CN100506769C - 蛋白酪氨酸磷酸酯酶1b抑制剂1，3-二羟基-5-烷基苯类化合物的用途 - Google Patents
蛋白酪氨酸磷酸酯酶1b抑制剂1，3-二羟基-5-烷基苯类化合物的用途 Download PDFInfo
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Abstract
本发明涉及医药技术领域，具体是一类从红树林植物榄李(Lumnitzera racemosa Willd)枝叶中提取、分离获得的具有蛋白酪氨酸磷酸酯酶1B抑制活性的1，3-二羟基-5-烷基苯类化合物(结构如下)的制备方法及其用途：其中R1、R2为H或Ac；R3为H或CH3；n＝8或10.干燥粉碎的榄李枝叶经过甲醇提取后，依次用石油醚、乙酸乙酯、正丁醇萃取分部，由乙酸乙酯部分经过硅胶柱层析和Sephadex LH-20凝胶柱层析，分离得到单体化合物，经波谱解析，鉴定为1，3-二羟基-5-烷基苯类化合物。1，3-二羟基-5-烷基苯类化合物经乙酰化和甲基化反应，分别得到其乙酰化物和甲基化物经多次体外蛋白酪氨酸磷酸酯酶1B抑制实验表明1，3-二羟基-5-烷基苯类化合物具有明显的PTP1B抑制活性，可在制备治疗各种糖尿病、肥胖症及其并发症药物中应用。
Description
技术领域
本发明涉及医药技术领域，具体是一种从红树林植物榄李中分离及衍生化得到的具有抑制蛋白酪氨酸磷酸酯酶1B(PTP1B)活性的1，3-二羟基-5-烷基苯类化合物的制备方法及其用途。该类化合物可作为蛋白酪氨酸磷酸酯酶1B的抑制剂和胰岛素增敏剂，可用于治疗各种糖尿病、肥胖症及其它由此引起的并发症。
技术背景
糖尿病(diabetes mellitus)是一组由遗传和环境因素相互作用而引起的临床综合症，因胰岛素分泌绝对或相对不足以及靶组织细胞对胰岛素敏感性降低，引起糖、蛋白、脂肪、水和电解质等一系列代谢紊乱。临床以高血糖为主要共同标志，久病可引起多个系统损害，病情严重和应激时可发生急性代谢紊乱如酮症酸中毒等。在糖尿病人中发生冠心病、缺铁性或出血性脑血管病、失明、肢端坏疽等严重并发症均明显高于非糖尿病人群。因此，糖尿病及其并发症已成为严重威胁人类健康的世界性公共卫生问题。
目前一般将糖尿病分为两类，I型糖尿病(胰岛素依赖型糖尿病，IDDM)与II型糖尿病(非胰岛素依赖型糖尿病，NIDDM)。糖尿病中90％以上是II型糖尿病。WHO预计，由于人口老龄化、肥胖、不健康的饮食以及缺乏运动的生活方式，到2025年，糖尿病患者的数目将由1995年的1.35亿上升为3亿。
I型糖尿病人由于第6对染色体短臂上的HLA-D基因决定了遗传易感性，对环境因素，特别是病毒感染或化学毒性物质刺激的反应异常，直接或间接通过自身免疫反应，引起胰岛B细胞破坏，以致胰岛素不足。临床特点是引起病急、多食、多尿、多饮、体重减轻等症状较明显，有发生酮症中毒的倾向，必须依赖胰岛素治疗维持生命。
II型糖尿病也有很强的遗传性和环境因素，并呈显著的异质性，发病机制多样而复杂，各病人间存在较大差异。总的来说可概括为胰岛素分泌的相对不足和胰岛素抵抗。对II型糖尿病人，尤其是肥胖性糖尿病患者的一系列研究证实，胰岛素抵抗是II型糖尿病发生、发展过程中的关键因素。在研究脂肪细胞和肌肉细胞内胰岛素信号传导途径的基础上，设计开发胰岛素增敏剂，以改善胰岛素抵抗状态，是目前II型糖尿病新药研究的重点，也是其主要方向之一。
