CN101327214A - 异喹啉生物碱类作为组织因子抑制剂的医药用途 - Google Patents
异喹啉生物碱类作为组织因子抑制剂的医药用途 Download PDFInfo
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- CN101327214A CN101327214A CNA2008100220928A CN200810022092A CN101327214A CN 101327214 A CN101327214 A CN 101327214A CN A2008100220928 A CNA2008100220928 A CN A2008100220928A CN 200810022092 A CN200810022092 A CN 200810022092A CN 101327214 A CN101327214 A CN 101327214A
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Abstract
本发明涉及医药技术领域，具体涉及异喹啉生物碱的医药用途，其可用于制备治疗或预防与组织因子相关的疾病的药物，用于预防和治疗人类由组织因子影响的疾病，包括心脑血管疾病、凝血障碍、败血症、侵入性医疗程序相关的再狭窄、动脉粥样硬化、肿瘤转移及糖尿病及其相关心血管并发症。
Description
技术领域
本发明涉及医药技术领域，具体涉及一类异喹啉生物碱作为组织因子(TF)抑制剂的医药用途。
发明内容
组织因子(tissue factor，TF)，即凝血因子III，又称为促凝血激酶或凝血致活酶(CD142)，为263个氨基酸组成的单链跨膜糖蛋白，属于细胞因子超家族成员。TF既是凝血因子VII在细胞表面的受体，又是FVII或激活的因子VII(F VIIa)的辅因子，是唯一存在于正常人血浆以外的细胞和组织中的凝血因子。
现代研究表明，TF和FVIIa复合物是凝血的最重要的启动因子，该复合物启动了凝血级联反应：当血管受损后，血液暴露于能表达TF的细胞表面，随后TF与其配体FVII或FVIIa形成复合物，进而激活凝血因子X和凝血因子IX，同时启动外源性和内源性凝血系统；激活的FXa和FIXa进一步激活凝血酶原(FII)成为FIIa，FIIa又使纤维蛋白原变成纤维蛋白，进而与激活的血小板形成凝块(Semeraro N，Colucci M.Tissue factor in health and disease.ThrombHaemost.1997；78：759-64)。
在病理状态下，例如动脉粥样硬化或微血管移植、血管造形术、部署植入装置(例如移植模、导管或动静脉分流器)或动脉内切开术的类侵入性外科程序后，TF引起的凝血可能引发血栓形成而导致各种心血管疾病诸如：心脏病发作、中风、不稳定性心绞痛、移植片衰竭或其他冠状动脉疾病。血栓形成同时亦可能并发各种血栓栓塞障碍及凝塞，分别例如肺栓塞(例如心房纤维颤动及栓塞、深度静脉血栓形成等)及扩散性血管内凝血。体液操作亦可能引起不良性血栓，特别是在输血或体液抽样及涉及体外循环(例如心肺迂回补助外科手术)及透析过程中。而目前，心血管疾病是现代社会最普遍的致死因素，因而寻找抗凝、抗血栓药物将会对上述心血管疾病的预防和治疗产生深远的意义并具有很好的应用前景。
有些抗凝血剂被用以减轻或避免与血栓形成有关的血凝块的形成。它包含使用一种或多种香豆素衍生物(如华发令(warfin)及二香豆醇)或带电聚合物(如肝磷脂，水蛭素或水蛭素类(hirulog))。有些具有抗血小板活性的抗体亦可用以减轻各种血栓形成。然而，使用先前的这些抗凝剂经常会并发一些副作用例如：出血、血栓形成复发、[白血块]症候群、过敏、新生儿缺陷、血小板减少及肝功能障碍。特别是长期给予抗凝剂可能提高患致命性疾病的危险性。蛋白质药剂在本质上较为安全，但一般限于用在急性症状的处理上，且给药常限于非肠道，此类药剂一般认为较不适合用于慢性疾病(例如动脉粥样硬化，即心脏病发作的主因)的长期治疗。因此急需新式抗凝血药剂，特别是可长期给药以治疗慢性疾病如动脉粥样硬化的新式抗凝血药剂。
