CN105037477A - Novel sodium taurocholate cotransporting polypeptide (NTCP) inhibitor - Google Patents
Novel sodium taurocholate cotransporting polypeptide (NTCP) inhibitor Download PDFInfo
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- 239000003112 inhibitor Substances 0.000 title claims abstract description 16
- 108010003524 sodium-bile acid cotransporter Proteins 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 230000005764 inhibitory process Effects 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims abstract description 3
- 108091006611 SLC10A1 Proteins 0.000 claims description 33
- 102100021988 Sodium/bile acid cotransporter Human genes 0.000 claims description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 8
- 239000004380 Cholic acid Substances 0.000 claims description 7
- 229960002685 biotin Drugs 0.000 claims description 7
- 239000011616 biotin Substances 0.000 claims description 7
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims description 7
- 229960002471 cholic acid Drugs 0.000 claims description 7
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 229960001661 ursodiol Drugs 0.000 claims description 6
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 claims description 5
- WBWWGRHZICKQGZ-UHFFFAOYSA-N Taurocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCCS(O)(=O)=O)C)C1(C)C(O)C2 WBWWGRHZICKQGZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- WBWWGRHZICKQGZ-GIHLXUJPSA-N taurocholic acid Chemical compound C([C@@H]1C[C@H]2O)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@H](O)C1 WBWWGRHZICKQGZ-GIHLXUJPSA-N 0.000 claims description 4
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 claims description 3
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims description 3
- 235000020958 biotin Nutrition 0.000 claims description 3
- 235000019416 cholic acid Nutrition 0.000 claims description 3
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims description 3
- 229920001184 polypeptide Polymers 0.000 claims description 3
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 3
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 3
- 229910001415 sodium ion Inorganic materials 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 125000001664 diethylamino group Chemical class [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 11
- 239000003613 bile acid Substances 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 8
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- 238000011160 research Methods 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 5
- 230000002503 metabolic effect Effects 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- 230000033228 biological regulation Effects 0.000 abstract description 3
- 230000002155 anti-virotic effect Effects 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 8
- 210000004185 liver Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 3
- 229940099352 cholate Drugs 0.000 description 3
- 210000003494 hepatocyte Anatomy 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 0 C*(CN(*)*)*N(*)C(CCCC[C@@]([C@]1N2)SC[C@@]1NC2=O)=O Chemical compound C*(CN(*)*)*N(*)C(CCCC[C@@]([C@]1N2)SC[C@@]1NC2=O)=O 0.000 description 2
- 108010078791 Carrier Proteins Proteins 0.000 description 2
- 108091006146 Channels Proteins 0.000 description 2
- 102000034573 Channels Human genes 0.000 description 2
- 206010008635 Cholestasis Diseases 0.000 description 2
- 108091006172 SLC21 Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 239000003833 bile salt Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- -1 ursodeoxycholic acid compound Chemical class 0.000 description 2
- JYKACEJSPSGKKG-QKIICEIZSA-N CC(C)C(CC[C@@H](C)[C@@H](CC1)[C@@](C)(CCC2[C@@](C)(CC[C@H](C3)O)C3C3)[C@@H]1[C@@H]2[C@H]3O)=O Chemical compound CC(C)C(CC[C@@H](C)[C@@H](CC1)[C@@](C)(CCC2[C@@](C)(CC[C@H](C3)O)C3C3)[C@@H]1[C@@H]2[C@H]3O)=O JYKACEJSPSGKKG-QKIICEIZSA-N 0.000 description 1
- 206010053759 Growth retardation Diseases 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- 102100032846 Solute carrier organic anion transporter family member 1A2 Human genes 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000001315 anti-hyperlipaemic effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 210000002469 basement membrane Anatomy 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 231100000359 cholestasis Toxicity 0.000 description 1
- 230000007870 cholestasis Effects 0.000 description 1
- 239000002812 cholic acid derivative Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000010235 enterohepatic circulation Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 231100000001 growth retardation Toxicity 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000031142 liver development Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 210000004738 parenchymal cell Anatomy 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- QYJVBVKFXDHFPQ-UHFFFAOYSA-N tert-butyl n-(2-aminoethyl)-n-methylcarbamate Chemical compound NCCN(C)C(=O)OC(C)(C)C QYJVBVKFXDHFPQ-UHFFFAOYSA-N 0.000 description 1
- 238000003041 virtual screening Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
Description
技术领域：Technical field:
本发明涉及生物素-胆酸/熊去氧胆酸化合物的合成及其对NTCP的抑制作用。The invention relates to the synthesis of biotin-cholic acid/ursodeoxycholic acid compound and its inhibitory effect on NTCP.
