶液(1ml)中加入65％的HNO3(0.5ml)，此反应混合物在室温条件下反应过夜，待反应完全，将反应混合液用H2O(2.5ml)稀释，过滤，水洗滤饼，所得固体过滤物经快速柱层析分离获得化合物A(甲醇/二氯甲烷1:50作为洗脱体系)；
取化合物A(50mg，0.12mmol)以及10％Pd/C(20mg)的甲醇悬浊液在氢气气体环境下50℃搅拌2小时，待反应完全后，将溶剂移除，剩余物溶于四氢呋喃溶剂，加入甲醛，反应混合物在50℃条件下搅拌6小时，再加入DDQ(55mg，0.24mmol)，反应混合物在50℃条件下继续反应10小时，待反应完全后，将溶剂移除，剩余物经快速柱层析分离获得化合物1(甲醇/二氯甲烷1:50作为洗脱体系)。
化合物1结构由核磁氢谱和碳谱数据确定，其核磁氢谱、碳谱图分别见图1和图2，表征数据如下：
1H NMR(500MHz,DMSO)δ9.10(s,1H),9.03(s,1H),8.31(d,J＝9.2Hz,1H),8.21(d,J＝9.2Hz,1H),7.35(s,1H),6.52(s,1H),5.43(s,2H),5.33(s,2H),1.87(m,2H),0.88(t,J＝7.3Hz,3H)。
13C NMR(75MHz,DMSO)δ172.90,156.94,155.17,151.74,150.27,147.50,146.23,145.42,135.07,130.70,127.65,125.75,121.10,119.27,115.64,96.84,72.79,65.67,50.67,30.81,8.25。
实施例2
化合物2：
制备方法：
上述化合物A(50mg,0.12mmol)以及10％Pd/C(20mg)的甲醇悬浊液在氢气气体环境下50℃搅拌2小时，待反应完全后，将溶剂移除，剩余物溶于四氢呋喃溶剂，加入异丁醛(17mg,0.24mmol)，反应混合物在50℃条件下搅拌6小时，再加入DDQ(55mg,0.24mmol)，反应混合物在50℃条件下继续反应10小时，待反应完全后，将溶剂移除，剩余物经快速柱层析分离获得化合物2(甲醇/二氯甲烷1:50作为洗脱体系)。
化合物2结构由核磁氢谱和碳谱数据确定，其核磁氢谱、碳谱图分别见图3和图4，表征数据如下：
1H NMR(300MHz,DMSO)δ9.08(s,1H),8.25(d,J＝9.2Hz,1H),8.14(d,J＝9.2Hz,1H),7.35(s,1H),6.55(s,1H),5.43(s,2H),5.32(s,2H),3.43(d,J＝6.9Hz,1H),1.87(dd,J＝11.5,4.5Hz,2H),1.46(d,J＝6.9Hz,6H),0.88(s,3H)。
13C NMR(75MHz,DMSO)δ172.93,171.85,156.95,151.43,150.32,147.93,145.94,145.50,135.89,130.32,126.62,125.67,120.71,119.13,115.17,96.85,72.82,65.63,50.64,30.76,28.75,20.52,8.23。
实施例3
化合物3：
制备方法：
上述化合物A(50mg,0.12mmol)以及10％Pd/C(20mg)的甲醇悬浊液在氢气气体环境下50℃搅拌2小时，待反应完全后，将溶剂移除，剩余物溶于四氢呋喃溶剂，加入正戊醛(21mg,0.24mmol)，反应混合物在50℃条件下搅拌6小时，再加入DDQ(55mg,0.24mmol)，反应混合物在50℃条件下继续反应10小时，待反应完全后，将溶剂移除，剩余物经快速柱层析分离获得化合物3(甲醇/二氯甲烷1:50作为洗脱体系)。
化合物3结构由核磁氢谱和碳谱数据确定，其核磁氢谱、碳谱图分别见图5和图6，表征数据如下：
1H NMR(400MHz,DMSO)δ8.93(s,1H),8.13(d,J＝9.1Hz,1H),8.03(d,J＝9.1Hz,1H),7.27(s,1H),6.52(s,1H),5.40(s,2H),5.20(s,2H),3.04(t,J＝7.4Hz,2H),1.85(dd,J＝15.3,7.7Hz,4H),1.44(dd,J＝14.7,7.3Hz,2H),0.95(t,J＝7.3Hz,3H),0.89(t,J＝7.1Hz,3H)。
13C NMR(101MHz,DMSO)δ172.95,168.26,157.18,151.91,150.43,148.20,146.24,145.82,136.31,130.86,126.74,126.01,120.99,119.31,115.42,96.94,72.85,65.71,50.90,30.78,28.78,28.06,22.12,14.06,8.24。
实施例4
化合物4：
