CN115068451A - 竹红菌素类化合物作为ltb4受体抑制剂的医药用途 - Google Patents
竹红菌素类化合物作为ltb4受体抑制剂的医药用途 Download PDFInfo
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Abstract
本发明属于医药技术领域，公开了竹红菌素类化合物在制备LTB4受体抑制剂中的应用。本发明对竹红菌素类化合物(竹红菌甲素，Hypocrellin A；竹红菌乙素，Hypocrellin B)进行了作用靶标研究，发现其在LTB4R抑制剂模型中具有显著抑制作用，因此本发明公开了竹红菌素类化合物及其药学上可接受的盐和药物组合物在制备LTB4受体抑制剂中的应用，以及在制备治疗肥胖、胰岛素抵抗、糖耐量异常，高血脂，糖尿病及其并发症等疾病药物中的应用，其中糖尿病并发症包括糖尿病肾病、糖尿病心血管并发症、糖尿病性脑血管病、糖尿病眼部并发症和糖尿病足。
Description
技术领域
本发明属于医药技术领域，涉及从中药竹黄分离纯化竹红菌素类化合物(竹红菌甲素，Hypocrellin A；竹红菌乙素，Hypocrellin B)的方法，竹红菌素类化合物(竹红菌甲素，Hypocrellin A；竹红菌乙素，Hypocrellin B)及其药学上可接受的盐和药物组合物在制备预防或治疗肥胖、胰岛素抵抗、糖耐量异常，高血脂，糖尿病及其并发症等疾病药物中的应用；糖尿病并发症包括糖尿病肾病、糖尿病心血管并发症、糖尿病性脑血管病、糖尿病眼部并发症和糖尿病足。
背景技术
糖尿病是以慢性高血糖为主要特征的一组内分泌代谢性疾病，可能导致身体各部位的并发症并会提升过早死亡的风险。近年来，随着我国经济的高速发展，人口社会的老龄化、环境污染、不良的生活方式以及过高的精神压力等因素的影响，糖尿病在我国日益恶化。糖尿病几乎无法完全治愈，其并发症会给患者带来生理伤害，精神痛苦，生活质量下降等，并且高昂持续的医疗费用会为患者及其家庭带来巨大经济负担。因此，糖尿病治疗研究迫在眉睫。
糖耐量异常(IGT)和空腹血糖受损(IFG)指血糖水平高于正常范围但还不到诊断标准，统称为糖调节受损，通常也被称为糖尿病前期。出现IGT和IFG的警示意义在于三方面：(1)发展为2型糖尿病的高风险；(2)心血管疾病风险增加；(3)提醒通过干预措施预防疾病发展。从IGT和IFG发展为2型糖尿病的风险受到年龄、体重等因素的影响，诊断IGT或IFG五年后发展为2型糖尿病的累积发生率分别约为26％和50％。肥胖、体力活动较少、血脂增高以及有糖尿病家族史和高胰岛素血症者，多为诱发糖耐量减低的危险因素。
所有2型糖尿病患者，几乎都要经过糖耐量减低这个阶段，故有人把糖耐量减低者视为糖尿病发病的高危人群，或者称“糖尿病前期”。糖耐量减低往往还同时伴有肥胖、高血压、高脂血症等情况。糖耐量异常者与正常人群比较，高血压、肥胖患病率要高2倍，而冠心病患病率则高8倍之多。
遏制糖尿病，须从防治糖耐量异常(IGT)着手。生活方式的改变包括饮食控制、运动增加、体重减轻、戒烟等是最基本的干预措施。相关研究报道，IGT者经过生活方式干预，3年后糖尿病发病率降低了58％，同时血压、体重较前亦明显下降，而未经任何干预措施的IGT者糖尿病发病率高达68％。最近对IGT人群的干预试验表明，药物干预IGT人群不仅显著降低糖尿病发病率，还可明显减少脑血管疾病(Cerebrovascular Disease，CVD)的危险性，其中新发生高血压降低34％，心肌梗死降低9％，任何心血管事件降低49％。因此，IGT患者诊断明确后，应主动就医，医生会根据病情选择恰当的治疗方案及药物，积极治疗高血糖及相关危险因素。
因此,早期采取针对性的IGT干预措施，有助于逆转IGT，降低IGT进展为糖尿病的风险，减少CVD的发生。
临床上将糖尿病主要分为3种类型：1型、2型及妊娠糖尿病，其中2型糖尿病最为常见，约占85％-95％，甚至更高。2型糖尿病的主要特征是胰岛素抵抗。胰岛素抵抗是肝脏、肌肉和脂肪组织等周围靶组织细胞对胰岛素的敏感性降低导致葡萄糖摄取和利用效率下降而产生的一种慢性亚临床性的炎症过程。细胞内的炎症因子，分泌各种可能削弱胰岛素信号的因素，使胰岛素信号的传导受到阻碍，诱发了胰岛素抵抗。2型糖尿病患者炎症因子和胰岛素抵抗脂联素水平的实验研究表明，2型糖尿病患者存在慢性炎症状态。因此，改善炎症诱导的胰岛素抵抗，提高胰岛素敏感性，便成了治疗2型糖尿病患者的重大问题。