最近的研究表明，TF和FVIIa复合物的抑制剂能有效的抗凝，同时和其他抗凝药相比又减少了出血的危险(Suleymanov OD等人，Pharmacological Interruption of Acute Thrombus Formationwith Minimal Hemorrhagic Complications by a Small Molecule Tissue Factor/Factor VIIa Inhibitor：Comparisonto Factor Xa and Thrombin Inhibition in a Nonhuman Primate Thrombosis Model.J.Pharmacol.Exp.Ther.2003；306：1115-21)，因此，TF或TF/FVII(a)复合物的抑制剂已经成为抗凝、抗血栓药物发展的一个新靶点！TF或TF/FVII(a)复合物的抑制剂也有望成为新式的抗凝血药剂，用于病理性血栓的预防和治疗。
同时，随着对TF作用的了解加深，除了其在凝血过程中的作用，TF还承担了信号受体和其他非凝血功能。这使得它在系统性炎症、凝血紊乱、动脉粥样硬化、肿瘤的血管发生及转移，糖尿病等疾病中起重要作用。TF的非凝血功能中，与肿瘤生长、侵袭、转移的关系甚为引人注目，它在恶性黑色素瘤、胰腺癌、乳腺癌、肺癌、结肠癌等多种肿瘤细胞及肿瘤血管内皮细胞表面的表达均异常增高，近年来国外临床观察及体内、体外实验均证实F VIIa/TF复合物具有促进肿瘤生长、侵袭、转移的作用。另外，有研究报道，TF是在人朗格罕胰岛中表达的，在大部分的胰岛内分泌细胞中发现了TF(“胰岛产生TF”)，这一发现表明TF的分泌和胰岛素的分泌存在着一定的联系。这种TF很有可能与II型糖尿病或其前期患者患动脉粥样硬化和心血管疾病的高发病率有关。因此，抑制TF的活性或合成的抑制剂可以用来预防这些患者患心血管疾病的危险。
TF的生物学作用多样性已经得到证实，TF的异常表达可能影响多种疾病的病理过程，干预TF的表达可能为多种疾病的治疗、预防提供新的策略。因此，TF或TF/FVII(a)复合物抑制剂将成为抗凝、抗血栓、抗肿瘤等药物发现的一个很有吸引力的新靶点，已成为当前倍受国内外关注的研究热点(Steffel J，Thomas F，Felix C.Tissue Factor in Cardiovascular Diseases：Molecular Mechanisms and Clinical Implications.Circulation.2006；113：722-31)。
中医、中药是中华民族几千年来与疾病作斗争的经验总结，中药有效成分是中草药发挥功效的物质基础。我国中药资源丰富，中药有效成分众多，很多成分都具有很好的生物活性，并已广泛用于临床，例如青蒿素、石杉碱甲等。利用中草药活性成分寻找新药是我国新药研发的特色和公认的捷径之一。
发明内容
本发明公开了一类异喹啉生物碱用作TF抑制剂的用途，其可用于制备治疗或预防与组织因子相关的疾病的药物。发明人从天然化合物中筛选出活性强的异喹啉生物碱类的TF抑制剂，这些天然化合物多数IC50＜0.1μM，为心血管疾病和肿瘤疾病的治疗提供新的治疗策略和候选的先导化合物或可能的治疗药物。
本发明所述的异喹啉生物碱优选下列结构的化合物：
其中R1、R2、R3或R4各自独立地代表OCH3、OH或-O-CH2-O。
更优选下列化合物：
紫堇达明(R，S)：R1＝R2＝OCH3，R3＝OCH3，R4＝OH；
四氢小檗碱：R1＝R2＝O-CH2-O，R3＝OCH3，R4＝OCH3；