制备方法：
上述化合物A(50mg,0.12mmol)以及10％Pd/C(20mg)的甲醇悬浊液在氢气气体环境下50℃搅拌2小时，待反应完全后，将溶剂移除，剩余物溶于四氢呋喃溶剂，加入异戊醛(21mg,0.24mmol)，反应混合物在50℃条件下搅拌6小时，再加入DDQ(55mg,0.24mmol)，反应混合物在50℃条件下继续反应10小时，待反应完全后，将溶剂移除，剩余物经快速柱层析分离获得化合物4(甲醇/二氯甲烷1:50作为洗脱体系)。
化合物4结构由核磁氢谱和碳谱数据确定，其核磁氢谱、碳谱图分别见图7和图8，表征数据如下：
1H NMR(400MHz,DMSO)δ8.98(s,1H),8.16(d,J＝9.1Hz,1H),8.06(d,J＝9.2Hz,1H),7.29(s,1H),6.52(s,1H),5.41(s,2H),5.24(s,2H),2.94(d,J＝7.1Hz,2H),2.27(dt,J＝13.5,6.7Hz,1H),1.92–1.82(m,2H),1.03(d,J＝6.6Hz,6H),0.89(t,J＝7.2Hz,3H)。
13C NMR(101MHz,DMSO)δ172.95,167.51,157.21,152.00,150.45,148.25,146.31,145.87,136.36,130.97,126.80,126.10,121.07,119.35,115.48,96.97,72.86,65.71,50.95,37.19,30.78,27.51,22.63,8.25。
实施例5
化合物5：
制备方法：
上述化合物A(50mg,0.12mmol)以及10％Pd/C(20mg)的甲醇悬浊液在氢气气体环境下50℃搅拌2小时，待反应完全后，将溶剂移除，剩余物溶于四氢呋喃溶剂，加入2-吡啶甲醛(26mg,0.24mmol)，反应混合物在50℃条件下搅拌6小时，再加入DDQ(55mg,0.24mmol)，反应混合物在50℃条件下继续反应10小时，待反应完全后，将溶剂移除，剩余物经快速柱层析分离获得化合物5(甲醇/二氯甲烷1:50作为洗脱体系)。
化合物5结构由核磁氢谱确定，其核磁氢谱见图9，表征数据如下：
1H NMR(300MHz,DMSO)δ9.16(s,1H),8.83(s,1H),8.44–8.32(m,2H),8.23(d,J＝9.3Hz,1H),8.10(s,1H),7.66(s,1H),7.35(s,1H),6.54(s,1H),5.42(s,2H),5.35(s,2H),1.86(dd,J＝12.0,6.6Hz,2H),0.89(t,J＝7.0Hz,3H)。
实施例6
化合物6：
制备方法：
化合物1(101mg,0.26mmol)、Sc(OTf)3(78mg,0.16mmol)以及DMAP(94mg,0.78mmol)溶于干燥的二氯甲烷溶剂中，反应混合物常温条件下搅拌30分钟，再加入Boc-甘氨酸(136mg,0.78mmol)，反应混合物再搅拌30分钟，然后再加入DCC(272mg,1.3mmol)，反应混合物再在室温条件下搅拌过夜，然后硅藻土过滤，滤液浓缩后经快速柱层析分离获得化合物B(甲醇/二氯甲烷1:100作为洗脱体系)。化合物B(82mg,0.15mmol)的二氯甲烷溶液中加入TFA(1ml)，反应混合物再室温条件下搅拌30分钟后，移除反应溶剂，剩余物溶于DMF(2ml)，向反应溶液中加入丁二酸酐(97mg,0.97mmol)以及4-甲基吡啶(73mg,0.81mmol)，反应混合物在室温条件下搅拌过夜，移除反应溶剂，剩余物经快速柱层析分离获得化合物6(甲醇/二氯甲烷1:50作为洗脱体系)。
化合物6结构由核磁氢谱和碳谱数据确定，其核磁氢谱、碳谱图分别见图10和图11，表征数据如下：
1H NMR(400MHz,DMSO)δ12.08(s,1H),9.02(s,1H),8.98(s,1H),8.43(t,J＝5.7Hz,1H),8.23(d,J＝9.2Hz,1H),8.15(d,J＝9.2Hz,1H),7.13(s,1H),5.50(s,2H),5.35–5.21(m,2H),4.10(ddd,J＝67.9,18.0,5.8Hz,2H),2.41(dd,J＝11.5,5.7Hz,4H),2.22–2.13(m,2H),0.94(t,J＝7.3Hz,3H)。
13C NMR(101MHz,DMSO)δ174.14,174.05,172.06,169.58,167.51,156.92,155.34,152.02,147.77,146.52,146.32,145.58,135.33,131.22,127.86,126.11,121.53,119.36,115.90,95.59,76.66,66.80,50.95,30.92,30.16,29.39,29.26,7.98。