炎症因子白三烯B4(LTB4)是一种与炎症反应相关的白三烯类物质，由花生四烯酸经过5-脂氧合酶，5-脂氧合酶激活蛋白，白三烯A4水解酶有序催化产生。 LTB4对巨噬细胞，嗜中性粒细胞和T细胞有强效的趋化性。LTB4可以通过活化和募集巨噬细胞，嗜酸性粒细胞，效应T细胞等，促进炎症的发生发展。同时能够诱导中性粒细胞中的溶酶体及活性氧类的形成与释放。
LTB4通过与G蛋白偶联受体Ltb4r1或Ltb4r2结合发挥趋化作用，调节促炎因子释放等生物学功能。Ltb4r1(也称为Blt1)是特异于LTB4的高亲和力受体，在炎症细胞及免疫细胞广泛表达，包括粒细胞，嗜酸性粒细胞，巨噬细胞，Th1 细胞，Th2细胞，Th17细胞，CD8效应T细胞，树突状细胞及破骨细胞等。Ltb4r2 (也称为Blt2)是低亲和力受体，表达更为广泛。LTB4-Ltb4r1系统在宿主急性感染期具有重要防御作用，降低炎症反应。慢性激活LTB4-Ltb4r1系统可以引起慢性炎症，包括动脉粥样硬化和关节炎等。近期一项研究表明，Ltb4r1基因敲除可以降低小鼠的炎症反应，改善胰岛素抵抗。这表明胰岛素敏感的表型是基于Ltb4r1 基因缺失之上的。高胰岛素-正葡萄糖钳夹实验也证实，大多小鼠经Ltb4r1抑制剂处理后表现出更高的胰岛素敏感性。
肥胖是导致胰岛素抵抗的重要因素。流行病学研究亦表明，肥胖是糖尿病的重大危险因素。过度肥胖，巨噬细胞会被过度积累的脂肪激活，激活后的巨噬细胞释放LTB4以及其它炎性分子进而吸引更多的巨噬细胞。这一正向反馈调节机制会产生更多的LTB4。过多的LTB4会激活巨噬细胞以外的其它细胞，像肝细胞，脂肪细胞，肌肉细胞等这些细胞受到刺激从而对胰岛素产生了耐受。在肥胖受试者的内脏脂肪中，巨噬细胞可占总细胞数的40％，并分泌多种可能损害胰岛素信号转导的因子。通过使用巨噬细胞的跟踪技术，发现Ltb4r1抑制剂处理的小鼠巨噬细胞在脂肪组织的标记程度基本上较低。LTB4促进单核细胞迁移入脂肪组织，以剂量依赖的方式刺激巨噬细胞的趋化性，促进胰岛素抵抗。此外，其他免疫细胞类型，如淋巴细胞、嗜酸性粒细胞和中性粒细胞也有助于肥胖组织的炎症状态。这种与细胞因子无关的胰岛素抵抗机制为炎症和胰岛素敏感性降低之间的关系提供了新的机制。
从胰岛素抵抗发生的分子机制来看，能量代谢紊乱、内质网应激、氧化应激、线粒体功能受损、沉默信息调节因子信号通路下调、炎症反应以及中枢调控紊乱等都参与了胰岛素抵抗的发生。胰岛素信号传导通路的障碍作为胰岛素抵抗的本质。葡萄糖转运蛋白4(GLUT4)重要功用是在脂肪和肌肉组织中转送、运输葡萄糖。研究表明，LTB4通过对GLUT4的抑制，导致胰岛素抵抗。LTB4能增强肝二酰甘油(DAG)和神经酰胺的合成，诱导内质网应激和线粒体膜通透性增加，抑制胰岛素信号通路，降低胰岛素敏感性，诱导胰岛素抵抗。同时，DAG增加会提高脂毒性风险，也是导致胰岛素抵抗的重要机制之一。
因此，抑制LTB4的作用有可能成为治疗胰岛素抵抗性疾病的有效方案。
竹黄又名竹赤团子、竹茧、竹参、淡竹黄、竹三七等，是一种我国传统的药用寄生性真菌，为子囊菌亚门，核菌纲(Ascomycotina)球壳目(Sphaeiales)肉座菌科(Hypocreaceae)竹黄属真菌竹黄(sharaia bambusicola P.Henn)的子座，其主要寄主为箭竹和短穗竹植物，短穗竹及其变种毛环短穗竹是其最重要的寄主，其寄生率最高，产量也最大。子座幼嫩时为肉质，呈细长纺锤形，紧贴或围抱嫩杆生长，表面近平滑。成熟时逐渐膨大并渐变为木栓质，粉红色、不规则瘤状。竹黄性味淡温，具活血化瘀、通经活络、震惊、化痰止咳、和补中益气的作用。《本草纲目》中即有记载：“竹黄，又名天竺黄，味甘、寒、无毒，主治小儿惊风、去诸风热、镇心明目、滋养五脏”。民间常用竹黄浸酒服用，用于治疗风湿性关节炎、虚寒胃痛、坐骨神经痛、跌打损伤、气管炎、小儿惊风和急性肝炎等病症。