延胡索乙素(dl-四氢巴马汀)：R1＝R2＝R3＝R4＝OCH3；
罗通定(l-四氢巴马汀)：R1＝R2＝R3＝R4＝OCH3
药根碱：R1＝OCH3，R2＝OH，R3＝R4＝OCH3；
小檗碱：R1＝R2＝O-CH2-O，R3＝OCH3，R4＝OCH3；
小檗红碱：R1＝R2＝OCH3，R3＝OH，R4＝OCH3；
巴马汀：R1＝R2＝R3＝R4＝OCH3
氯仿小檗碱：R1，R2＝O-CH2-O，R3＝OCH3，R4＝OCH3，R＝CCl3
丙酮小檗碱：R1，R2＝O-CH2-O，R3＝OCH3，R4＝OCH3，R＝CH2COCH3
本发明以组织因子为靶点，从天然或合成的化合物中筛选有效的TF抑制剂。采用人血管内皮细胞株(ECV304)及人外周血单核细胞，经炎症因子如肿瘤坏死因子(TNF)或细菌脂多糖(LPS)刺激表达TF，加入一定剂量的天然化合物与细胞共培养一定时间后，采用发色底物法，考察这些化合物对TF促凝活性的影响。
本发明优选的化合物可用于预防和治疗人类由组织因子影响的疾病，包括心脑血管疾病、凝血障碍、败血症、侵入性医疗程序相关的再狭窄、动脉粥样硬化、肿瘤转移及糖尿病及其相关心血管并发症。
下面是药理试验及结果
1.人外周血单核细胞的分离及培养
根据文献报道(Annu K，Konald S.Induction of monocyte tissue factor expression by homo-cysteine：apossible mechanism for thrombosis.Blood.2000；96(3)：966-70)，采用Ficoll-Hypaque分离液(密度1.077)，密度梯度离心法分离单个核细胞(PBMC)。
2.细胞株
ECV304细胞株，购自中国科学院细胞库。ECV304细胞复苏、传代后，反复吹打成细胞悬液，以含10％新生牛血清的RPMI 1640培养基稀释成1.5×105个.ml-1，每孔100μl接种于96孔培养板中，在37℃，5％CO2条件下培养24h，成融合状态。
3.刺激表达组织因子(TF)
实验分为三组：①空白对照组：加入90μl的0.1％DMSO溶液(溶媒)及10μl PBS或培养基；②模型组：加入90μl的0.1％DMSO溶液(溶媒)及10μl脂多糖LPS(终浓度为100ng/ml)或肿瘤坏死因子TNF-α(终浓度为20ng/ml)孵育5小时，以刺激TF的表达；③给药组：先加入90μl不同浓度药物(溶媒为0.1％DMSO)作用1小时，再加入10μl LPS(100ng/ml)或TNFα(20ng/ml)，共同孵育5小时。
各种待测药物先溶于纯DMSO中，配成浓度为100mmol.L-1的高浓度母液，然后在临用前以RPMI 1640培养基稀释到所需浓度，DMSO的最终体积分数均为0.1％。
4.TF活性的测定
本发明设计采用发色底物法(即采用商品化的人凝血酶原复合物，作为因子VII、X的来源)进行组织因子抑制剂的筛选。其原理是根据TF-FVII a复合物活化的FXa可以使发色底物(chromogenic substrate)分解为多肽和对硝基苯胺(pNA)，后者在405nm处有吸收高峰，用分光光度计或酶标仪测定405nm处的OD值，该值能反映TF的活性水平。该方法灵敏、简单、快速，是国际上公认的测定TF活性的方法。而改进的发色底物法(即采用商品化的人凝血酶原复合物，作为因子VII、X的来源)，降低了成本，简化了步骤，更适于实验室进行高通量筛选。
药物先与细胞孵育1小时，然后加入LPS或TNF与细胞共孵育5小时后，将细胞板内培养基吸去，用无血清培养基洗1次，再在每孔中加入无血清培养基100μl(96孔细胞培养板)，-70℃至室温反复冻融3次，使细胞裂解，将裂解液吹打均匀，吸取45μl细胞裂解液(每孔可吸两次)接种于另一块新的96孔板中，37℃温育5min，每孔加入5μl新鲜配制的人凝血酶原复合物溶液(PPSB，华兰生物工程股份公司，中国，含100mM的CaCL2)，37℃温育15min，再加入50μl新鲜配制的凝血因子Xa的发色底物溶液(Sigma，USA)(含100mM EDTA)，温育3min，用酶标仪以405nm测定吸光度。