实施例7
化合物7：
制备方法：
化合物2(120mg,0.26mmol)，Sc(OTf)3(78mg,0.16mmol)以及DMAP(94mg,0.78mmol)溶于干燥的二氯甲烷溶剂中，反应混合物常温条件下搅拌30分钟，再加入Boc-甘氨酸(136mg,0.78mmol)，反应混合物再搅拌30分钟，然后再加入DCC(272mg,1.3mmol)，反应混合物再在室温条件下搅拌过夜，然后硅藻土过滤，滤液浓缩后经快速柱层析分离获得化合物C(甲醇/二氯甲烷1:100作为洗脱体系)。化合物C(88mg,0.15mmol)的二氯甲烷溶液中加入TFA(1ml)，反应混合物再室温条件下搅拌30分钟后，移除反应溶剂，剩余物溶于DMF(2ml)，向反应溶液中加入丁二酸酐(97mg,0.97mmol)以及4-甲基吡啶(73mg,0.81mmol)，反应混合物在室温条件下搅拌过夜，移除反应溶剂，剩余物经快速柱层析分离获得化合物7(甲醇/二氯甲烷1:50作为洗脱体系)。
化合物7结构由核磁氢谱和碳谱数据确定，其核磁氢谱、碳谱图分别见图12和图13，表征数据如下：
1H NMR(400MHz,DMSO)δ12.07(s,1H),9.06(s,1H),8.44(s,1H),8.21(d,J＝9.0Hz,1H),8.13(d,J＝8.9Hz,1H),7.15(s,1H),5.50(s,2H),5.30(s,2H),4.22–4.14(m,1H),4.00(dd,J＝17.8,4.9Hz,1H),3.43–3.38(m,1H),2.43(d,J＝5.5Hz,2H),2.38(s,2H),2.16(d,J＝6.5Hz,2H),1.46(d,J＝6.8Hz,6H),0.93(d,J＝6.7Hz,3H)。
13C NMR(400MHz；DMSO-d6)δ7.96,20.66,28.84,29.38,30.14,30.86,50.97,66.80,76.65,95.57,115.65,119.29,121.29,126.20,126.83,131.05,136.29,145.53,146.35,146.43,148.31,151.92,156.97,167.56,169.57,172.03,172.22,174.16。
应用例
1、喜树碱衍生物的体内抗急性炎症实验
化合物7体内抗急性炎症的效果通过药物对小鼠注射内毒素(LPS)后存活率的影响来评价。
将C57小鼠随机分为10组，每组数量为10只。在开始实验前一天下午为小鼠禁食，不禁水。次日开始实验，为小鼠称重，根据体重各组小鼠分别给予相应的药物一次，给药后0.5h腹腔注射LPS，剂量为10mg/kg。注射LPS后1h、4h和8h后受试各组再分别给予一次受试药物。
观察记录各组小鼠注射LPS后的死亡时间，连续观察72h。72h后对存活小鼠摘眼球取血约0.5ml/只，置离心机3000r/min离心10min，取血清，-80℃保存。监测动物体内炎症介质的表达，如前炎症细胞因子TNF-α、IL-6等。
腹腔注射LPS 10mg/kg后，各组小鼠活动明显减少，四肢蜷缩无力，毛发竖起，呼吸加快并伴有轻度腹泻。在注射LPS 24h左右小鼠开始出现死亡，溶剂对照组24h存活率仅为40％，其它各给药组存活率较高(表1)。72h后，各组小鼠存活率分别为：溶剂对照组30％，阳性组100％，与溶剂对照组比较差异非常显著。化合物7组3(po，10mg/kg)存活率可达到80％；灌胃给药组小鼠的存活率高于静脉注射给药途径。此外，从表2和表3中可以看出化合物7(YH-009)可以显著降低脓毒症小鼠血液中IL-6和TNF-α浓度。
表1.注射LPS后各时间段小鼠存活率(％)(n＝10)
*P<0.05，**P<0.01vs溶剂对照组
表2.对血液中IL-6浓度的影响(pg/mL)
表3.对血液中TNF-α浓度的影响(ng/L)
上述结果表明，本发明提供的喜树碱衍生物在在小鼠抗急性炎症模型中表现出优良的体内活性，能够显著降低小鼠死亡率。因此，本发明的喜树碱衍生物在作为一类高效的抗急性炎症候选新药应用具有广泛前景。
Claims (4)
1.结构式如式(Ⅷ)所示的喜树碱衍生物在制备抗炎症药物中的应用，其特征在于，所述喜树碱衍生物降低血液中前炎症细胞因子IL-6和TNF-α的浓度，
2.如权利要求1所述的应用，其特征在于，所述炎症为败血症、脓毒症、关节炎、肺炎、肠炎。
3.如权利要求1所述的应用，其特征在于，药物还包括药学上可接受的载体、赋形剂或稀释剂。
4.如权利要求1所述的应用，其特征在于，所述的抗炎症药物为口服给药剂型。
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