CN116999424A - 一种酰基奎宁酸类化合物及其应用 - Google Patents
一种酰基奎宁酸类化合物及其应用 Download PDFInfo
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- CN116999424A CN116999424A CN202310995075.7A CN202310995075A CN116999424A CN 116999424 A CN116999424 A CN 116999424A CN 202310995075 A CN202310995075 A CN 202310995075A CN 116999424 A CN116999424 A CN 116999424A
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- acathopanacid
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- -1 Acyl quinic acid compound Chemical class 0.000 title claims abstract description 94
- AAWZDTNXLSGCEK-UHFFFAOYSA-N Cordycepinsaeure Natural products OC1CC(O)(C(O)=O)CC(O)C1O AAWZDTNXLSGCEK-UHFFFAOYSA-N 0.000 title claims abstract description 34
- AAWZDTNXLSGCEK-ZHQZDSKASA-N Quinic acid Natural products O[C@H]1CC(O)(C(O)=O)C[C@H](O)C1O AAWZDTNXLSGCEK-ZHQZDSKASA-N 0.000 title claims abstract description 33
- 102000010907 Cyclooxygenase 2 Human genes 0.000 claims abstract description 14
- 108010037462 Cyclooxygenase 2 Proteins 0.000 claims abstract description 14
- 229940124599 anti-inflammatory drug Drugs 0.000 claims abstract description 3
- 239000002253 acid Substances 0.000 claims description 42
- 150000001875 compounds Chemical class 0.000 claims description 41
- 235000001258 Cinchona calisaya Nutrition 0.000 claims description 39
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Natural products C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 claims description 37
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 claims description 37
- 229960000948 quinine Drugs 0.000 claims description 37
- 229940126214 compound 3 Drugs 0.000 claims description 8
- YDDUMTOHNYZQPO-UHFFFAOYSA-N 1,3-bis{[(2E)-3-(3,4-dihydroxyphenyl)prop-2-enoyl]oxy}-4,5-dihydroxycyclohexanecarboxylic acid Natural products OC1C(O)CC(C(O)=O)(OC(=O)C=CC=2C=C(O)C(O)=CC=2)CC1OC(=O)C=CC1=CC=C(O)C(O)=C1 YDDUMTOHNYZQPO-UHFFFAOYSA-N 0.000 claims description 7
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- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 claims description 6
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- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 claims description 6
