CN115197190A - 一种新型植物黄酮衍生物及其制备方法和应用 - Google Patents
一种新型植物黄酮衍生物及其制备方法和应用 Download PDFInfo
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- CN115197190A CN115197190A CN202110381741.9A CN202110381741A CN115197190A CN 115197190 A CN115197190 A CN 115197190A CN 202110381741 A CN202110381741 A CN 202110381741A CN 115197190 A CN115197190 A CN 115197190A
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Abstract
Description
技术领域
本发明属于医药技术领域,具体涉及一种新型植物黄酮衍生物及其制备方法和应用。
背景技术
磷酸二酯酶是酶家族的一员,迄今为止已知有11个PDE酶家族(PDE1-PDE11),它们的不同在于其底物特异性(cAMP、cGMP或者二者)及其对其它底物的依赖性(例如钙调蛋白)。抑制不同类型的PDE同工酶导致cAMP和/或者cGMP在细胞内聚集,这可用于治疗不同的炎症相关的疾病。PDE4主要分布于各种炎症细胞内,肥大细胞、巨噬细胞、嗜酸粒细胞、淋巴细胞和上皮细胞等,可通过抑制酶的活性来提高细胞内浓度,将有助于减轻炎症反应对机体的伤害。在对于过敏炎症很重要的细胞中(淋巴细胞、肥大细胞、嗜酸性粒细胞、巨噬细胞),主要的PDE同工酶也是4型。因此,用合适的抑制剂抑制PDE4视为治疗多种变态反应引起的疾病的重要开始。目前,PDE4抑制剂已被开发成抗炎的药物,如罗氟司特主要用于肺部的炎症治疗,尤其是哮喘和慢性阻塞性肺疾病;Difamilast被用于特异性皮炎的治疗;而阿普斯特被用于银屑病关节炎的治疗;同时PDE1、PDE3和PDE5的抑制剂也已应用于临床心脑血管疾病的治疗,如长春西汀、双嘧达莫、米力农、西地那非等。
同时,PDE4抑制剂的一个重要特征是抑制肿瘤坏死因子(TNF-α)从炎性细胞中释放。TNF-α是影响多种生物过程的重要的促炎性细胞因子,其能从激活的局势细胞、激活的T淋巴细胞、肥大细胞、嗜碱性粒细胞、成纤维细胞、内皮细胞和脑中的星形细胞释放。TNF-α自身对于中性白细胞、嗜酸性细胞、成纤维细吧和内皮细胞有激活作用,进而释放出不同的组织破坏性介质。在单核细胞、巨噬细胞和T淋巴细胞中,TNF-α导致其他的促炎性细胞因子例如GM-CSF(粒细胞-巨噬细胞集落刺激因子)或白介素-8的含量增加。由于TNF-α促进炎症和分解代谢作用,TNF-α在多种疾病中起着关键作用,这些疾病有例如呼吸道炎症、关节炎症、内毒素性休克、组织排斥、AIDS和多种其它免疫疾病。因此,PDE4抑制剂也是适用于治疗与TNF-α有关的疾病。
尽管已知PDE4抑制剂已经显示了其有益药理作用,但这类抑制剂存在引起腹泻、恶心等不良作用。因此,研究新型的特异性抑制剂来克服这些不良反应,就成为抑制剂药物研究的热点之一。天然中药衍生物是新药研发先导化合物发现的宝库,从中寻找具有新型抑制剂,对于研发疗效高、副作用小的抑制剂抗炎药物具有重要意义。
泽兰林素,也称异泽兰黄素(Eupatilin),是来源于菊科蒿属(Artemisia Linn.),是植物中的一种黄酮类成分,呈黄色粉末,其具有多种显著的药理活性。我国作为蒿属资源大国,对该成分的研究利用并未予以重视,大量药材和提取物被廉价出口至其他国家。由于异泽兰黄素丰富的药理作用,在植物中含量高且毒性低等特点,在新药和保健品开发研究中是一个值得重视的资源。
蔓荆子黄素,又名紫花牡荆素,程棕色粉末,源自马鞭草科植物单叶蔓荆,因其广泛的药理活性备受关注。但泽兰林素和蔓荆子黄素本身难溶于水,体内易代谢,生物利用度较低,大大限制了其在临床应用方面的开发。
泽兰林素和蔓荆子黄素的天然结构分别如下:
发明内容
为了克服背景技术中的问题,本发明提供了一种新型植物黄酮衍生物及其制备方法和应用。本发明对植物黄酮进行了进一步的结构改造,增强了其对新靶点PDE的靶向抑制活性,且经药理学实验证明,这些衍生物具有显著抑制磷酸二酯酶活性、保护神经细胞、心肌细胞和血管内皮细胞的作用。
为实现上述发明目的,本发明的技术方案如下:
本发明提供了一种新型植物黄酮衍生物,所述新型植物黄酮衍生物具有如下通式的结构:
其中,R1选自1-5个碳原子组成的直链烷基、3-6个碳原子组成的环烷基或者环烷甲基、C2-C6的饱和或不饱和烷基、或1-5个碳原子组成的含氟烷基;R2选自1-5个碳原子组成的直链烷基、3-6个碳原子组成的环烷基或者环烷甲基、C2-C6的饱和或不饱和烷基、或1-5个碳原子组成的含氟烷基;R3选自氢、或甲基;R4选自氢、或甲基;R5选自氢、或甲基;R6选自氢、羟基、或烷氧基。
