CN112957352A - 天然绿原酸类衍生物在制备atp柠檬酸裂解酶抑制剂中的用途 - Google Patents
天然绿原酸类衍生物在制备atp柠檬酸裂解酶抑制剂中的用途 Download PDFInfo
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- CN112957352A CN112957352A CN202110100457.XA CN202110100457A CN112957352A CN 112957352 A CN112957352 A CN 112957352A CN 202110100457 A CN202110100457 A CN 202110100457A CN 112957352 A CN112957352 A CN 112957352A
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Abstract
本申请公开一种天然绿原酸类衍生物在制备ATP柠檬酸裂解酶抑制剂中的用途，所述天然绿原酸类衍生物的结构式式(1)～式(3)任一一种所示：
Description
技术领域
本申请涉及医药技术邻域，具体涉及天然绿原酸类衍生物在制备ATP柠檬酸裂解酶抑制剂中的用途。
背景技术
ATP-柠檬酸裂解酶(ATP-citrate lyase,ACL)是糖代谢与脂肪酸和胆固醇生物合成的关键酶，其作用底物和产物是糖代谢中的关键中间产物，并可作为脂肪酸合成的底物。人体ACL酶蛋白是由4个相同的120KDa亚基组成的同源四聚体，每个多肽链含有1101个氨基残基(Singh et al,J.Biol.Chem.1976,251, 5254-5250)。ACL是一种胞质酶，催化柠檬酸和辅酶A转化为乙酰辅酶A和草酰乙酸，同时伴随着ATP的水解。ACL在肝脏、肾脏、胰腺等生脂细胞和胆碱能神经细胞中高度表达(Beigneux et al.,J.Biol.Chem.2004,279,9557-9564)，其催化衍生的乙酰辅酶A也被用于胆固醇的生物合成。作为胞质乙酰辅酶A的主要来源，ACL与脂肪酸和胆固醇的合成密切相关，其表达的改变与人类心血管疾病、脂肪肝、II型糖尿病、癌症等密切相关。
心血管疾病(cardiovascular diseases,CVDs)是世界上最主要的死亡原因，据世界卫生组织(world health organization,WHO)指出，CVDs几乎占全球死亡人数的三分之一(Mendis et al,Prog.Cardiovasc.Dis.2010,53,10-14)。寻找预防或治疗CDVs药物已成为全球公共卫生的优先事项。ACL是联结营养代谢与胆固醇和脂肪酸合成之间普遍存在的酶，研究表明，胆固醇和甘油三酯代谢紊乱促进人类心血管疾病的发生。新生胆固醇和脂肪酸的生物合成途径都依赖于ACL催化衍生所提供的乙酰辅酶A，ACL抑制剂能够有效阻断脂肪酸和胆固醇的从头合成，并降低血脂(Burke et al.,Curr.Opin.Lipidol.2017,28,193–200； Pinkosky et al.,Trends Mol.Med.2017,23,1047–1063)。因此，寻找有效的ACL 抑制剂对于治疗或预防CDVs的发生有着非常重要的应用前景。此外，甘油三脂酸的代谢异常也增加非酒精性脂肪肝(Nonalcoholic Fatty Liver Disease, NAFLD)和II型糖尿病(Type IIDiabetes Mellitus,T2DM)的危险因素，因此， ACL还可作为非酒精性脂肪肝和II型糖尿病的潜在靶点(Cohen et al,Science 2011,332,1519-1523；Armstrong et al.,Hepatology 2014,59,1174-1197)。