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- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 claims description 5
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- 235000001368 chlorogenic acid Nutrition 0.000 claims description 5
- BMRSEYFENKXDIS-KLZCAUPSSA-N cis-3-O-p-coumaroylquinic acid Natural products O[C@H]1C[C@@](O)(C[C@@H](OC(=O)C=Cc2ccc(O)cc2)[C@@H]1O)C(=O)O BMRSEYFENKXDIS-KLZCAUPSSA-N 0.000 claims description 5
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- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 4
- SDMADMBVKYOYQN-UHFFFAOYSA-N 4-O-caffeoyl-5-O-feruloylquinic acid Natural products COc1cc(C=CC(=O)OC2CC(O)(CC(O)C2OC(=O)C=Cc3ccc(O)c(O)c3)C(=O)O)ccc1O SDMADMBVKYOYQN-UHFFFAOYSA-N 0.000 claims description 4
- CPYDMLXRLHYXSV-UHFFFAOYSA-N 5-O-(E)-feruloylquinic acid methyl ester Natural products C1C(C(=O)OC)(O)CC(O)C(O)C1OC(=O)C=CC1=CC=C(O)C(OC)=C1 CPYDMLXRLHYXSV-UHFFFAOYSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- CWVRJTMFETXNAD-JUHZACGLSA-N chlorogenic acid Chemical compound O[C@@H]1[C@H](O)C[C@@](O)(C(O)=O)C[C@H]1OC(=O)\C=C\C1=CC=C(O)C(O)=C1 CWVRJTMFETXNAD-JUHZACGLSA-N 0.000 claims description 4
- 150000004702 methyl esters Chemical class 0.000 claims description 4
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 3
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- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 3
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Abstract
本发明公开了一种酰基奎宁酸类化合物及其应用。本发明涉及26个酰基奎宁酸类化合物，其中11个酰基奎宁酸类化合物是从五加皮中首次分离、纯化得到。这26个酰基奎宁酸类化合物均显示较好的环氧化酶‑2抑制活性，可用于制备抗炎药物。
Description
技术领域
本发明属于天然药物化学技术领域，涉及一种酰基奎宁酸类化合物及其应用。
背景技术
炎症反应作为免疫的一部分是人体最基本的生理过程之一，其在各个方面影响着我们的健康。目前，临床上使用的抗炎药物主要为非甾体抗炎药和皮质类固醇药。其他药物如血管紧张素转化酶(ACE)抑制剂、抗组胺药和激素替代疗法，也可用来治疗和控制与炎症相关的一些疾病。虽然这些药物能在一定程度上减轻和缓解炎症反应，但也会导致胃肠道不良反应、抑制免疫***等副作用。
中药在炎症治疗中，往往具有多效、可双向调节等特点，其不良反应较少、来源较丰富，寻找和开发具有抗炎作用的中药也逐渐成为本技术领域的研究热点。五加皮为五加科植物细柱五加(Acanthopanax gracilistylus W.W.Smith)的干燥根皮，具有祛风除湿、补益肝肾、利水消肿、强筋壮骨等功效，临床上常用于风湿痹病、筋骨痿软、小儿行迟、体虚泛力、水肿和脚气等疾病的治疗。
从五加皮中分离、纯化的化学成分主要包括：二萜类化合物、三萜类化合物、苯丙素类化合物、植物甾醇、挥发油、脂肪酸、维生素、多糖、大分子蛋白等。目前还未有从五加皮中获得酰基奎宁酸类化合物的相关报道。因此，为实现五加皮药用植物的资源化利用，进一步分离、鉴定五加皮中具有医药活性成分具有重要意义。
发明内容