进一步的:所述新型植物黄酮衍生物具有如下通式的结构:
进一步的:所述新型植物黄酮衍生物具体为A、B、C、D、E、F、G、H、I、J、K、L、M、N、O、P、Q、R、S、T,其结构式分别如下:
进一步的,所述新型植物黄酮衍生物包括泽兰林素衍生物和蔓荆子黄素衍生物。
进一步的,所述新型植物黄酮衍生物是在泽兰林素或蔓荆子黄素的基础上进行结构修饰的。
本发明还提供了所述的新型植物黄酮衍生物的制备方法,所述制备方法包括以下步骤:
将MOM羟基保护的2-甲氧基苯乙酮的衍生物X与苯甲醛的衍生物Y混合后,在碱催化下进行亲核加成,利用克莱森-斯密特法生成查耳酮后,经分子内环合,在酸性条件下脱除保护基团,得到新型植物黄酮衍生物A、B、C、D、E、F、G、H、I;
或者将MOM羟基保护的2-羟苯乙酮的衍生物Z与苯甲醛的衍生物Y混合后,加入吡咯烷反应完全后脱除保护基团,萃取、洗涤干燥和浓缩后,用硅胶柱层析纯化,得到新型植物黄酮衍生物J、K、L、M、N、O、P、Q、R、S、T;
所述衍生物X的结构为:
所述衍生物Y的结构为:
所述衍生物Z的结构为:
进一步的:所述的新型植物黄酮衍生物还包括其药学上可接受的盐,并可通过用无机碱或有机碱中和酸,或者用无机酸或有机酸中和碱来以常规方法获得。
进一步的:所述的新型植物黄酮衍生物还包括其D型、L型或D,L-混合物。
进一步的:所述的新型植物黄酮衍生物还包括其非对映异构体。
本发明还提供了所述的新型植物黄酮衍生物在用于制备磷酸二酯酶PDEs和/或TNF-α抑制剂中的应用。
进一步的:所述的新型植物黄酮衍生物能够有效抑制磷酸二酯酶PDEs以及TNF-α。
本发明还提供了所述的新型植物黄酮衍生物在用于制备防治炎症性和/或过敏性疾病的药物中的应用。
进一步的,所述新型植物黄酮衍生物能够通过有效抑制磷酸二酯酶PDEs的活性、抑制TNF-α的释放、抑制中性白细胞和嗜酸性细胞的增加来减轻炎症性和/或过敏性疾病的症状。
进一步的:所述磷酸二酯酶为PDE4、PDE2、PDE3、PDE5和PDE10。
优选的:所述磷酸二酯酶为PDE4。
进一步的:与抑制TNF-α的释放相关的炎症性疾病包括关节炎、类风湿性关节炎、类风湿性脊椎炎、骨关节炎、痛风性关节炎、胃炎、胃溃疡、骨质疏松、脓毒症、脓毒性休克、格兰氏阴性脓毒症、中毒性休克综合征、呼吸窘迫综合征、哮喘和其它慢性肺病、骨吸收疾病或移植排斥反应或其它自身免疫性、红斑狼疮、多发性硬化、肾小球性肾炎和眼色素层炎、胰岛素依赖性糖尿病和慢性脱髓鞘。
进一步的:与嗜酸性细胞的增多相关的炎症性或过敏性疾病包括支气管哮喘、过敏性鼻炎、过敏性结膜炎、特应性皮炎、湿疹、过敏性脉管炎、嗜酸性细胞引起的炎症,例如嗜酸细胞性筋膜炎、嗜酸细胞性肺炎和PIE综合征(嗜酸性细胞增多的肺浸润)、荨麻疹、溃疡性结膜炎、局限性回肠炎、牛皮癣和角化病。
进一步的:本发明化合物还可用于治疗与TNF-α相关的感染,包括病毒感染和寄生虫感染、疟疾、利什曼病、感染引起的发烧、感染引起的肌肉疼痛、AIDS和恶病质。
进一步的:与中性白细胞的增多相关的疾病包括慢性堵塞性肺病。
本发明还提供了所述的新型植物黄酮衍生物在用于制备防治神经系统和/或心血管系统疾病的药物中的应用。
进一步的:所述新型植物黄酮衍生物能够通过有效抑制Aβ聚集体和/或CoCl2诱导的神经细胞和/或心肌细胞损伤、或者有效逆转氧化低密度脂蛋白ox-LDL诱导的血管内皮细胞损伤,进而增加神经细胞或心肌细胞的活力,避免血管内皮细胞受ox-LDL的损伤,达到保护神经细胞或心血管细胞的作用。
进一步的:所述神经系统和/或心血管系统疾病包括老年痴呆(阿尔茨海默氏症)、记忆遗失、帕金森氏病、抑郁焦虑症、精神分裂症、中风、间歇性跛行、心血管损伤、动脉硬化、高血脂高血糖、脑缺血损伤疾病、良性前列腺增生、频尿、夜尿症,以及失禁、尿石引起的纹痛和性功能障碍。
进一步的:所述的药物为片剂、口服液、气雾剂、丸剂、胶囊剂、颗粒剂、膏剂、滴丸剂、糖浆剂、散剂、冲剂、酊剂、粉针剂或注射液。
进一步的:所述的药物通过口服、非胃肠道、静脉内、透皮、局部、吸入和鼻内给药。
进一步的:所述的药物的剂量为每天施用一次的单一剂量给药,或者每天分成两次或更多次剂量给药,每次为0.001-100mg。
进一步的:所述的药物中还包括辅助剂、载体和添加剂中的至少一种。
进一步的:所述载体包括碳酸钙、磷酸钙、磷酸钠、乳糖、淀粉、甘露醇、藻酸盐、明胶、瓜尔胶、硬脂酸镁、硬脂酸铝、甲基纤维素、滑石粉、高度分散的二氧化硅、硅油、硬脂酸、明胶、琼脂、植物或动物脂肪和油、聚乙二醇中的至少一种。
进一步的:所述辅助剂包括甜味剂、调味剂、防腐剂、稳定剂、润湿剂、渗透剂、乳化剂、涂布剂、助溶剂,用于控制渗透压或用于起缓冲作用的盐、糖或糖醇和/或粘度调节剂中的至少一种。
进一步的:所述添加剂包括酒石酸盐和柠檬酸盐缓冲剂、乙醇、络合剂中的至少一种。
进一步的:为了控制粘度,所述添加剂还能够使用液体聚氧化乙烯、微晶纤维素、聚乙烯吡咯烷酮、葡聚糖或明胶。