竹黄化学成分类型多样，其中苝醌类化合物竹红菌素为其特征性化学成分。苝醌类化合物是从子囊菌纲和半知菌类真菌中提取分离的一类新型色素，同时也是光敏活性化合物。苝醌类化合物在肿瘤治疗方面具有广阔的应用前景，目前对竹黄属进行的研究主要集中在苝醌类化合物上。
竹红菌素类化合物是竹黄的代表活性成分，含有多种该类化合物，是一种重要的天然光敏色素。已经从竹黄中已分离得到竹红菌甲素(Hypocrellin A)、竹红菌乙素(Hypocrellin B)等。
竹红菌素类化合物具有较好的镇痛作用，同时可提高坐骨神经干的刺激阈，故具有局麻作用；竹红菌乙素能显著减轻大鼠足趾肿胀程度；小鼠耳肿胀实验中结果表明竹红菌乙素组小鼠的鼠耳肿胀程度普遍低于生理盐水组。
竹红菌甲素对枯草杆菌等革兰氏阳性菌具有很好的抑制作用，但对革兰氏阴性菌没有抑制效果或抑制效果不明显。
在竹红菌乙素对人体细胞膜的光敏损伤研究中发现，光敏损伤的红细胞膜膜蛋白的发生交联，膜脂质过氧化，膜流动性和离子通透性均增加，最终细胞膜功能发生改变，并揭示他们有链的断裂；竹红菌甲素和竹红菌乙素对牛犊胸腺DNA 有光敏损伤作用，其对DNA分子的损伤既表现在链的断裂，还表现在一些氢键的断裂及碱基堆积力的破坏，并且竹红菌乙素的DNA损伤作用强于竹红菌甲素；竹红菌甲素和竹红菌乙素的抗肿瘤作用通过其对人Hce-8693盲肠癌细胞增殖周期的影响及细胞凋亡诱导作用的研究可以表明。竹红菌甲素使细胞阻断于Gl期，使 Gl期峰前出现典型的亚二倍体凋亡峰，进而表明竹红菌甲素具有诱导细胞凋亡及抑制肿瘤细胞增殖的作用。
发明内容
本发明解决的技术问题是提供一类红菌素类化合物(竹红菌甲素，HypocrellinA；竹红菌乙素，Hypocrellin B)及其药学上可接受的盐和药物组合物在制备预防或治疗肥胖、胰岛素抵抗、糖耐量异常，高血脂，糖尿病及其并发症等疾病药物中的应用；其中糖尿病并发症包括糖尿病肾病、糖尿病心血管并发症、糖尿病性脑血管病、糖尿病眼部并发症和糖尿病足。
为解决本发明的技术问题，本发明提供如下技术方案：
本发明技术方案的第一方面是提供了一类竹红菌素类化合物及其药学上可接受的盐在制备LTB4受体抑制剂中的应用，其特征在于，所述的竹红菌素类化合物包括竹红菌甲素Hypocrellin A、竹红菌乙素Hypocrellin B；
本发明技术方案的第二方面是提供了一类竹红菌素类化合物及其药学上可接受的盐在制备预防或治疗肥胖、胰岛素抵抗、糖耐量异常、高血脂、糖尿病及其并发症疾病药物中的应用，其特征在于，所述的竹红菌素类化合物包括竹红菌甲素Hypocrellin A、竹红菌乙素Hypocrellin B；
所述的糖尿病并发症包括糖尿病肾病、糖尿病心血管并发症、糖尿病性脑血管病、糖尿病眼部并发症和糖尿病足。。
本发明技术方案的第三方面是提供了一种药物组合物在制备LTB4受体抑制剂中的应用，其特征在于，所述的药物组合物包括有效剂量的竹红菌素类化合物或药学上可接受的载体或赋形剂；所述的竹红菌素类化合物包括竹红菌甲素 Hypocrellin A、竹红菌乙素Hypocrellin B；
所述的药物组合物选自片剂、胶囊、丸剂、注射剂、缓释制剂、控释制剂、及各种微粒给药系统。
本发明的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、肌肉、皮下、鼻腔、口腔粘膜、皮肤、腹膜或直肠等。
本发明的药物组合物的给药途径可为注射给药。注射包括静脉注射、肌肉注射、皮下注射、皮内注射和穴位注射等。给药剂型可以是液体剂型、固体剂型。如液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混悬剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂等。