为了丰富五加皮中化学成分的研究以及深入对其药理作用的研究，本发明提供了一种基于五加皮的酰基奎宁酸类化合物及其应用，经过对五加皮提取、分离、纯化，得到了26个对环氧化酶-2具有显著抑制作用的酰基奎宁酸类化合物1a、1b、2a、2b以及3～24，为细柱五加的资源化利用提供参考。
基于上述目的，一方面，本发明提供26种酰基奎宁酸类化合物，其结构式如(Ⅰ)所示：
进一步，本发明提供的26种酰基奎宁酸类化合物中，R1选自COOMe、COOH、和butylester中的一种；R2选自OH、caffeoyl和feruloy中的一种；R3选自OH、caffeoyl、feruloy以及(i)、(ii)中的一种；R4选自OH、caffeoyl、syringoyl、sinapoyl、feruloy以及(i)、(ii)中的一种；R5选自OH、coumaroyl、caffeoyl、feruloy以及(iii)、(iv)、(v)中的一种。
进一步，本发明提供的26种酰基奎宁酸类化合物中，coumaroyl、caffeoyl、feruloy、syringoyl、sinapoyl、butyl ester的结构式如(vi)所示：
进一步，本发明提供的26种酰基奎宁酸类化合物包括：11个未见报道过的酰基奎宁酸类化合物：acanthopacid A(1a,氧新酰基奎宁酸A)、acanthopacid B(1b,氧新酰基奎宁酸B)、acanthopacid C(2a,氧新酰基奎宁酸C)、acanthopacid D(2b,氧新酰基奎宁酸D)、acanthopacid E(3,氧新酰基奎宁酸E)、acanthopacid F(4,氧新酰基奎宁酸F)、acanthopacid G(5,氧新酰基奎宁酸G)、acanthopacid H(6,氧新酰基奎宁酸H)、4-O-vanilloyl-5-O-caffeoylquinic acid methyl ester(7,4-O-香草酰-5-O-咖啡酰奎宁酸甲酯)、4-O-caffeoyl-5-O-feruloylquinic acid methyl ester(8,4-O-咖啡酰-5-O-阿魏酰奎宁酸甲酯)、1-O-feruloyl-3,4-di-O-caffeoylquinic acid(9,1-O-阿魏酰-3,4-二-O-奎宁酸)；以及15个已知的酰基奎宁酸类化合物：5-p-trans-coumaroylquinic acid(10,反式-5-O-对香豆酰奎宁酸)、chlorogenic acid butyl ester(11,绿原酸正丁酯)、chlorogenic acid(12,绿原酸)、5-O-feruloylquinic acid methyl ester(13,5-O-阿魏酰奎宁酸甲酯)、1-O-caffeoyl-4-O-feruloylquinic acid(14,1-O-咖啡酰-4-O-阿魏酰奎宁酸)、1,3-di-O-feruloylquinic acid(15,1,3-二-O-阿魏酰奎宁酸)、1,3-di-O-caffeoylquinic acid(16,1,3-二-O-咖啡酰奎宁酸)、1,5-dicaffeoylquininic acid(17,1,5-二-O-咖啡酰奎宁酸)、1-O-caffeoyl-5-O-feruloylquinic acid(18,1-O-咖啡酰-5-O-阿魏酰奎宁酸)、1-O-feruloyl-5-O-caffeoylquinic acid(19,1-O-阿魏酰-5-O-咖啡酰奎宁酸)、3,5-dicaffeoylquinic acid methyl ester(20,3,5-二-O-咖啡酰奎宁酸甲酯)、4,5-O-dicaffeoylquinic acid methyl ester(21,4,5-二-O-咖啡酰奎宁酸甲酯)、4-O-syringoyl-5-O-caffeoylquinic acid methyl ester(22,4-O-紫丁香酰-5-O-咖啡酰奎宁酸甲酯)、4-O-sinapoyl-5-O-caffeoylquinic acid methyl ester(23,4-O-芥子酰-5-O-咖啡酰奎宁酸甲酯)、1,3,4-tri-O-caffeoylquinic acid(24,1,3,4-三-O-咖啡酰奎宁酸)。
进一步，本发明提供的26种酰基奎宁酸类化合物，15个已知的酰基奎宁酸类化合物中，酰基奎宁酸类化合物10的R1为COOH，R2为OH，R3为OH，R4为OH，R5为coumaroyl；酰基奎宁酸类化合物11的R1为butyl ester，R2为OH，R3为OH，R4为OH，R5为caffeoyl；酰基奎宁酸类化合物12的R1为COOH，R2为OH，R3为OH，R4为OH，R5为caffeoyl；酰基奎宁酸类化合物13的R1为COOH，R2为OH，R3为OH，R4为OH，R5为caffeoyl；酰基奎宁酸类化合物14的R1为COOH，R2为caffeoyl，R3为OH，R4为feruloy，R5为OH；酰基奎宁酸类化合物15的R1为COOH，R2为feruloy，R3为feruloy，R4为OH，R5为OH；酰基奎宁酸类化合物16的R1为COOH，R2为caffeoyl，R3为caffeoyl，R4为OH，R5为OH；酰基奎宁酸类化合物17的R1为COOH，R2为caffeoyl，