进一步的:用于非胃肠道或局部施用的油悬浮液可含有植物的合成或半合成油,包括其在脂肪酸链中具有8-22个碳原子的液体脂肪酸酯,所述脂肪酸包括棕榈酸、月桂酸、十三烷酸、十七烷酸、硬脂酸、二十烷酸、肉豆蔻酸、二十二烷酸、十五烷酸、亚油酸、反油酸、巴西勒酸、芥酸或油酸,这些脂肪酸被具有1-6个碳原子的一元一三元醇酯化,所述醇包括甲醇、乙醇、丙醇、丁醇、戊醇或其异构体,乙二醇或甘油;所述脂肪酸酣包括Miglyole、肉豆蔻酸异丙酯、棕桐酸异丙酯、硬脂酸异丙酯、PEG-6癸酸、饱和脂肪醇的辛酸/癸酸酯、聚氧化乙烯甘油三油酸酯、油酸乙酯、蜡状脂肪酸酯例如合成的鸭尾腺脂肪、椰油脂肪酸的异丙酯、油酸油酯、油酸癸酯、乳酸乙醋、邻苯二甲酸二丁酯、己二酸二异丙酯、多元醇的脂肪酸酯;还能够使用硅油或脂肪醇包括异十三烷醇,2一辛基十二烷醇、鲸蜡基硬脂醇或油醇、油酸以及植物油包括蓖麻油、杏仁油、橄榄油、芝麻油、棉子油、花生油或豆油。
进一步的:作为溶剂、凝胶形成剂和助溶剂,使用水或醇包括乙醇或异丙醇、苯甲醇、2一辛基十二烷醇、聚乙二醇、邻苯二甲酸酯、己二酸酯、丙二醇、甘油、一缩二丙二醇、三丙二醇、蜡、甲基溶纤剂、溶纤剂、酯、呜琳、二氧杂环己烷、二甲亚砜、二甲基甲酰胺、四氢吠喃、环己酮。
进一步的:作为成膜剂,使用可溶解在或膨胀在水和有机溶剂中的纤维素醚,包括羟丙基甲基纤维素、甲基纤维素、乙基纤维素或可溶性淀粉、羧甲基纤维素钠、聚丙烯酸、聚异丁烯酸和其盐、支链淀粉半羟乙酸钠、藻酸或作为钠盐的丙二醇藻酸醋、阿拉伯胶、黄原胶、瓜尔胶或角叉菜胶。
进一步的:作为其它制剂辅料,还能够使用甘油、不同粘度的石蜡、三乙醇胺、胶原或尿囊素。
进一步的:所述药物中还能够包括表面活性剂、乳化剂或润湿剂,包括月桂基硫酸钠、脂肪醇醚硫酸盐、N-月桂基-β-亚氨基二丙酸二钠、聚乙氧基化蓖麻油或脱水山梨醇油酸醋、脱水山梨醇硬脂酸酯、聚山梨醇酯、鲸蜡醇、卵磷脂、甘油-硬脂酸酯、聚氧乙烯硬脂酸酯、烷基苯酚聚乙二醇醚、氛化鲸蜡基三甲基铵或烷基或二烷基聚乙二醇醚正磷酸乙醇胺盐;稳定剂包括蒙脱石或胶态二氧化硅;抗氧化剂包括生育酚或丁基羟基茴香醚;防腐剂包括对羟基苯甲酸酯。
与现有技术相比,本发明的优点和有益效果为:
本发明基于天然的泽兰林素和蔓荆子黄素的原始结构,进行了改造,并合成得到了新型植物黄酮衍生物,其结构新颖,并通过药理学实验证明,新型植物黄酮衍生物具有很好的抑制PDEs活性、TNF-α的释放、中性白细胞增多和嗜酸性细胞增多的作用,进而减轻炎症性疾病或过敏的症状,并且还能够抑制Aβ聚集体诱导的神经细胞损伤,或者抑制CoCl2诱导的神经细胞或心肌细胞缺氧性损伤,并有效逆转ox-LDL诱导的血管内皮细胞损伤,进而增加神经细胞或心肌细胞的活力,避免血管内皮细胞受氧化低密度脂蛋白损伤、达到保护神经细胞或心血管细胞的作用。本发明的新型植物黄酮衍生物能够对多种疾病具有良好的治疗效果,并且均具有良好的安全性,增加了植物黄酮的生物利用度,具有进一步开发的价值。
具体实施方式
以下结合具体实施例对本发明的技术方案做进一步详细的说明。
本发明的新型植物黄酮衍生物具有如下通式的结构:
实施例1:新型植物黄酮衍生物的合成
在室温条件下,将1mol的5,7-二甲氧基甲基醚(MOM)羟基保护的2-甲氧基苯乙酮与等量的3-环丙氧基-4-二氟甲氧基苯甲醛共同溶解在100mL甲醇中,加入0.3mol的氢氧化钾,通过亲核加成,并失去一分子的水,得到2,4-MOM羟基保护的4-二氟甲氧基-5-环丙氧基-3,6-二甲氧基查耳酮,该反应是一个经典反应;再将产物0.65mol溶解于DMSO溶液中,加入单质碘,升温回流3-6h,冷却至室温后,将反应液倒入2%的NaHSO3溶液中,充分搅拌后滤出固体,再在室温下,将得到的固体化合物在甲醇和盐酸(3mol/L)中,在氩气保护下,脱除保护基团,然后冷却至室温,减压浓缩出去甲醇,经过滤水洗,干燥后用无水乙醇重结晶,得代表化合物2-(3-环丙甲氧基-4-二氟甲氧基苯)-5,7-二羟基-6-甲氧基-4H-色烯-4-酮(A)。核磁共振氢谱和碳谱的数据如下:
化合物A氢谱:1H NMR(400MHz,DMSO-d6)δ7.75(s,8H),7.62(s,21H),7.35(s,16H),7.13(d,J=5.0Hz,33H),6.34(s,16H),6.02(s,16H),5.36(s,16H),3.71(s,48H),3.48(s,6H),0.72(s,32H),0.31(s,32H)
化合物A碳谱:13C NMR(101MHz,DMSO-d6)δ182.11(s),162.48(s),157.05(s),154.20(s),153.55(s),153.28(s),149.39(s),129.93(s),125.50(s),124.01(s),122.50(s),118.56(s),116.59(s),104.41(s),103.90(s),94.15(s),60.70(s),58.77(s),7.98(s).