本发明的组合物可以制成普通制剂、也可以是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将单位给药剂型制成片剂，可以广泛使用本领域公知的各种载体。关于载体的例子，例如稀释剂与吸收剂，如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化纳、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等；湿润剂与粘合剂，如水、甘泊、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素纳、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等；崩解剂，例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢纳与枸橼酸、碳酸钙、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等；崩解抑制剂，例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等；吸收促进剂，例如季铵盐、十二烷基硫酸纳等；润滑剂，例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。还可将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成丸剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如稀释剂与吸收剂，如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、Gelucire、高岭土、滑石粉等；粘合剂，如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等；崩解剂，如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。
为了将给药单元制成栓剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如聚乙二醇、卵磷脂、可可脂、高级醇、高级醇的酶、明胶、半合成甘油酶等。
为了将给药单元制成胶囊，将有效成分与上述的各种载体混合，并将由此得到的混合物置于硬的明胶胶囊或软胶囊中。也可将有效成分制成微囊剂，混悬于水性介质中形成混悬剂，亦可装入硬胶囊中或制成注射剂应用。
例如，将本发明的组合物制成注射用制剂，如溶液剂、混悬剂溶液剂、乳剂、冻干粉针剂，这种制剂可以是含水或非水的，可含一种和/或多种药效学上可接受的载体、稀释剂、粘合剂、润滑剂、防腐剂、表面活性剂或分散剂。如稀释剂可选自水、乙醇、聚乙二醇、1，3一丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酶等。另外，为了制备等渗注射液，可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油，此外，还可以添加常规的助溶剂、缓冲剂、pH调节剂等。这些辅料是本领域常用的。
此外如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其它材料。
本发明药用组合物的给药剂量取决于许多因素，例如所要预防或治疗疾病的性质和严重程度，患者或动物的性别、年龄、体重、性格及个体反应，给药途径、给药次数等，因此本发明的治疗剂量可以有大范围的变化。一般来讲，本发明化合物使用剂量是本领域技术人员公知的。可以根据本发明药用组合物中最后的制剂中所含有的实际有效药物数量，加以适当的调整，以达到其治疗有效量的要求，完成本发明在制备预防或治疗肥胖、胰岛素抵抗、糖耐量异常，高血脂，糖尿病及其并发症等疾病药物中的应用；其中糖尿病并发症包括糖尿病肾病、糖尿病心血管并发症、糖尿病性脑血管病、糖尿病眼部并发症和糖尿病足。
通常对体重约75公斤患者，所给本发明化合物的日剂量为0.001mg/kg体重～200mg/kg体重，优选1mg/kg体重～100mg/kg体重。上述剂量可以单一剂量形式或分成几个，例如二、三或四个剂量形式给药，这受限于给药医生的临床经验以及给药方案。本发明的化合物或组合物可单独服用，或与其它治疗药物或对症药物合并使用。