研究表明ACL还与癌症的发生密切相关。脂类合成的增加为细胞生长和分裂提供必须的脂质，是癌症的重要标志之一，也是肿瘤发生的早期事件(Migita et al,CancerRes.2008,68,8547-8554)。乙酰辅酶A是脂肪酸从头合成的重要组成部分，ACL作为乙酰辅酶A的主要来源，抑制其基因的表达能显著的抑制肿瘤细胞的增殖并诱导其凋亡。因此，ACL作为抗癌的潜在靶点在近年来被广泛研究，寻找其有效的抑制剂有望成为新的抗癌药物(Granchi et al.,Eur.J.Med. Chem.2018,157,1276–1291；Zaidi et al.,CancerRes.2012,72:3709–3714)。
ACL作为新的药用靶点已成为近年糖脂代谢紊乱疾病创新药物研究的一个热点。随着高通量筛选技术的广泛运用，已陆续发现较多种类的ACL小分子抑制剂。但目前尚未有ACL抑制剂得以成功上市，因此在医药领域竞争十分激烈。Bempedoic acid是有效的ACL小分子抑制剂，目前处于临床IIb试验阶段，用于治疗低密度脂蛋白胆固醇和动脉粥样化性心血管疾病。除Bempedoic acid 外，其它ACL抑制剂，由于其低细胞穿透力、与ACL的低亲和力以及特异性不强等原因，研制受到限制。因此寻找高效、高选择性，同时兼具良好药代动力学性质的小分子ACL抑制剂具有重要意义，对于心血管疾病和癌症等疾病的治疗有着广阔的应用前景。
发明内容
本申请首次从七子花花蕾的75％乙醇提取物中分离得到化合物 5-caffeoylquinic acid、3,5-dicaffeoylquinic acid和methyl 3,5-dicaffeoylquinate，并在在ACL抑制生物学实验中发现化合物5-caffeoylquinic acid、 3,5-dicaffeoylquinic acid和methyl 3,5-dicaffeoylquinate具有显著的ACL抑制作用，由此可能对高血脂、动脉粥样硬化、脂肪肝、II型糖尿病、癌症及其它ACL所介导的疾病具有治疗作用，从而在制药领域有巨大的潜在用途。基于此，本申请提供一种天然绿原酸类衍生物的新用途。
天然绿原酸类衍生物在制备ATP柠檬酸裂解酶抑制剂中的用途，所述天然绿原酸类衍生物的结构式如式(1)～式(3)任一一种所示：
本申请对绿原酸类衍生物5-caffeoylquinic acid、3,5-dicaffeoylquinic acid和 methyl 3,5-dicaffeoylquinate进行了ATP-柠檬酸裂解酶(ATP-citrate lyase,ACL)抑制活性实验，表明该化合物具有明显的ACL抑制活性，可用于制备由ACL 所介导疾病的药物或是作为该类药物的先导化合物。
本申请所述的化合物可通过从植物中分离纯化得到；也可经本领域技术人员熟知的化学方法合成获得。
本申请所述的化合物可单独应用或者与其他活性成分合用，亦可与药学上可接受的载体或赋形剂结合，按照常规方法制成口服或者非口服剂型。
本申请还提供一种天然绿原酸类衍生物在制备预防或防治ATP-柠檬酸裂解酶介导的糖脂代谢紊乱疾病的药物中的用途，所述天然绿原酸类衍生物的结构式如如前所述的式(1)～式(3)任一一种所示。
可选的，糖脂代谢紊乱疾病为高脂血症、动脉粥样硬化、非酒精性脂肪肝、 II型糖尿病或肥胖症。所述药物为预防或治疗高脂血症、动脉粥样硬化、非酒精性脂肪肝、II型糖尿病或肥胖症的药物。
本申请还提供一种ATP柠檬酸裂解酶抑制剂，以如前所述的式(1)～式(3) 所示化合物中的至少一种为活性成分。
可选的，ATP柠檬酸裂解酶抑制剂还包括药剂学上可接受的药物辅料。
可选的，ATP柠檬酸裂解酶抑制剂还包括赋形剂，所述化合物与赋形剂制成片剂、丸剂、胶囊剂或颗粒。
本申请还提供一种用于预防或治疗ATP-柠檬酸裂解酶介导的糖脂代谢紊乱疾病的药物组合物，其特征在于，包含治疗有效量的如如前所述式(1)～(3) 所示化合物中的至少一种。
可选的，所述药物组合物还包括药剂学上可接受的药物辅料。
可选的，所述药物组合物还包括赋形剂。所述化合物与赋形剂制成片剂、丸剂、胶囊剂或颗粒。
具体实施方式