2、使用上述经典的克莱森-斯密特法方法,可合成化合物B-I,具体如下:
化合物B氢谱:1H NMR(400MHz,DMSO-d6)δ7.62(s,3H),7.13(d,J=5.0Hz,6H),6.39(d,J=18.6Hz,6H),6.02(s,3H),5.35(s,3H),3.83(s,9H),3.71(s,9H),3.47(s,1H),0.72(s,6H),0.24(s,6H).
化合物B碳谱:13C NMR(101MHz,DMSO-d6))δ182.11(s),162.48(s),157.05(s),154.54(s),154.20(s),153.55(s),148.51(s),129.93(s),124.08(s),122.29(s),115.10(s),113.44(s),104.41(s),103.90(s),94.15(s),60.70(s),58.77(s),56.83(s),7.98(s).
化合物C氢谱:1H NMR(400MHz,DMSO-d6)δ7.62(s,5H),7.13(d,J=5.0Hz,10H),6.41(s,5H),6.02(s,5H),5.98(s,5H),5.85(s,5H),4.67(s,2H),3.83(s,15H),3.71(s,15H),1.32(s,31H).
化合物C碳谱:13C NMR(101MHz,DMSO-d6)δ182.11(s),162.48(s),157.05(s),155.03(s),154.20(s),153.55(s),149.16(s),129.93(s),124.16(s),122.37(s),115.74(s),112.22(s),104.41(s),103.90(s),94.15(s),73.89(s),60.70(s),56.83(s),21.81(s).
化合物D氢谱:1H NMR(400MHz,DMSO-d6)δ9.61(s,18H),7.97(s,9H),7.62(s,23H),7.13(d,J=5.0Hz,37H),6.40(s,18H),5.85(s,18H),5.30(s,18H),4.48(s,18H),3.52(s,7H),0.75(s,36H),0.23(s,36H).
化合物D碳谱:13C NMR(101MHz,DMSO-d6)δ182.11(s),162.48(s),154.05(s),153.28(s),151.54(s),150.21(s),149.39(s),129.39(s),125.50(s),124.01(s),122.50(s),118.56(s),116.59(s),104.41(s),103.97(s),94.25(s),58.77(s),7.98(s).
化合物E氢谱:1H NMR(400MHz,DMSO-d6)δ7.62(s,3H),7.13(d,J=5.0Hz,6H),5.85(s,3H),3.83(s,9H),3.47(s,1H),2.03(s,3H),0.70(s,6H),0.30(s,6H),-1.00(s,9H).
化合物E碳谱:13C NMR(101MHz,DMSO-d6)δ182.11(s),162.48(s),154.54(s),154.05(s),151.54(s),150.21(s),148.51(s),129.39(s),124.08(s),122.29(s),115.10(s),113.44(s),104.41(s),103.97(s),94.25(s),58.77(s),56.83(s),7.98(s).
化合物F氢谱:1H NMR(400MHz,DMSO-d6)δ7.62(s,1H),7.13(d,J=5.0Hz,2H),6.41(s,1H),5.85(s,1H),5.30(s,1H),4.53(s,1H),3.84(d,J=10.0Hz,6H).
化合物F碳谱:13C NMR(101MHz,DMSO-d6)δ182.11(s),162.48(s),154.05(s),152.40(s),151.54(s),150.69(s),150.21(s),129.39(s),122.87(s),121.14(s),112.92(s),110.92(s),104.41(s),103.97(s),94.25(s),56.83(s).
化合物G氢谱:1HNMR(400MHz,DMSO-d6)δ8.20(s,1H),7.62(s,2H),7.13(d,J=5.0Hz,4H),6.40(s,2H),6.29(s,2H),4.13(s,4H),3.89(s,6H),3.83(s,6H),3.71(s,6H),1.42(s,3H).
化合物G碳谱:13C NMR(101MHz,DMSO-d6)δ178.23(s),162.48(s),159.60(s),156.26(s),155.07(s),153.64(s),149.30(s),139.08(s),126.05(s),125.58(s),122.33(s),118.56(s),118.30(s),113.88(s),104.41(s),95.05(s),64.46(s),60.70(s),56.83(s),13.80(s).
化合物H氢谱:1H NMR(400MHz,DMSO-d6)δ7.62(s,3H),7.13(d,J=5.0Hz,6H),6.42(s,3H),6.17(s,3H),3.83(s,18H),3.71(s,9H),3.53(s,1H),0.73(s,6H),0.22(s,6H).
化合物H碳谱:13C NMR(101MHz,DMSO-d6)δ182.11(s),162.48(s),159.78(s),154.54(s),153.98(d,J=2.3Hz),148.51(s),131.76(s),124.08(s),122.29(s),115.10(s),113.44(s),106.39(s),104.41(s),91.93(s),60.70(s),58.77(s),56.83(s),7.98(s).
化合物I氢谱:1H NMR(400MHz,DMSO-d6)δ7.62(s,1H),7.14(d,J=5.0Hz,2H),6.42(s,1H),6.29(s,1H),3.89(s,3H),3.84(d,J=10.0Hz,9H),3.71(s,3H).
化合物I碳谱:13C NMR(101MHz,DMSO-d6)δ178.23(s),162.48(s),159.60(s),155.07(s),153.64(s),152.40(s),150.69(s),139.08(s),122.87(s),121.14(s),113.88(s),112.92(s),110.92(s),104.41(s),95.05(s),60.70(s),56.83(s).