有益技术效果
本发明首次发现从中药竹黄竹红菌素类化合物(竹红菌甲素，Hypocrellin A；竹红菌乙素，Hypocrellin B)具有显著抗糖尿病活性，且作用靶标为LTB4受体，上述化合物具有较好的制备抗糖尿病药物的应用前景。
具体实施方式
为进一步阐述本发明，下面以具体实例对本发明进行详细说明，这些实施例完全是例证性的，旨在对本发明作具体描述，非意图限制根据本申请的示例性实施方式。
实施例1
竹红菌素类化合物(竹红菌甲素，Hypocrellin A；竹红菌乙素，Hypocrellin B)的制备方法制备方法，步骤如下：
(1)将竹黄药材粉碎后以丙酮于70℃加热回流提取3次，每次2小时，提取液40～50℃减压回收溶剂得竹黄粗提物。
(2)将竹黄粗提物进行石油醚脱脂，得到石油醚部分(Zh-PE)和丙酮部分 (Zh-A)。
(3)取竹黄粗提物丙酮部分(Zh-A)进行硅胶柱层析，以石油醚乙酸乙酯梯度进行洗脱，体积比分别为4:1,3:1,2:1,1:1；每个梯度洗脱两个柱体积。
(4)取(3)中石油醚和乙酸乙酯体积比2:1洗脱的第23份Fr23，经硅胶柱层析和葡聚糖凝胶LH-20柱层析，得到化合物竹红菌甲素(Hypocrellin A)和竹红菌乙素(Hypocrellin B)。
结构鉴定：对分得化合物通过核磁共振氢谱和碳谱，质谱等方法确定了其结构。竹红菌甲素：紫红色固体。MS m/z：545[M-1]-。1H-NMR(CDCl3)δ：6.55、6.51 (2H，S，H-5或H-8)，4.11、4.08(3H，S，2-OCH3或11-OCH3)，4.07、4.05(各 3H，s，6-OCH3或7-OCH3)，3.51(1H，d，J＝12.0Hz，Hα-15)，3.49(1H，s，H-13)， 2.64(1H，d，J＝12.0Hz，Hβ-15)，1.90(3H，s，H-18)，1.71(3H，s，H-16)。以上色谱数据与文献[沈云修,荣先国,高宗华.竹黄的化学成分研究[J].中国中药杂志,2002,27(9):674-676；Dashi Kish,Satoshi Tahara,NaokiTaniguehi,et a1.New Perylenequinones from Shiraia bambusicola[J].PlantaMed,1991,57:376-379]报道一致，鉴定为竹红菌甲素(HypocrellinA)。
竹红菌乙素：黑紫色块晶(丙酮)，溶于丙酮、甲醇。MS m/z：547[M+1]+。1H-NMR(CDCl3)δ：6.45、6.35(各1H，s，H-5或H-8)，4.10、4.03(各3H，s， 2-OCH3或11-OCH3)，4.06(1H，d，J＝11.6Hz，Hα-15)，3.99、3.98(各3H， s，6-OCH3或7-OCH3)，3.17(1H，d，J＝11.6Hz，Hβ-15)，2.32(3H，s，H-18)， 1.80(3H，s，H-16)。以上光谱数据与文献报道一致[沈云修,荣先国,高宗华.竹黄的化学成分研究[J].中国中药杂志,2002,27(9):674-676]，鉴定为竹红菌乙素 (Hypocrellin B)。
实施例2
药理学实验：测定竹红菌素类化合物(竹红菌甲素，Hypocrellin A；竹红菌乙素，Hypocrellin B)对LTB4R抑制剂模型的作用。
LTB4R是白三烯B4(LTB4)的受体，隶属于GPCR家族。当LTB4结合LTB4R 时，LTB4R会募集对应的G-protein Gα16介导下游的信号通路，引起内质网中钙离子的释放到细胞质中。通过Fluo-8钙离子荧光螯合剂结合细胞质中的钙离子后发出荧光，可以在488/525nm下检测荧光信号，确定LTB4R信号通路的激活。当加入LTB4R的抑制剂时，该信号通路不激活，就不会看到荧光信号的变化。
我们用DMSO和化合物处理过表达LTB4R和Gα16的仓鼠卵巢癌细胞 (CHO)。通过孵育Fluo-8使之进入细胞质，加入LTB4刺激后比较钙离子信号的上升程度。如果低于DMSO处理的细胞，说明化合物有一定的抑制效果。如果和DMSO接近，说明没有抑制效果。再通过cell-titer试剂盒确定化合物对细胞没有毒性，即可证明化合物对于LTB4R有抑制效果。
