CN111568894A - 2-(乙基氨甲基)-5-(苯基)呋喃在制备用于抑制tlr7/8的药物中的用途 - Google Patents
2-(乙基氨甲基)-5-(苯基)呋喃在制备用于抑制tlr7/8的药物中的用途 Download PDFInfo
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- CN111568894A CN111568894A CN202010418422.6A CN202010418422A CN111568894A CN 111568894 A CN111568894 A CN 111568894A CN 202010418422 A CN202010418422 A CN 202010418422A CN 111568894 A CN111568894 A CN 111568894A
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- tlr7
- ethylaminomethyl
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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Abstract
Description
技术领域
本发明涉及一种TLRs受体抑制剂,特别是关于一种2-(取代乙基氨甲基)-5-(取代苯基)呋喃化合物或其药用盐在制备用于抑制TLR7/8的药物中的用途。
背景技术
TLRs(Toll-like receptors)受体是白介素受体(IL-1R)超家族成员,主要在先天免疫***中发挥作用,是一类单一的、跨膜的、非催化性的受体,识别来源于微生物的结构特异分子。其中,TLR7不仅识别具有抗病毒抗肿瘤作用的小分子化合物如咪唑喹啉类似物,而且识别病毒ssRNA,激活MyD88信号通路,活化免疫细胞,促进下游的IFN、TNF-α、IL-12等细胞因子的表达,从而介导机体免疫调节以及对肿瘤细胞的调控。TLR7激动剂可以激活先天的和细胞调节的免疫通路。但是,通过TLR7激活内源免疫***是胰岛素耐受、糖尿病和动脉粥样硬化发病机理原因之一。
高血糖是肿瘤和肿瘤治疗的一个主要副反应,高血糖情况的发生与否和糖尿病无关。葡萄糖是肿瘤细胞唯一的能量来源。高血糖状态可作为营养基而促进肿瘤细胞的生长,使肿瘤细胞有更充足的能量来完成快速增殖。高血糖会导致一系列不良结果,如感染和非恶性肿瘤相关的死亡。高血糖会增加临床毒性、中性粒细胞减少、中性粒细胞减少性发热、败血症和神经病变的风险。肿瘤治疗过程中的高血糖也是导致化疗疗效延迟的临床毒性之一,降低患者对化疗药物的反应。
高血糖反过来可以激活TLR通路。长期的高血糖与炎症(高NO水平)和氧化应激相关。高血糖导致的神经炎症状态激活NF-κB通路,进而激活小胶质细胞和星形胶质细胞,从而导致大脑相关的神经病理反应。
因此,TLR激活NF-κB通路带来的副作用以及其与高血糖、炎症的关系促进了TLR抑制剂的进一步研究。
公开于该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解,而不应当被视为承认或以任何形式暗示该信息构成已为本领域一般技术人员所公知的现有技术。
发明内容
本发明的目的在于提供2-(取代乙基氨甲基)-5-(取代苯基)呋喃化合物或其药用盐在制备用于抑制TLR7/8的药物中的用途,其能够解决现有TLR激动剂具有副作用的问题。
为实现上述目的,本发明提供了2-(取代乙基氨甲基)-5-(取代苯基)呋喃化合物或其药用盐在制备用于抑制TLR7/8的药物中的用途,所述2-(取代乙基氨甲基)-5-(取代苯基)呋喃化合物如下式I所示:
其中,R1选自如下取代基的任意一种:
R2选自如下取代基的任意一种或多种:
在一优选的实施方式中,上述药物用于体外抗炎、抑制MyD88通路、抑制NF-κB通路。
在一优选的实施方式中,上述药物用于治疗和/或预防炎症、高血糖。
在一优选的实施方式中,上述高血糖是肿瘤治疗所致高血糖。
在一优选的实施方式中,上述药用盐包括但不限于碳酸盐、盐酸盐、硫酸盐、亚硫酸盐、马来酸盐、琥珀酸盐、氢溴酸盐、硝酸盐、磷酸盐、偏磷酸盐、高氯酸盐以及甲酸盐、乙酸盐、丙酸盐、丙二酸盐、丙烯酸盐、丁二酸盐、草酸盐、D或L苹果酸盐、富马酸盐、苯甲酸盐、羟基丁酸盐、邻苯二甲酸盐、甲磺酸盐、乙磺酸盐、磺酸盐、水杨酸盐、酒石酸盐、柠檬酸盐、乳酸盐、扁桃酸盐的一种或多种。
在一优选的实施方式中,上述R1选自如下取代基的任意一种:
在一优选的实施方式中,上述R2选自如下取代基的任意一种:
在一优选的实施方式中,上述式I的化合物是如下式1的化合物:
在一优选的实施方式中,上述式I的化合物是如下式2的化合物:
与现有技术相比,根据本发明具有如下有益效果:
(1)化合物1和化合物2基本都与Asp555,Thr586形成氢键,但是与TLR7/8激动剂不同的是氢键强度没有R848(resiquimod,雷西莫特)等激动剂强;另外,从TLR7/8抑制剂分子化合物1和化合物2的结合方向来看,与TLR7/8激动剂的结合模式差异明显,TLR7/8抑制剂分子化合物1和化合物2几乎都是在X轴向上与TLR7/8蛋白结合,多与相邻的2-3个TLR7/8的loop形成相互作用,像cap结合模式一样,牢牢扣在first-site位置上,如此形成了一个比较保守体系结构,对于两个TLR7/8叠在一起的dimer体系就很难形成。
(2)本发明抑制剂的测试原理为先加抑制剂培育细胞,然后加激动剂,再测试激动效果,如果无激动效果,则表明有抑制活性。CL097的激动效果为100%,化合物1或化合物2的TLR7/8激动效果百分比较低,说明2-(取代乙基氨甲基)-5-(取代苯基)呋喃化合物或其药用盐具有TLR7/8抑制剂效果,效果优于TLR7/8激动剂CL097,并且通过抑制TLR7/8可阻断肿瘤治疗所致高血糖及其带来的不良后果,如感染和非恶性肿瘤相关的死亡。同时,化合物1和化合物2的细胞增值率均>80%,说明2-(取代乙基氨甲基)-5-(取代苯基)呋喃化合物或其药用盐细胞毒性较低,不影响细胞正常生长。
(3)本发明用LPS刺激细胞产生炎性,然后加入抗炎化合物,再测定NO浓度,最后确定抗炎效果。化合物1的抗炎效果优于吲哚美辛,其细胞增值率高于阴性对照,说明2-(取代乙基氨甲基)-5-(取代苯基)呋喃化合物或其药用盐有较好的抗炎活性和较低的细胞毒性,可通过抑制TLR7/8来阻断NF-κB,从而抑制促炎性基因的表达,进而达到治疗炎症的目的。
总之,式I的2-(取代乙基氨甲基)-5-(取代苯基)呋喃化合物或其药用盐具有TLR7/8抑制活性,细胞毒性低,不具有现有TLR激动剂的副作用,在能够治疗炎症和高血糖的同时,不影响细胞的正常生长。
附图说明
图1是化合物1、化合物2和对照化合物TLR7/8激活剂对HEK293细胞中TLR7/8蛋白的抑制活性的影响及通过CCK-8测定的细胞增值率。
图2是化合物1与TLR7/8蛋白分子对接示意图。
图3是化合物2与TLR7/8蛋白分子对接示意图。
图4是化合物1、化合物2和对照抗炎化合物吲哚美辛对NO抑制活性的影响。
具体实施方式
下面结合附图,对本发明的具体实施方式进行详细描述,但应当理解本发明的保护范围并不受具体实施方式的限制。
根据计算机辅助药物设计,第一轮进行虚拟筛选,第二轮进行成药性经验评估,第三轮进行合成可行性评估,第四轮外购先导化合物1和化合物2,最后对化合物1和化合物2进行进行药理实验确证。
实施例1
化合物1、化合物2和对照化合物TLR7/8激活剂对HEK293细胞中TLR7/8蛋白的抑制活性的影响及通过CCK-8测定的细胞增值率
方案:将HEK-BlueTM-hTLR7细胞(经过人源化TLR7转染的HEK293细胞,购于InvivoGen公司)接种于96孔板中,密度为4×104个/孔,加入激动剂CL097(5μM)和待测化合物1或化合物2(40μM)过夜,得到上清液。所得上清液用移液枪吸取,将上清液(20μL)采用Quanti-blue(OD 630nm)测试,残留液用CCK-8测试细胞增殖率。如果细胞增值率高说明对细胞毒性小,细胞能够正常生长。
Index of Quanti-Blue value=(A-B)/(C-B);其中A:待测孔平均值;B:含细胞基质平均值;C:阳性对照(CL097)。
操作步骤:
①将HEK293系的HEK-TLR7/8细胞株种于96孔板,4×104个/孔/100μL。加入待测化合物1或待测化合物2(40μM,100μL),37℃,5%CO2,过夜;
50mL培养基DMEM:FBS(10%)5mL,PS(100×)500μL,Normocin(0.01%)100μL,L-谷氨酰胺500μL,Zeocin(100mg/mL)50μL,Blastin(10mg/mL)50μL。
②次日,取上清液20μL加QUANTI-Blue至200μL,显色(630nm)。
③原96孔板中加入TLR7/8激动剂CL097(购于InvivoGen公司),5μM/孔;次日,取上清液20μL加QUANTI-Blue至200μL,显色(630nm)。
④残留液中加入10μL试剂CCK-8,检测(450nm)细胞增殖率,计算公式如下:
本实施例原理是:通过测定TLR7/8激动剂活性来测试化合物1和化合物2的抑制效果。如果TLR7/8被抑制了,其下游的激动活性就会减弱。