在室温环境下,取2,4-二甲氧基甲基醚羟基保护的3-甲氧基-6-羟基-苯乙酮1.9mmol和3-环丙氧基-4-二氟甲氧基苯甲醛(2.05mmol)、以及MeOH(3.5mL)和H2O(9.2mL)加入反应瓶中,然后加入吡咯烷(1.7mL),加毕,升至50℃,敞口搅拌反应15h,反应至TLC监测原料消失,将反应液冷至室温,倒入冰水中,淬灭反应。用1N盐酸调pH=4.0,使用12mL二氯甲烷萃取三次,合并有机相并依次经饱和氯化钠溶液洗涤、无水硫酸钠干燥后,减压浓缩有机相至干燥,再在室温下,将得到的固体化合物在甲醇和盐酸(3mol/L)中,在氩气保护下,脱除保护基团,然后冷却至室温,再经硅胶柱层析[V(石油醚):V(丙酮)=5:1]纯化,得代表化合物2-(3-环丙甲氧基-4-二氟甲氧基苯)-3,5,7-三羟基-6-甲氧基-4H-色烯-4-酮(K)。核磁共振氢谱和碳谱的数据如下:
化合物K氢谱:1H NMR(400MHz,DMSO-d6)δ7.70(s,3H),7.62(s,6H),7.13(d,J=5.0Hz,12H),6.47(s,6H),6.02(s,6H),5.94(s,6H),5.16(s,6H),3.71(s,18H),3.64(s,5H),0.77(s,12H),0.22(s,12H).
化合物K碳谱:13C NMR(101MHz,DMSO-d6)δ175.99(s),158.68(s),153.57(s),152.81(d,J=17.1Hz),147.76(d,J=3.6Hz),137.31(s),128.42(s),126.62(s),125.15(s),122.94(s),118.56(s),114.70(s),103.88(s),95.32(s),60.70(s),58.77(s),7.98(s).
4、使用上述方法,可合成化合物J-P,具体如下:
化合物J氢谱:1H NMR(400MHz,DMSO-d6)δ7.59(s,2H),7.10(d,J=5.0Hz,4H),6.37(s,2H),5.99(s,2H),4.87(s,2H),3.81(s,6H),3.69(s,6H),3.44(s,1H),3.24(s,2H),0.68(s,3H),0.30(s,3H).
化合物J碳谱:13C NMR(101MHz,DMSO-d6)δ175.99(s),158.68(s),153.56(d,J=2.8Hz),152.88(s),147.76(d,J=3.6Hz),137.31(s),128.42(s),124.31(s),124.01(s),113.72(s),113.53(s),103.88(s),95.32(s),60.70(s),58.77(s),56.83(s),7.98(s).
化合物L氢谱:1H NMR(400MHz,DMSO-d6)δ8.36(s,1H),7.62(s,2H),7.13(d,J=5.0Hz,4H),6.29(s,2H),5.70(s,2H),3.89(s,6H),3.83(s,6H),3.72(d,J=10.6Hz,7H),0.80(s,4H),0.19(s,4H).
化合物L碳谱:13C NMR(101MHz,DMSO-d6)δ170.81(s),159.36(s),153.21(s),152.74(s),152.14(s),147.76(d,J=3.6Hz),137.70(s),137.31(s),126.62(s),125.15(s),122.94(s),118.56(s),114.70(s),112.44(s),95.28(s),60.70(s),58.77(s),56.83(s),7.98(s).
化合物M氢谱:1H NMR(400MHz,DMSO-d6)δ7.67(d,J=54.5Hz,9H),7.16–7.09(m,15H),6.60(s,5H),6.17(s,5H),3.83(s,15H),3.71(s,15H),3.49(s,2H),0.70(s,7H),0.44(s,7H).
化合物M碳谱:13C NMR(101MHz,DMSO-d6)δ175.99(s),159.58(s),154.06(s),153.88(s),152.74(s),147.76(d,J=3.6Hz),137.31(s),130.42(s),126.62(s),125.15(s),122.94(s),118.56(s),114.70(s),105.74(s),93.43(s),60.70(s),58.77(s),56.83(s),7.98(s).
化合物N氢谱:1H NMR(400MHz,DMSO-d6)δ7.62(s,1H),7.13(d,J=5.0Hz,2H),6.17(s,1H),5.49(s,1H),5.41(s,1H),3.83(s,6H),3.71(s,3H),3.49(s,1H),0.71(s,2H),0.18(s,2H).
化合物N碳谱:13C NMR(101MHz,DMSO-d6)δ175.99(s),159.58(s),154.06(s),153.88(s),153.55(s),147.76(d,J=3.6Hz),137.31(s),130.42(s),124.31(s),124.01(s),113.72(s),113.53(s),105.74(s),93.43(s),60.70(s),58.77(s),56.83(s),7.98(s).
化合物O氢谱:1H NMR(400MHz,DMSO-d6)δ7.96(s,1H),7.62(s,3H),7.13(d,J=5.0Hz,4H),6.02(s,2H),5.39(s,2H),3.84(s,6H),3.71(s,6H),3.55(s,1H),0.73(s,3H),0.37(s,3H).
化合物O碳谱:13C NMR(101MHz,DMSO-d6)δ179.30(s),158.57(s),154.43(d,J=6.0Hz),153.75(s),152.59(s),148.63(s),138.59(s),128.86(s),125.96(s),124.85(s),123.94(s),118.56(s),115.17(s),104.77(s),95.28(s),61.51(s),60.70(s),58.77(s),7.98(s).
化合物P氢谱:1H NMR(400MHz,DMSO-d6)δ7.62(s,2H),7.13(d,J=5.0Hz,4H),6.41(s,2H),6.17(s,2H),4.67(s,1H),3.83(d,J=5.0Hz,18H),3.71(s,6H),1.32(s,12H).
化合物P碳谱:13C NMR(101MHz,DMSO-d6)δ179.30(s),159.50(s),155.03–154.60(m),154.41(s),148.71(s),138.59(s),130.84(s),125.09(s),123.25(s),115.34(s),112.78(s),106.65(s),93.58(s),73.89(s),61.51(s),60.70(s),56.83(s),21.81(s).
化合物Q氢谱:1H NMR(400MHz,DMSO-d6)δ7.59(s,2H),7.11(d,J=5.0Hz,4H),6.32(s,2H),6.15(s,2H),3.82(d,J=5.0Hz,18H),3.70(s,6H),3.53(s,1H),0.73(s,4H),0.21(s,4H).
化合物Q碳谱:13C NMR(101MHz,DMSO-d6)δ179.30(s),159.50(s),154.88(d,J=12.0Hz),154.41(s),154.14(s),147.86(s),138.59(s),130.84(s),124.36(s),123.70(s),114.69(s),114.16(s),106.65(s),93.58(s),61.51(s),60.70(s),58.77(s),56.83(s),7.98(s).