R3为OH，R4为OH，R5为caffeoyl；酰基奎宁酸类化合物18的R1为COOH，R2为caffeoyl，R3为OH，R4为OH，R5为feruloy；酰基奎宁酸类化合物19的R1为COOH，R2为feruloy，R3为OH，R4为OH，R5为caffeoyl；酰基奎宁酸类化合物20的R1为COOMe，R2为OH，R3为caffeoyl，R4为OH，R5为caffeoyl；酰基奎宁酸类化合物21的R1为COOMe，R2为OH，R3为OH，R4为caffeoyl，R5为caffeoyl；酰基奎宁酸类化合物22的R1为COOMe，R2为OH，R3为OH，R4为syringoyl，R5为caffeoyl；酰基奎宁酸类化合物23的R1为COOMe，R2为OH，R3为OH，R4为sinapoyl，R5为caffeoyl；酰基奎宁酸类化合物24的R1为COOH，R2为caffeoyl，R3为caffeoyl，R4为caffeoyl，R5为OH。
进一步本发明提供的26种酰基奎宁酸类化合物，其结构式如(II)所示。
进一步，经鉴定26种酰基奎宁酸类化合物中，酰基奎宁酸类化合物1a、1b、2a、2b和3～6为氧新木质素-(–)奎宁酸异源二聚体衍生物。
另一方面，本发明提供上述26种酰基奎宁酸类化合物的制备方法，具体包括以下步骤：
S1：将干燥的五加皮粉碎成粗粉(过2号筛)，使用70％丙酮室温下浸泡三次，每次浸泡72h。以质量比计，五加皮:70％丙酮＝15:68.2。
S2：合并浸泡液，减压浓缩至浸膏，将浸膏溶于水中，以体积比计，浸膏:水＝48:1。先用乙酸乙酯萃取3次，再用正丁醇萃取3次(与乙酸乙酯萃取用量一致)，分别合并萃取液，得乙酸乙酯部分(Fr.A)和正丁醇部分(Fr.B)。
S3：Fr.B经过大孔树脂柱色谱(D101)，有效成分吸附于树脂上，用水-甲醇梯度洗脱，薄层色谱检测(TLC检测)并合并相同组分后得到3个组分Fr.B-1～Fr.B-3。
S4：从Fr.B-2部位中取73mg样品，其经过半制备高效液相色谱(半制备HPLC)得到酰基奎宁酸类化合物12、16、17。剩余的Fr.B-2样品经过二氯甲烷-甲醇梯度洗脱(硅胶)得到Fr.B-2-1～Fr.B-2-3。Fr.B-2-3经过MSI柱层析甲醇-水梯度洗脱得到Fr.B-2-3-1～Fr.B-2-3-4。Fr.B-2-3-1和Fr.B-2-3-4经过半制备HPLC纯化(乙腈-水，25:75)后分别得到酰基奎宁酸类化合物10和13。
S5：Fr.B-3经过硅胶柱色谱，用二氯甲烷-甲醇梯度洗脱得到7个组分Fr.B-3-1～Fr.B-3-7。Fr.B-3-5经过凝胶柱层析(Sephadex LH-20)，用甲醇洗脱得到酰基奎宁酸类化合物11。
S6：Fr.B-3-6经过硅胶柱层析，用二氯甲烷-甲醇梯度洗脱得到3个组分Fr.B-3-6-1～Fr.B-3-6-3。Fr.B-3-6-1经过凝胶柱层析(Sephadex LH-20)，用甲醇洗脱得到8个组分Fr.B-3-6-1-1～Fr.B-3-6-1-8。Fr.B-3-6-1-5经半制备HPLC纯化(甲醇-水，50％～100％)得到Fr.B-3-6-1-5-1～Fr.B-3-6-1-5-7以及酰基奎宁酸类化合物4和15。
S7：Fr.B-3-6-1-5-5经半制备HPLC纯化(乙腈-水，35:65)得到Fr.B-3-6-1-5-5-1～Fr.B-3-6-1-5-5-3以及酰基奎宁酸类化合物6、7和22。
S8：Fr.B-3-6-1-5-5-1经半制备HPLC纯化(乙腈-水，30:70)得到酰基奎宁酸类化合物1和2。
S9：酰基奎宁酸类化合物1和2分别经过HPLC(SHIMADZU，C18，5μm，10×250mm2，甲醇-水，60:40，流速为2mL/min)拆分得到酰基奎宁酸类化合物1a、1b、2a和2b。
S10：Fr.B-3-6-1-6经半制备HPLC纯化(乙腈-水，50:50)得到酰基奎宁酸类化合物14和23。
S11：Fr.B-3-6-1-7经半制备HPLC纯化(甲醇-水，55:45)得到酰基奎宁酸类化合物20。
S12：Fr.B-3-6-1-8经半制备HPLC纯化[(甲醇-乙腈，1:1)-水，50:50]得到酰基奎宁酸类化合物9。
S13：Fr.B-3-6-2凝胶柱层析(Sephadex LH-20)，用甲醇洗脱得到Fr.B-3-6-2-1～Fr.B-3-6-2-9，Fr.B-3-6-2-5经过经半制备HPLC(甲醇-水，55:45)纯化得到酰基奎宁酸类化合物3。
S14：Fr.B-3-6-2-6经半制备HPLC纯化(甲醇-水，40:60)得到酰基奎宁酸类化合物18和19。
S15：Fr.B-3-7经过MCI甲醇-水梯度洗脱得到Fr.B-3-7-1～Fr.B-3-7-10，Fr.B-3-7-5经半制备HPLC纯化[(甲醇-乙腈，1:1)-水，50:50]梯度洗脱得到酰基奎宁酸类化合物21和24。
还有，本发明请求保护上述26种酰基奎宁酸类化合物在抗炎方面的应用。
进一步，本发明通过对上述26种酰基奎宁酸类化合物的体外抗炎活性测试，得知所述26种酰基奎宁酸类化合物均显示较好的环氧化酶-2(COX-2)抑制活性。