实验样品
被测样品溶液的配置：测试样品为竹红菌素类化合物(竹红菌甲素，HypocrellinA；竹红菌乙素，Hypocrellin B)。准确称取适量样品，使用DMSO配制成0.1M 的储存溶液，供药理活性测试。
细胞株：仓鼠卵巢癌细胞CHO细胞
[实验材料及试剂]：
试剂：胎牛血清，DMED培养基，DMSO，Fluo-8 NW检测试剂盒，化合物 LTB4，CP-105956
材料：黑色透明底96孔细胞培养板，6cm细胞培养皿
[实验仪器]
CO2培养箱，酶标仪(带有滴定功能)
1.实验方法
(1)LTB4R抑制剂模型建立：、
1)选用对数生长期的贴壁CHO细胞，胰酶消化后用含10％胎牛血清的 DMEM培养液，接种在6cm细胞培养皿中。待细胞汇合度达到70-80％，转染3ug LTB4R-pReceiver和1.5ug Gα16-pReceiver质粒进细胞。
2)转染36小时后，胰酶消化收集细胞，并用含10％胎牛血清的DMEM培养液重悬按照每孔50,000个细胞铺入黑色透明底96孔细胞培养板中，37℃， 5％CO2培养12h。
3)第二日，将培养基替换含0.5％胎牛血清的DMEM培养液，按照设计分别加入DMSO，不同浓度的竹红菌素类化合物及阳性对照。37℃，5％CO2培养2h。
4)加入Fluo-8孵育30分钟。设置酶标仪，在488/525nm下读取6s静息状态下的钙信号后，滴加LTB4进细胞孔，滴加LTB4的终浓度为400nM，继续在488/525nm下读取45s受到刺激后钙离子信号的变化。
(2)实验分组：实验组加入不同浓度的竹红菌素类化合物，对照组则加入等体积溶剂的DMSO，DMSO比例不超过1％.
(3)细胞毒性的检测方法：
1)通过LTB4R抑制剂模型建立中步骤1)的方法建立可以对LTB4响应的 LTB4R和Gα16共表达的CHO细胞系。
2)转染36小时后，胰酶消化收集细胞，并用含10％胎牛血清的DMEM培养液重悬按照每孔50,000个细胞铺入白色透明底96孔细胞培养板中。
3)加入DMSO和熊果酸。其中竹红菌素类化合物的终浓度为10uM，DMSO 加入相同体积。37℃，5％CO2培养过夜。
4)加入新鲜配置的Cell-titer化学发光检测试剂，迅速通过酶标仪读取荧光值。如果细胞死亡，则荧光值降低
2.实验结果
竹红菌素类化合物(竹红菌甲素，Hypocrellin A；竹红菌乙素，Hypocrellin B)在10μΜ浓度下对CHO细胞毒性较低或无毒性，且均具有显著抑制作用。
以上所述仅为本申请的优选示例，不用于限制本申请。在本申请的中心思想和原则内对本申请所作的任何修改、等同替换、改进等，均应包含在本申请保护范围内。
表1.化合物对LTB4R抑制剂模型中对CHO细胞的影响
Claims (5)
1.一类竹红菌素类化合物及其药学上可接受的盐在制备LTB4受体抑制剂中的应用，其特征在于，所述的竹红菌素类化合物包括竹红菌甲素Hypocrellin A、竹红菌乙素Hypocrellin B；
2.一类竹红菌素类化合物及其药学上可接受的盐在制备预防或治疗肥胖、胰岛素抵抗、糖耐量异常、高血脂、糖尿病及其并发症疾病药物中的应用，其特征在于，所述的竹红菌素类化合物包括竹红菌甲素Hypocrellin A、竹红菌乙素Hypocrellin B；
3.根据权利要求2的应用，其特征在于，所述的糖尿病并发症包括糖尿病肾病、糖尿病心血管并发症、糖尿病性脑血管病、糖尿病眼部并发症和糖尿病足。
4.一种药物组合物在制备LTB4受体抑制剂中的应用，其特征在于，所述的药物组合物包括有效剂量的竹红菌素类化合物或药学上可接受的载体或赋形剂；所述的竹红菌素类化合物包括竹红菌甲素Hypocrellin A、竹红菌乙素Hypocrellin B；
5.根据权利要求4的应用，其特征在于，所述的药物组合物选自片剂、胶囊、丸剂、注射剂、缓释制剂、控释制剂、及各种微粒给药系统。
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Application publication date: 20220920 |