II型糖尿病的特点是胰岛素敏感组织如骨骼肌、肝、脂肪组织对胰岛素作用的抵抗。虽然其具体机制尚不清楚，但胰岛素信号在其传导通路中的减弱甚至阻断必定是直接因素。胰岛素通过与其受体胞外α亚单位结合激活受体胞内β亚单位内在的酪氨酸激酶活性，导致调节结构域中关键的酪氨酸残基自身磷酸化，从而完全激活胰岛素受体酪氨酸激酶活性，胰岛素受体酪氨酸激酶再通过磷酸化其底物将信号传递下去。随着对细胞内胰岛素作用通路中可逆性酪氨酸磷酸化认识的加深，蛋白酪氨酸磷酸酯酶(PTPases)在平衡该通路中相关蛋白酪氨酸磷酸化水平中的作用越来越受到重视。PTPases可能作用于该通路中多个环节，例如将自身磷酸化活化的胰岛素受体(IR)去磷酸化，从而降低受体激酶活性；或将诸如胰岛素受体底物1(IRS-1)、胰岛素受体底物2(IRS-2)、Shc等胰岛素受体的底物中蛋白酪氨酸残基致病磷酸化，从而负调控胰岛素作用受体后通路。特定PTPases和胰岛素通路中酪氨酸激酶间酶活性的不平衡可能是引起II型糖尿病胰岛素抵抗的原因。因此，通过寻找选择性作用于该通路中PTPases的抑制剂抑制其活性，加强和延长胰岛素信号，成为越来越受重视的治疗II型糖尿病的新途径。
PTPases包括一大族跨膜(受体型)和胞内(非受体型)酶，参与调控一系列重要生命过程。虽然多种PTPases在胰岛素敏感的组织中有表达，如跨膜的CD45和LAR-PTPase等；胞内的SHPTP-1、SHPTP-2、PTP1B、PTP1C等，但只有几种PTPases可能在胰岛素通路中受体或受体后环节影响正常胰岛素作用。目前的研究主要集中在LAR-PTPase、SHPTP-2、PTP1B。
PTP1B是最早被纯化和确定生物学特性的PTPase，全长大约50KD。早期研究证明能在体外有效地将胰岛素受体去磷酸化；将来源于人胎盘的PTP1B显微注射入非洲蟾蜍卵母细胞中，将减少胰岛素诱导的卵母细胞成熟及S6肽磷酸化水平。随后发现PTP1B在所有胰岛素敏感组织中高表达；用渗透休克的方法给予PTP1B抗体后，小鼠KRC-7肝细胞经胰岛素刺激时DNA合成和PI3激酶活性水平显著升高，IR自身磷酸化水平、IR激酶活性水平和IRS-1酪氨酸磷酸化水平也显著升高。最近有研究表明，PTP1B直接与激活状态的IR相互作用；在体外实验中也对IRS-1显示最高的选择性活性；大鼠成纤维细胞中PTP1B的高表达能明显降低配体诱导的IR磷酸化水平；用腺病毒介导基因转染的方法，在胰岛素靶向组织骨骼肌和肝组织的模型细胞L6肌细胞和Fao细胞中高表达PTP1B，明显抑制胰岛素诱导的IR和IRS-1的酪氨酸磷酸化，并从而显著抑制IRS-1和PI3激酶P85亚单位复合物的形成以及Akt、MAPK的磷酸化水平，而且胰岛素诱导的糖原合成也被抑制[Egawa K.et al.J.Biol.Chem.276(13)：10207-10211]。用同样的方法在另一胰岛素靶向组织脂肪组织的模型细胞3T3-L1细胞中高表达PTP1B，同样明显抑制胰岛素诱导的IR、IRS-1和PI3激酶的酪氨酸磷酸化，P42和P44 MAPK磷酸化水平也明显降低，而Akt磷酸化水平和活性不受影响[Venable C.L.et al.J.Biol.Chem.275(24)：18318-18326]。PTP1B的高表达对基本的、中等的及最大量胰岛素诱导的葡萄糖转运无影响，对转运的EC50胰岛素浓度无影响。这些研究证明PTP1B能够负调控胰岛素信号转导通路并主要作用于胰岛素受体。更重要的实验证据来自PTP1B基因敲除小鼠。Elchebly等报道，运用同源重组的方法产生的PTP1B基因敲除的小鼠生长正常，有生殖力，对胰岛素敏感性显著增强，而且这一增强作用与肝脏和骨骼肌中胰岛素受体及胰岛素受体底物1磷酸化水平的增强相关[Elchebly M.，et al.Science，283，1544-1548]。令人惊奇的是，PTP1B基因敲除的小鼠对食物诱导的体重增加和胰岛素抵抗也有抵抗作用。Klaman等运用大致相同的方法产生的PTP1B基因敲除的小鼠也得到同样的结果，而且发现PTP1B基因敲除的小鼠之所以对食物诱导的体重增加有抵抗作用，是由于脂肪细胞体积的减少，而脂肪细胞的数量并不改变。PTP1B基因敲除的小鼠基本代谢水平和总体能量消耗升高[Klaman L.D.，et al.Molecular and Cellular Biology，20(15)：5479-5489]。这些实验更加有力地证明了PTP1B在胰岛素敏感性、能量消耗和脂肪储存方面的重要作用，从而更加明确了它是治疗二型糖尿病和肥胖症的一个潜在药物作用靶点。