进一步，酰基奎宁酸类化合物1a、1b、2a、2b、3、7、8、9、11、12、15～21、23和24对COX-2的抑制活性较高。
进一步，所述26种酰基奎宁酸类化合物可制备的药剂类型多样，本发明不做具体限定，本领域技术人员可将所述26种酰基奎宁酸类化合物制备为片剂、滴丸剂、膏剂、喷雾剂、胶囊剂等。所述药剂中还含有配制药剂所需的辅料，辅料可以是矫味剂、崩解剂、助溶剂、缓冲剂中的一种或几种的混合。
与现有技术相比，本发明提供的技术方案至少具备下述的有益效果或优点：本发明从五加皮中经提取、分离、纯化得到26种酰基奎宁酸类化合物如(Ⅰ)所示，其中1a、1b、2a、2b以及3～9这11个酰基奎宁酸类化合物及其相关药物此前尚未被报道过。
本发明提供了26种酰基奎宁酸类化合物在抗炎方面的应用，均显示较好的COX-2抑制活性，其IC50分别为0.63±0.014(1a)、0.75±0.028(1b)、0.15±0.023(2a)、0.63±0.016(2b)、0.30±0.013(3)、35.63±4.600(4)、8.70±1.241(5)、16.51±0.480(6)、0.69±0.049(7)、0.39±0.017(8)、0.26±0.080(9)、1.39±0.253(10)、0.72±0.042(11)、0.56±0.020(12)、2.98±0.234(13)、38.01±3.262(14)、0.41±0.051(15)、0.40±0.039(16)、0.28±0.038(17)、0.42±0.024(18)、0.69±0.038(19)、0.25±0.044(20)、0.26±0.038(21)、4.56±0.322(22)、0.17±0.012(23)、和0.26±0.055μM(24)。其中酰基奎宁酸类化合物1a、1b、2a、2b、3、7、8、9、11、12、15～21、23和24对COX-2的抑制活性较高。
附图说明
图1为酰基奎宁酸类化合物1a的1H-NMR谱图。
图2为酰基奎宁酸类化合物1a的13C-NMR谱图。
图3为酰基奎宁酸类化合物1b的1H-NMR谱图。
图4为酰基奎宁酸类化合物1b的13C-NMR谱图。
图5为酰基奎宁酸类化合物2a的1H-NMR谱图。
图6为酰基奎宁酸类化合物2a的13C-NMR谱图。
图7为酰基奎宁酸类化合物2b的1H-NMR谱图。
图8为酰基奎宁酸类化合物2b的13C-NMR谱图。
图9为酰基奎宁酸类化合物3的1H-NMR谱图。
图10为酰基奎宁酸类化合物3的13C-NMR谱图。
图11为酰基奎宁酸类化合物4的1H-NMR谱图。
图12为酰基奎宁酸类化合物4的13C-NMR谱图。
图13为酰基奎宁酸类化合物5的1H-NMR谱图。
图14为酰基奎宁酸类化合物5的13C-NMR谱图。
图15为酰基奎宁酸类化合物6的1H-NMR谱图。
图16为酰基奎宁酸类化合物6的13C-NMR谱图。
图17为酰基奎宁酸类化合物7的1H-NMR谱图。
图18为酰基奎宁酸类化合物7的13C-NMR谱图。
图19为酰基奎宁酸类化合物8的1H-NMR谱图。
图20为酰基奎宁酸类化合物8的13C-NMR谱图。
图21为酰基奎宁酸类化合物9的1H-NMR谱图。
图22为酰基奎宁酸类化合物9的13C-NMR谱图。
具体实施方式
下面，结合实施例对本发明的技术方案进行说明，但是，本发明并不限于下述的实施例。各实施例中所述实验方法和检测方法，如无特殊说明，均为常规方法；所述试剂和材料，如无特殊说明，均可在市场上购买得到。
实施例1
本实施例提供了酰基奎宁酸类化合物1a、1b、2a、2b以及3～24的制备方法，具体包括以下步骤：
干燥的五加皮15kg(从湖北省蕲春县购买)，粉碎后用70％丙酮室温下浸泡3次(80L/次)，每次浸泡72h。合并浸泡液，减压浓缩至浸膏，之后将该浸膏混悬于适量水中(5L)，先用乙酸乙酯萃取3次得到乙酸乙酯部分(Fr.A)，再用等量的正丁醇萃取3次得到正丁醇部分(Fr.B)。
Fr.B(正丁醇部分)经大孔树脂柱色谱(D101)，其有效成分吸附于树脂上，用水-甲醇梯度洗脱，薄层色谱检测(TLC检测)并合并相同组分后得到3个组分Fr.B-1～Fr.B-3。从Fr.B-2部位中取73mg样品，其经过半制备高效液相色谱(半制备HPLC)得到酰基奎宁酸类化合物12、16、17。
剩余的Fr.B-2样品经过二氯甲烷-甲醇梯度洗脱(硅胶)得到Fr.B-2-1～Fr.B-2-3。Fr.B-2-3经过MSI柱层析甲醇-水梯度洗脱得到Fr.B-2-3-1～Fr.B-2-3-4。Fr.B-2-3-1和Fr.B-2-3-4经过半制备HPLC纯化(乙腈-水，25:75)后分别得到酰基奎宁酸类化合物10和13。Fr.B-3经过硅胶柱色谱，用二氯甲烷-甲醇梯度洗脱得到7个组分Fr.B-3-1～Fr.B-3-7。Fr.B-3-5经过凝胶柱层析(Sephadex LH-20)，用甲醇洗脱得到酰基奎宁酸类化合物11。
Fr.B-3-6经过硅胶柱层析，用二氯甲烷-甲醇梯度洗脱得到3个组分Fr.B-3-6-1～Fr.B-3-6-3。Fr.B-3-6-1经过凝胶柱层析(Sephadex LH-20)，用甲醇洗脱得到8个组分Fr.B-3-6-1-1～Fr.B-3-6-1-8。Fr.B-3-6-1-5经半制备HPLC纯化(甲醇-水，50％～100％)得到Fr.B-3-6-1-5-1～Fr.B-3-6-1-5-7以及酰基奎宁酸类化合物4和15。