下面将结合实施例，进行清楚、完整地描述，显然，所描述的实施例仅仅是本申请一部分实施例，而不是全部的实施例。基于本申请中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本申请保护的范围。
除非另有定义，本文所使用的所有的技术和科学术语与属于本申请的技术领域的技术人员通常理解的含义相同。本文中在本申请的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本申请。
天然产物具有结构复杂性和结构多样性的特点，是新药发现的重要来源。天然产物及其衍生物独特的化学结构，使其具有高药效和对特定靶点高选择性的优点以及潜在的独特的作用机制等优点。因此从天然活性成分中寻找开发新型、高效的ACL抑制剂具有重要的研究价值。
七子花(HeptacodiummiconioidesRehd.)是忍冬科，七子花属落叶小乔木，为我国特有种，间断分布于湖北兴山、浙江天台山以及安徽宣城等地。喜生长于山谷、溪边的阴湿环境中，是一种观赏性珍稀濒危植物，现被收录于《中国植物红皮书—稀有濒危植物》(第一册，1992出版)，是国家首批二级重点保护植物，被列入中国被子植物关键类群中高度濒危种类和中国多样性保护行动计划中优先保护物种。其株高可达7米，幼枝呈红褐色菱形状；茎干树皮灰白色，呈片状剥落；叶厚纸质略呈心形；穗状花序有1-2轮，每轮有七朵花。由于其叶和花姿态优美，可作为优良的园林绿化观赏树种，已被美国和西方国家引种繁衍。目前，其化学成分尚未有任何报道，如果能保护性地采集少许七子花植物样品进行系统的化学成分研究，将会积极促进保护和利用这一珍稀植物资源为人类服务。
本申请首次从七子花花蕾的75％乙醇提取物中分离得到化合物 5-caffeoylquinic acid、3,5-dicaffeoylquinic acid和methyl 3,5-dicaffeoylquinate。经多次药理试验研究表明，该类化合物具有显著的ACL抑制活性。
在另外的实施方式中，该化合物也可通过常规化学方法合成。
以下以具体的实施例进行说明：
七子花花蕾采自浙江省台州市，经阴干后粉碎制成粉末；比旋光测试通过 RudolfAutopol IV旋光仪于21℃下完成；紫外和红外光谱数据分别由Hitachi U-2900E型紫外光谱仪和Thermo Scientific Nicolet Is5 FT-IR型红外光谱仪测试获得；低分辩质谱(ESI-MS)和高分辨质谱(HR-ESI-MS)分别由Agilent 1100 LC/MSD型质谱仪和AB Sciex TripleTOF 5600型质谱仪获得，使用ESI离子源同时获得正负离子模式；NMR从BrukerAvanceII400型核磁共振仪和 BrukerAvanceⅡ600型核磁共振仪获得，化学位移参照未氘代的残余溶剂峰，用δ(ppm)表示；分析所用的薄层层析板(TLC)购自烟台康比诺公司，使用UV(λ:254 nm,365nm)和硫酸-香草醛溶液显色；柱色谱主要使用MCI微孔树脂CHP 20P (MitsubishiChemical Industries,75-150μm)，凝胶Sephadex LH-20(GE Healthcare BioSciencesAB)；分析及半制备型液相Waters e2695配备Waters 2998Photodiode Array Detector(PDA)和Waters 2424Evaporative Light-Scattering Detector(ELSD) 检测器以及Waters Sunfire柱(5μm,250×10mm)；实验所用分析纯溶剂石油醚、丙酮、乙酸乙酯、甲醇等购自上海泰坦化学有限公司，色谱级甲醇和乙腈由北京百灵威公司采购。
实施例1：化合物5-caffeoylquinic acid、3,5-dicaffeoylquinic acid和methyl3,5-dicaffeoylquinate的制备