PTP1B选择性抑制剂的研究取得了一定的进展，但大多局限于一些肽类或非肽类化合物，例如基于PTP1B去磷酸化的底物序列设计的抑制剂EEDE(F2PMP)M(Ki＝7.2nM)、Glu-F2PMP-F2PMP(IC50＝40nM)，虽然这些肽类抑制剂具有较强的抑制活性及较高的选择性，但它们是肽类磷酸化合物的事实使其很难成为药物候选化合物。最近，一系列非肽类非磷酸化合物类PTP1B抑制剂被报道，它们具有一定的选择性，更重要的是，其中一些化合物对降低ob/ob小鼠血浆中葡萄糖和胰岛素水平有显著作用。这是第一例药理学的直接证据，证明PTP1B抑制剂具有抗糖尿病活性[Malamas，M.S.，et al.J.Med.Chem.，2000，43，1293-1310]。这些无疑为我们寻找新的小分子非肽类有机化合物作为高效、高选择性PTP1B抑制剂提供了机遇。
榄李(Lumnitzera racemosa Willd)为红树林植物，专一生长于热带或亚热带海岸潮间带，属于使君子科。《中华本草》记载，榄李主治鹅口疮、湿疹、皮肤瘙痒等症[国家中医药管理局《中华本草》编委会.中华本草，上海：上海科学技术出版社，1999，5，615]。
本发明是首次从红树林植物榄李中分离得到1，3-二羟基-5-烷基苯类化合物，并经过衍生化反应得到了它们的甲基化物和乙酰化物，经多次药理试验研究表明，该类化合物具有抑制蛋白酪氨酸磷酸酯酶1B的显著活性，经文献检索，未见该类化合物具有此方面活性的报道。
发明内容
本发明的目的是提供一种从红树林植物榄李中提取分离1，3-二羟基-5-烷基苯类化合物及制备其衍生物的方法；
本发明的另一目的是提供一种上述1，3-二羟基-5-烷基苯类化合物的用途。
本发明的1，3-二羟基-5-烷基苯类化合物具有如下化学结构式：
其中当n＝10，R3＝CH3时，R1、R2同时为H、CH3或Ac；
当n＝8，R3＝H时，R1、R2同时为H、CH3或Ac。
本发明从红树林植物榄李中提取分离1，3-二羟基-5-烷基苯类化合物的方法，其步骤如下：
将干燥粉碎的榄李枝叶用甲醇浸提三次，每次一周，合并甲醇提取液，减压蒸去甲醇，得甲醇提取物，甲醇提取物用H2O溶解，再分别用石油醚、乙酸乙酯、正丁醇萃取三次，分别蒸干溶剂得石油醚部分、乙酸乙酯部分、正丁醇部分和水溶性部分。乙酸乙酯部分经过硅胶(100-200目)柱层析，用石油醚/乙酸乙酯95:5-50:50洗脱，再经过Sephadex LH-20凝胶柱层析，用CHCl3/MeOH(1:1)洗脱，得到1，3-二羟基-5-烷基苯类化合物。
1，3-二羟基-5-烷基苯类化合物与醋酐和吡啶反应，得到其乙酰化物；1，3-二羟基-5-烷基苯类化合物与甲基化试剂CH2N2反应，得到其甲基化物。
本发明对所得1，3-二羟基-5-烷基苯类化合物进行了蛋白酪氨酸磷酸酯酶1B抑制活性实验，表明其有明显的抑制活性。
测试原理：利用分子生物学手段在大肠杆菌系统表达人源蛋白质酪氨酸磷酸酯酶1B(hPTP1B)催化结构域，经纯化后的hPTP1B重组蛋白能水解底物pNPP的磷脂键，得到的产物在410nm处有很强的光吸收，因此可以通过直接检测410nm处光吸收的变化以观察酶的活性变化以及化合物对酶活性的抑制情况。标准的测活体系如下：10mM Tris.Cl，pH 7.6，10mM pNPP，2％ DMSO，100nM hPTP1B。
观察指标：动态测定波长为410nm处的光吸收，时间为3分钟，其动力学曲线一级反应的斜率作为酶的活性指标。
抑制率(％)＝[1-Vmax(待测样品)/Vmax(空白对照)]×100％
实验结果的评判与解释：筛选结果是当化合物的浓度为10μg/ml时对酶活性的百分抑制率，抑制活性高于50％时，按常规筛选得出IC50，阳性对照正钒酸钠的IC50为2μM.