Fr.B-3-6-1-5-5经半制备HPLC纯化(乙腈-水，35:65)得到Fr.B-3-6-1-5-5-1～Fr.B-3-6-1-5-5-3以及酰基奎宁酸类化合物6、7和22。
Fr.B-3-6-1-5-5-1经半制备HPLC纯化(乙腈-水，30:70)得到酰基奎宁酸类化合物1和2。酰基奎宁酸类化合物1和2分别经过HPLC(SHIMADZU，C18，5μm，10×250mm2，甲醇-水，60:40，流速为2mL/min)拆分得到酰基奎宁酸类化合物1a、1b、2a和2b。
Fr.B-3-6-1-6经半制备HPLC纯化(乙腈-水，50:50)得到酰基奎宁酸类化合物14和23。Fr.B-3-6-1-7经半制备HPLC纯化(甲醇-水，55:45)得到酰基奎宁酸类化合物20。
Fr.B-3-6-1-8经半制备HPLC纯化[(甲醇-乙腈，1:1)-水，50:50]得到酰基奎宁酸类化合物9。
Fr.B-3-6-2凝胶柱层析(Sephadex LH-20)，用甲醇洗脱得到Fr.B-3-6-2-1～Fr.B-3-6-2-9，Fr.B-3-6-2-5经过经半制备HPLC(甲醇-水，55:45)纯化得到酰基奎宁酸类化合物3。
Fr.B-3-6-2-6经半制备HPLC纯化(甲醇-水，40:60)得到酰基奎宁酸类化合物18和19。
Fr.B-3-7经过MCI甲醇-水梯度洗脱得到Fr.B-3-7-1～Fr.B-3-7-10，Fr.B-3-7-5经半制备HPLC纯化[(甲醇-乙腈，1:1)-水，50:50]梯度洗脱得到酰基奎宁酸类化合物21和24。
本发明提供的26种酰基奎宁酸类化合物，其结构式如(II)所示。
实施例2
本实施例提供了酰基奎宁酸类化合物1a、1b、2a、2b以及3～9的结构鉴定。
高分辨质谱(HR-ESI-MS)使用质谱仪IT-TOF-LC-MS(Shimadzu，Kyoto，Japan)测定；核磁共振谱图用Brucker Avance III-600型超导核磁共振仪(Bruker，Bremerhaven，Germany)测定，TMS(四甲基硅烷)作内标；比旋光度通过Jascomodel 1020旋光仪(Horiba，Tokyo，Japan)测定；电子圆二色谱(ECD谱)由圆二色光谱仪J-815spectropolarimeter(Japan)测定；紫外光谱图由UV-2600spectrophotometer(Shimadzu,Kyoto,Japan)测定；红外光谱图由Bruker VERTEX70(USA)测定。
经鉴定，化合物1a为黄色油状物(甲醇)，分子式为C37H40O16，HR-ESI-MS m/z为739.2202[M-H]-。1H-NMR和13C-NMR数据见图1和图2。比旋光值(c 0.05，MeOH)。UV(MeOH)λmax(logε)204(1.35)、328(1.02)nm。IR vmax 3363、2919、2851、1706、1631、1600、1512、1451cm-1。
经鉴定，化合物1b为黄色油状物(甲醇)，分子式C37H40O16，HR-ESI-MS m/z为739.2201[M-H]-。1H-NMR和13C-NMR数据见图3和图4。比旋光值(c 0.05，MeOH)。UV(MeOH)λmax(logε)206(2.27)、326(2.13)nm。IR vmax 3363、2958、2846、1705、1633、1601、1512、1430cm-1。
经鉴定，化合物2a为黄色油状物(甲醇)，分子式C37H40O16，HR-ESI-MS m/z为739.2189[M-H]-。1H-NMR和13C-NMR数据见图5和图6。比旋光值(c 0.05，MeOH)。UV(MeOH)λmax(logε)206(2.22)、328(2.01)nm。IR vmax 3363、2921、2851、1702、1631、1600、1512、1450cm-1。
经鉴定，化合物2b为黄色油状物(甲醇)，分子式C37H40O16，HR-ESI-MS m/z为739.2199[M-H]-。1H-NMR和13C-NMR数据见图7和图8。比旋光值(c 0.1，MeOH)。UV(MeOH)λmax(logε)204(1.10)、328(0.90)nm。IR vmax 3384、2920、2851、1699、1631、1513、1452cm-1。
经鉴定，化合物3为无色油状物(甲醇)，分子式C36H38O16，HR-ESI-MS m/z为725.2046[M-H]-。1H-NMR和13C-NMR数据见图9和图10。比旋光值(c 0.05，MeOH)。UV(MeOH)λmax(logε)206(1.99)、326(1.92)nm。IR vmax 3388、2927、1695、1630、1598、1509、1449cm-1。