化合物R氢谱:1H NMR(400MHz,DMSO-d6)δ8.36(s,1H),7.62(s,2H),7.13(d,J=5.0Hz,4H),6.17(s,2H),5.99(s,2H),3.83(d,J=5.0Hz,12H),3.71(d,J=1.7Hz,7H),0.80(s,4H),0.23(s,4H).
化合物R碳谱:13C NMR(101MHz,DMSO-d6)δ179.30(s),159.50(s),154.88(d,J=12.0Hz),154.41(s),152.59(s),148.63(s),138.59(s),130.84(s),125.96(s),124.85(s),123.94(s),118.56(s),115.17(s),106.65(s),93.58(s),61.51(s),60.70(s),58.77(s),56.83(s),7.98(s).
化合物S氢谱:1H NMR(400MHz,DMSO-d6)δ7.62(s,1H),7.13(d,J=5.0Hz,2H),6.40(s,1H),6.17(s,1H),4.13(s,4H),3.83(d,J=5.0Hz,6H),3.71(s,3H),1.42(s,3H).
化合物S碳谱:13C NMR(101MHz,DMSO-d6)δ179.30(s),159.50(s),154.88(d,J=12.0Hz),154.44(d,J=7.4Hz),149.09(s),138.59(s),130.84(s),124.72(s),124.42(s),118.99(s),116.33(s),106.65(s),93.58(s),64.46(s),61.51(s),60.70(s),56.83(s),13.80(s).
化合物T氢谱:1H NMR(400MHz,DMSO-d6)δ7.62(s,1H),7.13(d,J=5.0Hz,2H),6.40(s,1H),6.17(s,1H),3.87–3.81(m,12H),3.71(s,3H).
化合物T碳谱:13C NMR(101MHz,DMSO-d6)δ179.30(s),159.50(s),154.88(d,J=12.0Hz),154.41(s),151.82(s),149.93(s),138.59(s),130.84(s),123.83(s),123.08(s),112.85(s),111.93(s),106.65(s),93.58(s),61.51(s),60.70(s),56.83(s).
实施例2:新型植物黄酮衍生物抑制磷酸二酯酶(PDEs)
在大鼠多形核淋巴细胞(PMNL)的酶制备物中测定PDE4活性,用分离的血小板的PDE测定PDE2、PDE3和PDE5、PDE10的活性。用柠檬酸盐防止提取的大鼠血液凝结;通过在室温离心的方法将上清液中的富含血小板的血浆与红细胞和白细胞分离开;再通过超声将血小板裂解,预留在PDE3和PDE5测定中使用。为了测定PDE2活性,在阴离子交换柱上通过NaCl梯度纯化胞质血小板级分,获得了用于测定的PDE2峰;再通过葡聚糖沉降后,用Ficoll梯度离心分离出用于PDE4测定的PMNL细胞。将PMNL细胞洗涤2次后,通过加入10mL低渗裂解缓冲液于4℃裂解6分钟以去除残留的红细胞。将仍然完整的PMNL细胞再用PBS洗涤两次,并通过超声裂解,于4℃以高速离心1h,获得的上清液含有PDE4的胞质级分以用于下述测定中PDE4、PDE2、PDE3和PDE5、PDE10测定中酶的原料。
使用磷酸二酯酶活性测定试剂盒(购自Abcam公司,货号ab13940,PDE ActivityAssay kit,Colorimetric)来测定各种PDE酶的活性:将操作方法适当修改,把试剂盒提供的蛋白酶替换为如上述方法分离制备的蛋白酶即可,其它的按照操作说明书进行严格检测:先加入20微升cAMP底物,再加入15微升测定缓冲液,然后加入10微升5’核苷酸酶,混合均匀后加入适当浓度的测试化合物,然后加入已提取纯化准备好的PDE酶,30℃孵育30分钟后,最后加入Green Assay试剂检测分解出的磷酸根离子,混合20分钟后达到颜色均匀,通过测定OD620nm来计算化合物对PDE酶的抑制活性。
结果如表1所示,实施例1制备得到的各个化合物测定的抑制PDE4的IC50值为10-10-10-5M,对2、3和5、10型PDE的选择性为5-500的因数,说明新型植物黄酮衍生物具有抑制PDE4活性的作用,可作为PDE4强抑制剂。
表1:新型植物黄酮衍生物的抑制PDE4的IC50值
实施例3:新型植物黄酮衍生物抑制从鼻息肉细胞释放TNF-α
将实验室储存的鼻息肉组织用RPMI 1640洗涤,然后用蛋白酶(2.5mg/ml)、胶原酶(1.0mg/ml)、透明质酸酶(0.5mg/ml)和DNA酶(0.1mg/ml)于37℃溶解150分钟(1g组织和4mL含有酶的RPMI 1640)。将所得细胞(上皮细胞、单核细胞、巨噬细胞、淋巴细胞、成纤维细胞和粒细胞)的混合物过滤,通过在培养溶液中反复离心来洗涤,加入人源IgE来被动致敏,将细胞悬浮液在RPMI 1640(补充抗生素、10%胎牛血清、2mM谷氨酸胺和25mM Hepes)中稀释至2百万个细胞/mL的浓度。将悬浮液分配在6孔细胞培养平板上(1ml/孔)。将细胞与不同浓度的测试化合物预培养30分钟,然后通过加入抗IgE进行刺激以释放TNF-α,约16小时后发生了向培养基内的最大释放。在该期间,将细胞在37℃、含5%二氧化碳的培养箱中培养。通过离心来收集培养基(上清液),并在-80℃保持,直至测定细胞因子。用ELISA试剂盒测定上清液中的TNF-α。