具体实施方式
下面结合实施实例对本发明作进一步阐述，但不限制本发明。
NMR用Bruker-DRX400核磁共振仪测定。EI-MS用Finnigan-MAT-95质谱仪测定。柱层析硅胶、薄层硅胶板均为青岛海洋化工有限公司生产。所使用的Sephadex LH-20为E.Merk公司生产，试剂均为上海振兴化工一厂产品。
pNPP为Sigma公司生产，Tris·Cl和DMSO为生工生产，96孔板为Abgene公司生产，PTP1B由国家新药筛选中心表达、部分纯化，酶标仪为VERSAmax。
实施例一：化合物2-甲基-5-十三烷基-1，3-苯二醇(2-methyl-5-tridecyl-1，3-benzendiol)的制备
榄李3.0kg用甲醇浸提三次，每次一周，合并甲醇提取液，减压除去甲醇、再用H2O溶解，然后分别用石油醚、乙酸乙酯、正丁醇萃取三次，合并蒸干乙酸乙酯部分得浸膏28g。
乙酸乙酯部分28g浸膏上硅胶(100-200目)柱，用石油醚/乙酸乙酯95:5-50:50洗脱，500ml/份，共100份，经薄层层析检测后合并为15个部分，第四个部分又经硅胶(200-300目)柱层析，用石油醚/乙醚90:10-50:50洗脱，分为F41(500mg)、F42(850mg)、F43(350mg)三个部分，F41又经过Sephadex LH-20凝胶柱层析，用CHCl3/MeOH(1:1)洗脱，5ml/份，共30份，薄层层析检测，展开剂石油醚/乙醚(1:1)，合并13-18份，得化合物1(25mg)。
其1HNMR(TMS/CD3OD)δ：6.14(2H，s，H-4，6)，2.39(2H，t，J＝7.24Hz，H-1’)，1.99(3H，s，2-Me)，1.53(2H，m，H-2’)，1.26(20H，m，H-3’-H-12’)，0.88(3H，t，J＝7.15Hz，H-13’)；EIMS：m/z 306[M]+；参照文献[Manju，M.R.Parthasarathy.IndianJ.of Chemistry，1977，15(sect B)，1090-1093]，鉴定化合物1为2-甲基-5-十三烷基-1，3-苯二醇。(2-methyl-5-tridecyl-1，3-benzendiol).