经鉴定，化合物4为黄色油状物(甲醇)，分子式C26H28O12，HR-ESI-MS m/z为531.1462[M-H]-。1H-NMR和13C-NMR数据见图11和图12。比旋光值(c 0.1，MeOH)。UV(MeOH)λmax(logε)206(2.04)、322(1.43)nm。IR vmax 3416、2963、1702、1632、1607、1583、1508、1437cm-1。
经鉴定，化合物5为黄色油状物(甲醇)，分子式C27H30O12，HR-ESI-MS m/z为545.1616[M-H]-。1H-NMR和13C-NMR数据见图13和图14。比旋光值(c 0.1，MeOH)。UV(MeOH)λmax(logε)322(4.16)、206(3.84)nm。IR vmax 3436、2958、1700、1632、1607、1584、1509、1438cm-1。
经鉴定，化合物6为无色油状物(甲醇)，分子式C27H30O12，HR-ESI-MS m/z为545.1615[M-H]-。1H-NMR和13C-NMR数据见图15和图16。比旋光值(c 0.1，MeOH)。UV(MeOH)λmax(logε)202(2.00)、322(0.70)nm。IR vmax 3410、2917、1732、1633、1607、1583、1508、1435cm-1。
经鉴定，化合物7为黄色油状物(甲醇)，分子式C25H26O12，HR-ESI-MS m/z为517.1308[M-H]-。1H-NMR和13C-NMR数据见图17和图18。比旋光值(c 0.1，MeOH)。UV(MeOH)λmax(logε)204(3.07)nm。IR vmax3386、2956、2920、2851、1697、1600、1517、1432cm-1。
经鉴定，化合物8为黄色油状物(甲醇)，分子式C27H28O12，HR-ESI-MS m/z为543.1460[M-H]-。1H-NMR和13C-NMR数据见图19和图20。比旋光值(c 0.1，MeOH)。UV(MeOH)λmax(logε)328(1.85)nm。IR vmax3396、2922、2851、1697、1631、1600、1515、1433cm-1。
经鉴定，化合物9为黄色油状物(甲醇)，分子式C35H32O15，HR-ESI-MS m/z为691.1626[M-H]-。1H-NMR和13C-NMR数据见图21和图22。比旋光值(c 0.1，MeOH)。UV(MeOH)λmax(logε)324(2.57)nm。IR vmax3385、2961、1695、1630、1601、1517、1448cm-1。
实施例3
本实施例提供了酰基奎宁类化合物1a、1b、2a、2b以及3～24对COX-2的抑制活性试验，具体包括以下步骤：
以(人)环氧化酶-2(购于碧云天生物技术有限公司)抑制剂筛选试剂盒测定酰基奎宁类化合物1a、1b、2a、2b以及3～24对COX-2的抑制活性。塞来昔布(celecoxib)作为阳性药物。按照操作说明书的内容对化合物1a、1b、2a、2b以及3～24进行试验。
活性试验结果表明，化合物1a、1b、2a、2b以及3～24对COX-2均具有较好的抑制作用，其IC50分别为0.63±0.014(1a)、0.75±0.028(1b)、0.15±0.023(2a)、0.63±0.016(2b)、0.30±0.013(3)、35.63±4.600(4)、8.70±1.241(5)、16.51±0.480(6)、0.69±0.049(7)、0.39±0.017(8)、0.26±0.080(9)、1.39±0.253(10)、0.72±0.042(11)、0.56±0.020(12)、2.98±0.234(13)、38.01±3.262(14)、0.41±0.051(15)、0.40±0.039(16)、0.28±0.038(17)、0.42±0.024(18)、0.69±0.038(19)、0.25±0.044(20)、0.26±0.038(21)、4.56±0.322(22)、0.17±0.012(23)、和0.26±0.055μM(24)。阳性对照药物celecoxib的IC50为0.03±0.004μM(该值与试剂盒提供的信息相符)，表明酰基奎宁类化合物1a、1b、2a、2b以及3～24具有较好的COX-2活性抑制作用，能够用于制备COX-2的抑制剂。
如上所述，较好的描述了本发明的基本原理、主要特征和优点。上述实施例和说明书仅仅是对本发明的优选实施方式进行描述，本发明不受上述实施例的限制，在不脱离本发明精神和范围的前提下，本领域普通技术人员对本发明的技术方案做出的各种改变和改进，均应落入本发明确定的保护范围内。
Claims (5)