5.统计处理
所有数据采用平均值±标准差表示，对各组数据比较采用t检验，P＜0.05认为有统计学意义，并计算有效化合物的IC50值。
6.实验结果
6.1部分异喹啉类生物碱对脂多糖诱导的人外周血单核细胞TF表达的影响
脂多糖LPS(终浓度为100ng/ml)作用于人外周血单核细胞5h，能显著增加TF的表达；小檗碱、药根碱、紫堇达明、延胡索乙素、四氢小檗碱、氯仿小檗碱，丙酮小檗碱等在一定浓度范围内能剂量依赖的抑制LPS诱导的人外周血单核细胞TF表达，结果见表1。
6.2部分异喹啉类生物碱对肿瘤坏死因子诱导的人外周血单核细胞TF表达的影响
肿瘤坏死因子TNF-α(终浓度为20ng/ml)作用于人外周血单核细胞5h，能显著增加TF的表达；罗通定(左旋四氢巴马汀)、小檗红碱或巴马汀在一定浓度范围内能剂量依赖的抑制TNF诱导的人外周血单核细胞TF表达，结果见表1。
6.3部分异喹啉类生物碱对肿瘤坏死因子诱导的内皮细胞株(ECV304)TF表达的抑制作用
实验结果表明，TNF-α(终浓度为20ng/ml)作用于ECV304内皮细胞株5个小时后，能显著增加TF的表达；小檗碱、药根碱、紫堇达明、延胡索乙素在一定浓度范围内也能剂量依赖性的抑制TNF诱导的ECV304细胞TF的表达，结果见表3。
表1：异喹啉生物碱类化合物对LPS诱导的人外周血单核细胞TF表达的影响
(x±SD，n＝6)
##P＜0.01vs空白对照组；*P＜0.05，**P＜0.01vs模型组
表2：部分生物碱类化合物对TNF诱导的人外周血单核细胞TF表达的影响
(x±SD，n＝6)
##P＜0.01vs空白对照组；*P＜0.05vs模型组
表3：部分生物碱类化合物对TNF诱导的ECV304细胞的TF表达的影响(x±SD，n＝6)
##P＜0.01vs空白对照组；*P＜0.05，**P＜0.01vs模型组
综上所述，本发明从一些中药有效成分中筛选到小檗碱(IC50＝0.025μM)、药根碱(IC50＝0.027μM)、紫堇达明(IC50＝0.032μM)、延胡索乙素(IC50＝0.197μM)、罗通定(IC50＝3.75×10-5μM)、小檗红碱((IC50＝0.60μM)、巴马汀(IC50＝3.86×10-3μM)、氯仿小檗碱(IC50＝4×10-3μM)、丙酮小檗碱(IC50＝4.6×10-5μM)等异喹啉类生物碱具有较强的抑制TF表达的活性，
Claims (8)
1、异喹啉生物碱用于制备治疗或预防与组织因子相关疾病的药物的用途。
2、权利要求1的用途，其中异喹啉生物碱是具有式(I)、式(II)或式(III)任一结构的化合物：
其中R1、R2、R3或R4各自独立地代表OCH3、OH或-O-CH2-O。
3、权利要求2的用途，其中异喹啉生物碱是紫堇达明、四氢小檗碱、延胡索乙素或罗通定。
4、权利要求2的用途，其中异喹啉生物碱是药根碱、小檗碱、小檗红碱或巴马汀。
5、权利要求2的用途，其中异喹啉生物碱是氯仿小檗碱或丙酮小檗碱。
6、权利要求1的用途，其中与组织因子相关疾病是心脑血管疾病、凝血障碍、败血症、侵入性医疗程序、肿瘤转移、糖尿病或其相关心血管疾病并发症。
7、权利要求6的用途，其中心脑血管疾病是心脏病发作、心绞痛、动脉粥样硬化、中风、肺栓塞、深度静脉血栓形成或冠状动脉疾病。
8、权利要求6中的疾病，其中所述的侵入性医疗程序为：血管成形术、动脉内切开术、应用移植模、导管的使用、移植片的植入或动静脉分流器的使用。
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