实施例二：化合物1，3-二羟基-5-十一烷基苯(1，3-dihydroxy-5-undecylbenzene)的制备
乙酸乙酯部分28g浸膏上硅胶(100-200目)柱，用石油醚/乙酸乙酯95:5-50:50洗脱，500ml/份，共100份，经薄层层析检测后合并为15个部分，第五部分又经过硅胶(200-300目)柱层析，用石油醚/乙酸乙酯90:10-50:50洗脱，100ml/份，共90份。薄层层析检测，展开剂石油醚/乙醚(1:1)，合并为三个部分，F51(29-36，2.0g)，F52(40-55，500mg)，F53(65-85，200mg)；F52又经过Sephadex LH-20凝胶柱层析，用CHCl3/MeOH(1:1)洗脱，5ml/份，共30份，薄层层析检测，展开剂石油醚/乙醚(1:1)，合并为F521 (10-19，300mg)和F522(25-29，90mg)两个部分；F522又经过Sephadex LH-20凝胶柱层析，用MeOH洗脱，5ml/份，共30份，薄层层析检测，展开剂石油醚/乙醚(1:1)，合并18-20份得化合物2(20mg)。
其1HNMR(TMS/CDCl3)δ：6.25(2H，d，J＝2.01Hz，H-1，3)，6.18(1H，d，J＝1.83Hz，H-2)，2.44(2H，t，J＝7.33Hz，H-1’)，1.54(2H，m，H-2’)，1.25(16H，m，H-3’-H-10’)，0.88(3H，t，J＝6.60Hz，H-11’)；13CNMR(TMS/CDCl3)δ：156.6(C-1，3)，146.6(C-5)，108.4(C-4，6)，100.5(C-2)，36.2(C-1’)，23.0-32.2(C-2’-10’)，14.4(C-11’).参照文献[Marmor R.S.J.O.C，1972，37(18)：2901-2904]，鉴定化合物2为1，3-二羟基-5-十一烷基苯(1，3-dihydroxy-5-undecylbenzene).
实施例三：化合物1和化合物2衍生物的制备
(1)化合物1和化合物2甲基化物的制备
分别称取化合物1和化合物2样品5.0mg于10mL圆底烧瓶中，加入溶有CH2N2的乙醚溶液2mL，挥去乙醚和CH2N2后，得化合物1的甲基化物(n＝10，R3＝CH3，R1、R2＝CH3)和化合物2的甲基化物(n＝8，R3＝H，R1、R2＝CH3)
(2)化合物1和化合物2乙酰化物的制备
分别称取化合物1和化合物2样品5.0mg于25mL圆底烧瓶中，加入无水吡啶和醋酐各1.5mL，在磁力搅拌器上搅拌24h，减压除去吡啶和醋酐，得化合物1的乙酰化物(n＝10，R3＝CH3，R1、R2＝Ac)和化合物2的乙酰化物(n＝8，R3＝H，R1、R2＝Ac)。
实施例四：1，3-二羟基-5-烷基苯类化合物的PTP1B抑制活性实验
实验方法：用于筛选的蛋白酪氨酸磷酸酯酶PTP1B是从大肠杆菌中表达并纯化的GST融合蛋白。采用紫外底物pNPP，观察不同化合物对重组酶的活性的抑制，以初步评价化合物的药用效果。PTP1B水解底物pNPP的磷脂得到的产物在410nm处有很强的光吸收。因此可以直接监测410nm处光吸收的变化以观察酶的活性变化以及化合物对其的抑制情况。样品临用前溶于DMSO配成适当浓度，3倍稀释，7个稀释度，三复孔，取2μl样品溶液加入96孔板，加入88μl assay mix(Assay buffer，pNPP，H2O)，再加入10μlPTP1B，在VERSAmax上410nm处检测Vmax值。阳性对照正钒酸钠IC50为2μM。实验结果如下：
Claims (2)
1、一类结构如下的1，3-二羟基-5-烷基苯类化合物
其中n为8或10，
当n＝10，R3＝CH3时，R1、R2同时为H、CH3或Ac；
当n＝8，R3＝H时，R1、R2同时为H、CH3或Ac；
在制备治疗II型糖尿病、肥胖症及其并发症的药物中的应用。
2、如权利要求1所述的1，3-二羟基-5-烷基苯类化合物的用途，其特征在于，所述化合物在制备胰岛素增敏剂中的应用。
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| Title |
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| . M.Varma et al.Gazzetta Chimica Italiana,Vol.110 . 1980 * |
| . Manju & M.R.Parthasarathy.Indian Journal of Chemistry,Vol.15B . 1977 * |
| . Udai S.Singh, et al.J.Am.Chem.Soc,Vol.117 . 1995 * |
| 香港地区红树植物资源研究II红树植物LUMNITZERARACE-MOSA榄李 抑制植物真菌有效成分的分离与鉴定. 黄梁绮龄，苏美玲.天然产生研究与开发，第6卷第2期. 1994 * |
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