干燥的七子花花蕾(1.5kg)充分粉碎后，经75％乙醇(2L)室温提取7 次，每次24小时，合并提取液，减压浓缩得到总浸膏132.1g。用1L水分散浸膏，依次用等体积的石油醚、乙酸乙酯以及正丁醇各萃取三次，得到石油醚、乙酸乙酯、正丁醇和水四个组分。乙酸乙酯组分共32.1g，经大孔树脂以乙醇- 水(10:90→30:70→50:50→70:30→90:10→100:0,v/v)梯度洗脱，得到8 个组分(Fr.1-Fr.8)。
组分Fr.1(13.3g)首先先采用MCI柱层析，经甲醇-水梯度洗脱后得到5个亚组分(Fr.1A-Fr.1E)。Fr.1B经Sephadex LH-20(MeOH)和半制备HPLC (MeCN-H2O,13:87,v/v；flow rate,3mL/min,tR＝10.2min)纯化后得到化合物 5-caffeoylquinic acid。结构如式(1)所示。
组分Fr.3(9.7g)首先采用MCI柱层析粗分，经甲醇-水梯度洗脱得到7个亚组分(Fr.3A-Fr.3G)。Fr.3D经Sephadex LH-20(MeOH)和半制备HPLC (MeOH-H2O,40:60,v/v；flow rate,3mL/min,tR＝11.1min)纯化后得到化合物 3,5-dicaffeoylquinic acid。结构如式(2)所示。
组分Fr.4(12.2g)经硅胶柱层析，以二氯甲烷-甲醇(CH2Cl2-MeOH,30:1→ 20:1→10:1→5:1→1:1→neat MeOH)作为洗脱体系，根据TLC显色情况合并成7个亚组分Fr.4A–Fr.4G。亚组分Fr.4E经Sephadex LH-20(MeOH)和半制备HPLC[MeCN-H2O,22:78,v/v；flowrate,3mL/min,tR＝10.1min]纯化后得到化合物methyl 3,5-dicaffeoylquinate。结构如式(3)所示。
化合物的理化数据如下：
5-caffeoylquinic acid：pale yellow powder；[α]D 21-122.1(c 0.1,MeOH)；1HNMR(400MHz,CD3OD):δH:7.56(1H,d,J＝16.0Hz,H-7'),7.05(1H,br s,H-2'), 6.96(1H,brd,J＝8.0Hz,H-6'),6.77(1H,d,J＝8.0Hz,H-5'),6.26(1H,d,J＝16.0 Hz,H-8'),5.33(1H,m,H-5),4.16(1H,m,H-3),3.73(1H,m,H-4),2.21(2H,m, H-2),2.07(2H,m,H-6).ESIMS:m/z355[M+H]+,377[M+Na]+。
3,5-dicaffeoylquinic acid：pale yellow powders；[α]D 21-122.1(c 0.1,MeOH)；1H NMR(400MHz,CD3OD):δH:7.62(1H,d,J＝15.8Hz,H-7'),7.57(1H, d,J＝16.1Hz,H-7”),7.07(2H,s,H-2'and H-2”),6.98(1H,d,J＝8.2Hz,H-6'),6.96 (1H,d,J＝8.2Hz,H-6”),6.97(2H,d,J＝8.3Hz,H-5'and H-5”),5.41(2H,m,H-3 and H-5),3.98(1H,m,H-4),2.32(2H,m,H-2),2.21(2H,m,H-6)；13C NMR(150 MHz,CD3OD):δC:177.3(C-7),168.9(C-9'),168.4(C-9”),149.6(C-4'),149.5(C-4”), 147.3(C-7'),147.1(C-7”),146.8(C-3'and C-3”),127.9(C-1'),127.8(C-1”),123.0 (C-6'),122.9(C-6”),116.5(C-5'and C-5”),115.6(C-2'),115.3(C-2”),115.2(C-8'), 115.1(C-8”),74.7(C-1),72.5(C-3),72.1(C-5),70.6(C-4),37.6(C-6),36.0 (C-2).ESIMS:m/z 539[M+Na]+,515[M–H]-.