在图1中,纵坐标代表细胞增殖率和TLR7/8抑制效果,TLR7/8抑制效果越好,柱状图越低。由图1可知,阳性对照CL097的激动效果为100%,化合物1或化合物2的TLR7/8激动效果百分比较低,说明这两种化合物具有TLR7/8抑制剂效果,效果优于TLR7/8激动剂CL097。另外,化合物1的抑制效果优于化合物2。同时测定化合物1和化合物2的细胞增殖效果,以检测化合物1和化合物2的细胞毒性。化合物1和化合物2的细胞增值率均>80%,说明这两种化合物细胞毒性较低,不影响细胞正常生长。化合物1和化合物2通过抑制TLR7/8可阻断肿瘤治疗所致高血糖,如感染和非恶性肿瘤相关的死亡。
结合图2和图3进行分子对接说明。对于TLR7/8抑制剂分子化合物1和化合物2,从结合模式来看,目标抑制剂均能与TLR7/8稳定结合。化合物1和化合物2基本都与Asp555,Thr586形成氢键,但是与TLR7/8激动剂不同的是氢键强度没有R848等激动剂强;另外,从TLR7/8抑制剂分子化合物1和化合物2的结合方向来看,与TLR7/8激动剂的结合模式差异明显,TLR7/8抑制剂分子化合物1和化合物2几乎都是在X轴向上与TLR7/8蛋白结合,多与相邻的2-3个TLR7/8的loop形成相互作用,像cap结合模式一样,牢牢扣在first-site位置上,如此形成了一个比较保守体系结构,对于两个TLR7/8叠在一起的dimer体系就很难形成。
实施例2
化合物1/化合物2的NO活性测试及细胞存活实验
方案:RAW264.7细胞接种于96孔板中,密度为4×104个/孔,1.5h后加入化合物1、化合物2或吲哚美辛(40μM)和脂多糖(LPS)(1μg/mL,10μL/孔)。24h后,NO浓度由Griess试剂测试(540nm);细胞增长由MTT测试(200μL,0.5mg/mL,450nm)。
操作步骤:
①将RAW264.7细胞培养于DMEM培养基中(10%FBS+1%青霉素/链霉素)、37℃、5%CO2;待细胞生长稳定后接种于96孔板(5×104个/孔),过夜。
②加入化合物(40μM,100μL)后加入LPS(1μg/mL,10μL/孔)。
③次日取细胞上清液50μL用Griess试剂盒(一氧化氮试剂盒,购于碧云天生物技术有限公司)同时绘制标准曲线。
④弃去上清液,加MTT[3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐]200μL(0.5mg/mL),4h后细胞变黑,吸去上清液,残留物加150μL的DMSO振摇15min溶解,分别在450、490、520、570nm下检测化合物1、化合物2和抗炎化合物吲哚美辛对NO的抑制率。计算公式如下:
本实施例测定原理为:用LPS刺激细胞产生炎性,然后加入抗炎化合物,再测定NO浓度,最后确定抗炎效果。吲哚美辛是公认的抗炎化合物,也是常用的抗炎阳性对照。图2为NO抗炎活性和细胞增殖率,其中纵坐标代表细胞增殖率和NO抑制率,抗炎效果越好,柱状形状越高。由图2可知,本例中化合物1的抗炎效果优于吲哚美辛,其细胞增值率高于阴性对照,说明化合物1有较好的抗炎活性和较低的细胞毒性。
TLR清理病原时会产生有毒的炎性介质,其产量过多会出现许多副作用。化合物1和化合物2可通过抑制TLR7/8来阻断NF-κB,从而抑制促炎性基因的表达,进而达到治疗炎症的目的。
前述对本发明的具体示例性实施方案的描述是为了说明和例证的目的。这些描述并非想将本发明限定为所公开的精确形式,并且很显然,根据上述教导,可以进行很多改变和变化。对示例性实施例进行选择和描述的目的在于解释本发明的特定原理及其实际应用,从而使得本领域的技术人员能够实现并利用本发明的各种不同的示例性实施方案以及各种不同的选择和改变。本发明的范围意在由权利要求书及其等同形式所限定。
Claims (9)
2.根据权利要求1所述的用途,其特征在于,所述药物用于体外抗炎、抑制MyD88通路、抑制NF-κB通路。
3.根据权利要求1所述的用途,其特征在于,所述药物用于治疗和/或预防炎症、高血糖。
4.根据权利要求3所述的用途,其特征在于,所述高血糖是肿瘤治疗所致高血糖。
5.根据权利要求1所述的用途,其特征在于,所述药用盐包括但不限于碳酸盐、盐酸盐、硫酸盐、亚硫酸盐、马来酸盐、琥珀酸盐、氢溴酸盐、硝酸盐、磷酸盐、偏磷酸盐、高氯酸盐、甲酸盐、乙酸盐、丙酸盐、丙二酸盐、丙烯酸盐、丁二酸盐、草酸盐、D或L苹果酸盐、富马酸盐、苯甲酸盐、羟基丁酸盐、邻苯二甲酸盐、甲磺酸盐、乙磺酸盐、磺酸盐、水杨酸盐、酒石酸盐、柠檬酸盐、乳酸盐、扁桃酸盐的一种或多种。
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