1.酰基奎宁酸类化合物在制备抗炎药物方面的应用，其特征在于，所述酰基奎宁酸类化合物包括，化合物1a：acanthopacid A；化合物1b：acanthopacid B；化合物2a：acanthopacid C；化合物2b：acanthopacid D；化合物3：acanthopacid E；化合物4：acanthopacid F；化合物5：acanthopacid G；化合物6：acanthopacid H；化合物7：4-O-vanilloyl-5-O-caffeoylquinic acid methyl ester；化合物8：4-O-caffeoyl-5-O-feruloylquinic acid methyl ester；化合物9：1-O-feruloyl-3,4-di-O-caffeoylquinicacid；化合物10：5-p-trans-coumaroylquinic acid；化合物11：chlorogenic acid butylester；化合物12：chlorogenic acid；化合物13：5-O-feruloylquinic acid methylester；化合物14：1-O-caffeoyl-4-O-feruloylquinic acid；化合物15：1,3-di-O-feruloylquinic acid；化合物16：1,3-di-O-caffeoylquinic acid；化合物17：1,5-dicaffeoylquininic acid；化合物18：1-O-caffeoyl-5-O-feruloylquinic acid；化合物19：1-O-feruloyl-5-O-caffeoylquinic acid；化合物20：3,5-dicaffeoylquinic acidmethyl ester；化合物21：4,5-O-dicaffeoylquinic acid methyl ester；化合物22：4-O-syringoyl-5-O-caffeoylquinic acid methyl ester；化合物23：4-O-sinapoyl-5-O-caffeoylquinic acid methyl ester；化合物24：1,3,4-tri-O-caffeoylquinic acid。
2.根据权利要求1所述的应用，其特征在于，所述酰基奎宁酸类化合物对环氧化酶-2具有抑制活性。
3.一种抗炎药物，其特征在于，所述抗炎药物对环氧化酶-2具有抑制活性，其活性组分包括化合物1a：acanthopacid A；化合物1b：acanthopacid B；化合物2a：acanthopacid C；化合物2b：acanthopacid D；化合物3：acanthopacid E；化合物4：acanthopacid F；化合物5：acanthopacid G；化合物6：acanthopacid H；化合物7：4-O-vanilloyl-5-O-caffeoylquinic acid methyl ester；化合物8：4-O-caffeoyl-5-O-feruloylquinic acidmethyl ester；化合物9：1-O-feruloyl-3,4-di-O-caffeoylquinic acid；化合物10：5-p-trans-coumaroylquinic acid；化合物11：chlorogenic acid butyl ester；化合物12：chlorogenic acid；化合物13：5-O-feruloylquinic acid methyl ester；化合物14：1-O-caffeoyl-4-O-feruloylquinic acid；化合物15：1,3-di-O-feruloylquinic acid；化合物16：1,3-di-O-caffeoylquinic acid；化合物17：1,5-dicaffeoylquininic acid；化合物18：1-O-caffeoyl-5-O-feruloylquinic acid；化合物19：1-O-feruloyl-5-O-caffeoylquinic acid；化合物20：3,5-dicaffeoylquinic acid methyl ester；化合物21：4,5-O-dicaffeoylquinic acid methyl ester；化合物22：4-O-syringoyl-5-O-caffeoylquinic acid methyl ester；化合物23：4-O-sinapoyl-5-O-caffeoylquinicacid methyl ester；化合物24：1,3,4-tri-O-caffeoylquinic acid中的任一种。
4.一种酰基奎宁酸类化合物，其为化合物1a：acanthopacid A；化合物1b：acanthopacid B；化合物2a：acanthopacid C；化合物2b：acanthopacid D；化合物3：acanthopacid E；化合物4：acanthopacid F；化合物5：acanthopacid G；化合物6：acanthopacid H；化合物7：4-O-vanilloyl-5-O-caffeoylquinic acid methyl ester；化合物8：4-O-caffeoyl-5-O-feruloylquinic acid methyl ester；化合物9：1-O-feruloyl-3,4-di-O-caffeoylquinic acid。
5.根据权利要求4所述的应用，其特征在于，所述酰基奎宁酸类化合物从五加皮中分离纯化得到。
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