Methyl 3,5-dicaffeoylquinate：pale yellow powders；[α]D 21-144.5(c 0.1,MeOH)；1H NMR(400MHz,CD3OD):δH:7.62(1H,d,J＝15.5Hz,H-7'),7.55(1H, d,J＝15.8Hz,H-7”),7.07(2H,s,H-2'and H-2”),6.96(2H,d,J＝8.0Hz,H-6'and H-6”),6.79(2H,d,J＝8.0Hz,H-5'and H-5”),6.34(1H,d,J＝15.5Hz,H-8'),6.22 (1H,d,J＝15.8Hz,H-8”),5.40(1H,m,H-5),5.32(1H,m,H-3),3.98(1H,m,H-4), 3.69(H-OMe),2.32(2H,m,H-2),2.17(2H,m,H-6)；ESIMS m/z 531[M+H]+,553 [M+Na]+。
实施例2：如式(1)～式(3)所示的化合物的ACL抑制活性测试
实验方法：本实验中ATP依赖的柠檬酸裂解酶ACL能将柠檬酸催化转变为乙酰辅酶A，进而产生脂肪酸合成的前体分子－丙二酸单酰辅酶A。该反应伴随着ATP的消耗，因此可以使用ADP-Glo激酶检测试剂盒检测ATP的变化，来间接反应化合物对ACL的酶活性抑制作用。
具体来说，初筛选择化合物浓度为20μg/mL时对ACL酶活性的百分抑制率进行考察：将浓度为20μg/mL的化合物5-caffeoylquinic acid、 3,5-dicaffeoylquinic acid或methyl 3,5-dicaffeoylquinate取1μL分别加入2μLACL 酶液中，37℃度下反应0.5小时后检测ACL酶液的酶活力。试验结果表明 5-caffeoylquinic acid、3,5-dicaffeoylquinicacid和methyl 3,5-dicaffeoylquinate对 ACL酶活性抑制率分别为85.1％、95.1％和96.2％。
进一步测定IC50值：样品临用前溶于DMSO配成合适浓度，3倍稀释，7 个稀释度，三复孔，取2μL样品溶液加入到标准的测活体系(40mMTris,pH 8.0, 10mM MgCl2,5mM DTT,ATP,CoA,柠檬酸钠和ACL)，37℃下孵育30min。而后，体系内加入25μL ADP-Glo试剂，室温下孵育30min，以终止反应，并消耗完剩余的ATP。再加入激酶检测试剂孵育30min后，其荧光信号由EnVision 读出，其动力学曲线一级反应的斜率作为酶的活性指标。
以相对活性对化合物浓度作图，经公式v/v0＝100/(1+b*[I]/IC50)拟合得到 IC50值，实验重复三次，结果取三次的平均值，结果如表1所示。阳性对照 BMS303141的IC50值为0.46μM。
表1.如式(1)～式(3)所示化合物的ACL抑制活性数据
测试结果表明上述三个化合物均对ACL表现出显著的抑制活性，表明本申请所述化合物可用于制备治疗高脂血症、动脉粥样硬化、脂肪肝、II型糖尿病、癌症及其它ACL所介导的疾病或是作为该类药物的先导化合物。
以上所述实施例仅表达了本申请的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对申请专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本申请构思的前提下，还可以做出若干变形和改进，这些都属于本申请的保护范围。因此，本申请专利的保护范围应以所附权利要求为准。
Claims (10)
1.天然绿原酸类衍生物在制备ATP柠檬酸裂解酶抑制剂中的用途，所述天然绿原酸类衍生物的结构式如式(1)～式(3)任一一种所示：
2.天然绿原酸类衍生物在制备预防或防治ATP-柠檬酸裂解酶介导的糖脂代谢紊乱疾病的药物中的用途，所述天然绿原酸类衍生物的结构式如式(1)～式(3)任一一种所示：
3.根据权利要求2所述的用途，其特征在于，所述糖脂代谢紊乱疾病为高脂血症、动脉粥样硬化、非酒精性脂肪肝、2型糖尿病或肥胖症。
4.一种ATP柠檬酸裂解酶抑制剂，其特征在于，以如式(1)～式(3)所示化合物中的至少一种为活性成分：
5.根据权利要求4所述的ATP柠檬酸裂解酶抑制剂，其特征在于，还包括药剂学上可接受的药物辅料。
6.根据权利要求4所述的ATP柠檬酸裂解酶抑制剂，其特征在于，还包括赋形剂；如式(1)～(3)所示化合物中的至少一种与赋形剂制成片剂、丸剂、胶囊剂或颗粒。
7.一种用于预防或治疗ATP-柠檬酸裂解酶介导的糖脂代谢紊乱疾病的药物组合物，其特征在于，包含治疗有效量的如式(1)～(3)所示化合物中的至少一种：
8.根据权利要求7所述的药物组合物，其特征在于，还包括药剂学上可接受的药物辅料。
9.根据权利要求7所述的药物组合物，其特征在于，还包括赋形剂；如式(1)～(3)所示化合物中的至少一种与赋形剂制成片剂、丸剂、胶囊剂或颗粒。
10.根据权利要求7所述的药物组合物，其特征在于，所述药物组合物为预防或治疗高脂血症、动脉粥样硬化、非酒精性脂肪肝、II型糖尿病或肥胖症的药物。
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