未用抗IgE刺激的细胞几乎不产生任何TNF-α,而刺激的细胞分泌大量TNF-α,可通过PDE4抑制剂减少TNF-α的量,且减少程度与剂量有关。由不同浓度的化合物的抑制百分比(用抗IgE刺激的细胞TNF-α释放=100%)计算IC50(达到50%抑制的浓度)。结果如表2所示,实施例1制备的化合物的IC50值为10-11-10-4M,表明新型植物黄酮衍生物具有抑制TNF-α释放的作用,可作为TNF-α抑制剂。
表2:化合物的抑制TNF-α释放的结果
实施例4:新型植物黄酮衍生物抑制大鼠过敏模型的嗜酸性细胞增多
将V级卵清蛋白50mg,氢氧化铝100mg和灭活百日咳杆菌6×109个溶于生理盐水1ml中,配制成混悬液凝胶,并按此比例扩大配成12ml作为致敏液备用(为防止分10次注射使用时挂壁残留损耗,多配制出2ml)。第1天致敏:空白组大鼠给予腹腔注射1ml生理盐水,而模型组给予腹腔注射1ml致敏液致敏;第15天开始激发:将两组大鼠分别置于相同大小的雾化箱内,空白组给予生理盐水6ml雾化激发,模型组给予5%V级卵清蛋白溶液6ml雾化激发,每天激发一次,每次激发30min,连续激发10天。测试化合物是在变应原攻击前2小时,作为在10%聚乙二醇300和0.5%5-羟基乙基纤维素中的悬浮液腹膜内或口服施用的。对照组是依据测试化合物的施用形式用载体治疗。实验结束时固定大鼠四肢,使用75%酒精对颈部消毒,充分暴露气管,在喉部附近插入气管插管针(针头稍磨平),针头插入一定位置,切勿超过气管分叉处;用2mL预冷的PBS反复灌洗3次,收集肺泡灌洗液到EP管中,1000rpm、4℃离心,收集细胞,经瑞氏-吉姆萨染色,在显微镜下进行细胞分类计数。
白细胞是免疫进程中至关重要的一类细胞,细胞分类计数可以有效分析肺泡灌洗液BALF中白细胞比例的变化。在发病过程中,浸润大鼠支气管的炎症细胞主要是淋巴细胞和嗜酸性细胞。淋巴细胞能够扩大支气管粘膜上嗜酸性细胞的炎症反应,并且随着嗜酸性粒细胞的增多,会增加其在肺内聚集、活化以及与其它炎性细胞、炎性介质、细胞因子的相互作用,进而加重过敏。
结果如表3所示,以1-10mg/kg剂量腹膜内施用后,实施例1制备的化合物将嗜酸性细胞增多症状有效抑制了66%-92%;以10-100mg/kg的剂量口服施用后,各化合物将嗜酸性细胞增多症状抑制了43-77%。因此,本发明的新型植物黄酮衍生物适合制备用于治疗和预防与嗜酸性细胞活动有关的疾病的药物。
表3:化合物的抑制嗜酸性细胞增多的结果
实施例5:新型植物黄酮衍生物抑制脂多糖(LPS)引起的中性白细胞增多
在雄性Wistar大鼠(200±20g)中测试实施例1制备的化合物对肺中性白细胞浸润的抑制作用。在实验的当天,将动物单独置于开口的1L有机玻璃盒子中,该盒子与头鼻暴露装置连接。将动物暴露于脂多糖悬浮液(LPS 100μg/mL溶解于含有0.1%羟基胺的PBS溶液中)的气雾剂中(LPS攻击),暴露时间是45分钟,标准对照是用含有0.1%羟基胺的PBS溶液的气雾剂喷雾45分钟。LPS攻击6小时后,有大量中性粒细胞迁移到动物的肺内。测试各化合物是在LPS攻击前2小时,作为在10%聚乙二醇300和0.5%5-羟基乙基纤维素中的悬浮液口服施用的。对照组是依据测试物的施用形式用载体治疗。实验结束时固定大鼠四肢,使用75%酒精对颈部消毒,充分暴露气管,在喉部附近插入气管插管针(针头稍磨平),针头插入一定位置,切勿超过气管分叉处;用2mL预冷的PBS反复灌洗3次,收集肺泡灌洗液到EP管中,1000rpm、4℃离心,收集细胞,经瑞氏-吉姆萨染色,在显微镜下进行细胞分类计数。
结果如表4所示,以10-100mg/kg的剂量口服施用后,本发明的化合物将中性白细胞增多症状抑制了64%-90%。因此,本发明的新型植物黄酮衍生物适用于制备用于治疗和预防与中性白细胞活动有关的疾病的药物。
表4:化合物的抑制中性白细胞增多的结果
实施例6:新型植物黄酮衍生物对Aβ聚集体诱导神经细胞损伤的保护作用
以未加Aβ1-42的细胞活力为阴性对照,观察实施例1制备的化合物对Aβ诱导产生的神经细胞毒的抑制作用,具体实施步骤如下:将PC12细胞接种于MEM完全培养液中,置入96孔板中培养,放入恒温细胞培养箱孵育24小时后,加入提前聚集的Aβ蛋白寡聚体,2h后,各化合物组在每孔加入本化合物溶液,浓度为50μmol/L,模型组加入等量的无菌水,培养箱中继续孵育24h。结束后,采用MTT法测定细胞存活率。每次三个平行,实验重复三次。
结果如表5所示,以50μmol/L的给药浓度处理后,细胞存活率均较模型组显著提高,说明本发明化合物均具有较好的保护神经细胞的作用,对Aβ聚集体诱导神经细胞损伤具有明显的抑制作用。因此,本发明的新型植物黄酮衍生物适用于制备用于治疗和预防与神经保护有关的疾病的药物,其中以化合物B的作用效果最好。
表5:化合物的保护神经细胞的结果
实施例7、新型植物黄酮衍生物对CoCl2诱导神经细胞和心肌细胞缺氧损伤的保护作用
以未加CoCl2诱导的神经细胞PC12和心肌细胞H9C2的细胞活力为阴性对照,观察实施例1制备的化合物对诱导CoCl2产生的神经细胞和心肌细胞缺氧损伤的抑制作用,具体实施步骤如下:将PC12和H9C2细胞接种于MEM或者DMEM完全培养液中,置入96孔板中培养,放入恒温细胞培养箱孵育24小时后,加入提前溶解好的含CoCl2的损伤液,2h后,各化合物组每孔加入各化合物溶液,浓度为100μmol/L,模型组加入等量的无菌水,培养箱中继续孵育48小时。结束后,采用MTT法测定细胞存活率。每次三个平行,实验重复三次。
结果如表6和7所示,以100μmol/L的给药浓度处理后,神经细胞和心肌细胞的细胞存活率均较模型组均得到显著提高,说明本发明化合物具有较好的保护神经细胞和心肌细胞缺氧损伤的作用。因此,本发明的新型植物黄酮衍生物适用于制备用于治疗和预防与神经细胞和心血管系统损伤有关的疾病的药物。
表6:化合物的对缺氧导致的神经损伤的作用
表7:化合物的对缺氧导致的心血管细胞的保护作用
组别 | 细胞存活率(%) |
模型组 | 55±2.0 |
A | 79±2.4 |
B | 87±1.3 |
C | 76±2.1 |
D | 85±3.2 |
E | 84±3.0 |
F | 89±3.3 |
G | 70±1.2 |
H | 72±2.3 |
I | 78±2.1 |
J | 80±3.2 |
K | 79±2.0 |
L | 85±1.7 |
M | 76±2.6 |
N | 88±2.3 |
O | 90±2.7 |
P | 78±2.0 |
Q | 80±2.9 |
R | 76±2.3 |
S | 75±2.7 |
T | 81±3.2 |
实施例9:新型益母草碱衍生物对氧化性低密度脂蛋白(ox-LDL)诱导的血管内皮细胞损伤的抑制作用
将血管内皮细胞HUVEC接种于MEM完全培养液,以未加氧化性低密度脂蛋白ox-LDL组为阴性对照,观察化合物对ox-LDL诱导产生血管内皮类粥样损伤的保护作用。具体如下:将HUVEC细胞接种于MEM或者DMEM完全培养液中,置入96孔板中培养,放入恒温细胞培养箱孵育24小时后,加入提前溶解好的含ox-LDL的诱导液,2h后,每孔加入50μM植物黄酮衍生物,以未加ox-LDL组为阴性对照。结束后,采用并采用ELISA检测IL-6炎症因子的含量。
结果如表8表明,与模型组相比,新型植物黄酮衍生物可有效抑制氧化性低密度脂蛋白ox-LDL所刺激的血管内皮细胞中IL-6的增加,表明本发明的新型植物黄酮衍生物适用于制备用于治疗血管内皮细胞损伤相关疾病的药物。
表8:化合物对ox-LDL诱导内皮细胞粥样损伤的抑制结果
组别 | IL-6释放量(pg/L) |
模型组 | 1047±30.5 |
A | 782±30.2 |
B | 831±41.7 |
C | 653±40.5 |
D | 803±28.6 |
E | 831±32.4 |
F | 754±27.5 |
G | 704±27.8 |
H | 815±22.1 |
I | 792±32.3 |
J | 764±27.6 |
K | 837±30.2 |
L | 673±34.5 |
M | 658±23.7 |
N | 741±22.4 |
O | 762±30.2 |
P | 709±25.6 |
Q | 756±33.2 |
R | 721±27.5 |
S | 823±35.6 |
T | 762±32.8 |
以上实施例仅用以说明本发明的技术方案,而非对其进行限制;尽管参照前述实施例对本发明进行了详细的说明,对于本领域的普通技术人员来说,依然可以对前述实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换;而这些修改或替换,并不使相应技术方案的本质脱离本发明所要求保护的技术方案的精神和范围。
Claims (10)
4.如权利要求3所述的新型植物黄酮衍生物的制备方法,其特征在于,所述制备方法包括以下步骤:
将MOM羟基保护的2-甲氧基苯乙酮的衍生物X与苯甲醛的衍生物Y混合后,在碱催化下进行亲核加成,利用克莱森-斯密特法生成查耳酮后,经分子内环合,在酸性条件下脱除保护基团,得到新型植物黄酮衍生物A、B、C、D、E、F、G、H、I;
或者将MOM羟基保护的2-羟苯乙酮的衍生物Z与苯甲醛的衍生物Y混合后,加入吡咯烷反应完全后脱除保护基团,萃取、洗涤干燥和浓缩后,纯化后得到新型植物黄酮衍生物J、K、L、M、N、O、P、Q、R、S、T;
所述衍生物X的结构为:
所述衍生物Y的结构为:
所述衍生物Z的结构为:
5.权利要求1-3任一项所述的新型植物黄酮衍生物在用于制备磷酸二酯酶PDEs和/或TNF-α抑制剂中的应用。
6.权利要求1-3任一项所述的新型植物黄酮衍生物在用于制备防治炎症性和/或过敏性疾病的药物中的应用。
7.根据权利要求6所述的所述的新型植物黄酮衍生物在用于制备防治炎症性和/或过敏性疾病的药物中的应用,其特征在于,所述新型植物黄酮衍生物能够通过有效抑制磷酸二酯酶PDEs的活性、抑制TNF-α的释放、抑制中性白细胞和嗜酸性细胞的增加来减轻炎症性和/或过敏性疾病的症状。
8.权利要求1-3任一项所述的新型植物黄酮衍生物在用于制备防治神经系统和/或心血管系统疾病的药物中的应用。
9.根据权利要求8所述的新型植物黄酮衍生物在用于制备防治神经系统和/或心血管系统疾病的药物中的应用,其特征在于,所述新型植物黄酮衍生物能够通过有效抑制Aβ聚集体和/或CoCl2诱导的神经细胞和/或心肌细胞损伤、或者有效逆转氧化低密度脂蛋白ox-LDL诱导的血管内皮细胞损伤,进而达到保护神经细胞或心血管细胞的作用。
10.根据权利要求6所述的新型植物黄酮衍生物在用于制备防治炎症性和/或过敏性疾病的药物中的应用、或者权利要求8所述的新型植物黄酮衍生物在用于制备防治神经系统和/或心血管系统疾病的药物中的应用,其特征在于,所述的药物为片剂、口服液、气雾剂、丸剂、胶囊剂、颗粒剂、膏剂、滴丸剂、糖浆剂、散剂、冲剂、酊剂、粉针剂或注射液。
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