背景技术：Background technique:
在肝细胞上发现的钠离子牛磺胆酸共转运多肽(sodium-taurocholateco-transportingpolypeptide,NTCP)，是由SLC10A1基因编码的分布于肝细胞表面基底膜的转运蛋白，是钠盐胆汁酸肝肠循环中的重要通道蛋白。人NTCP蛋白含有349氨基酸，分子量56KDa，与大鼠NTCP蛋白有77％的同源性，含有9个跨膜区。人的NTCP蛋白绝大部分表达在肝脏，定位于肝细胞基底侧。NTCP对结合型胆酸盐有很高的转运亲和力，是肝脏从血液中摄取胆酸盐的主要通道蛋白，同时能够使血中的胆酸盐维持在很低的水平。The sodium-taurocholateco-transporting polypeptide (NTCP) found on hepatocytes is a transporter encoded by the SLC10A1 gene and distributed on the basement membrane on the surface of hepatocytes. important channel proteins. Human NTCP protein contains 349 amino acids, molecular weight 56KDa, has 77% homology with rat NTCP protein, and contains 9 transmembrane regions. The vast majority of human NTCP protein is expressed in the liver, located in the basal side of hepatocytes. NTCP has a high transport affinity for conjugated cholate, and is the main channel protein for the liver to take up cholate from the blood, while maintaining a low level of cholate in the blood.
多个研究表明，NTCP的抑制可以影响胆酸的肝肠循环，抑制胆酸从血液中进入肝脏，从而缓解胆汁淤积，降低代谢水平。2015年报道了一例NTCP点突变的病例，所涉女婴由于携带NTCP的突变蛋白NTCPR252H，导致胆酸转运活性降低，血清中的胆酸浓度达到了445μM(正常<16μM)，并出现了多种代谢相关调节因子含量低和生长迟缓等症状，但肝脏发育正常。因此，NTCP的抑制可以阻滞胆酸回收进入肝脏，在抗胆汁淤积及代谢调节中可以起到潜在的应用价值。Several studies have shown that the inhibition of NTCP can affect the enterohepatic circulation of bile acid, inhibit the entry of bile acid from the blood into the liver, thereby alleviating cholestasis and reducing the metabolic level. In 2015, a case of NTCP point mutation was reported. The baby girl involved was carrying NTCP mutant protein NTCP R252H , resulting in reduced bile acid transport activity, and the concentration of bile acid in serum reached 445 μM (normal <16 μM), and multiple symptoms appeared. Symptoms include low levels of a metabolic-related regulator and growth retardation, but normal liver development. Therefore, the inhibition of NTCP can block bile acid recycling into the liver, which can play a potential application value in anti-cholestasis and metabolic regulation.
2012年，李文辉课题组还发现NTCP是乙型肝炎病毒HBV进入肝细胞的受体，这也是HBV研究的重大突破。后续的研究表明，NTCP抑制剂可以抑制HBV感染肝细胞，为乙肝治疗的药物研发提供了很好的理论基础。In 2012, Li Wenhui's research group also discovered that NTCP is the receptor for hepatitis B virus HBV to enter liver cells, which is also a major breakthrough in HBV research. Subsequent studies have shown that NTCP inhibitors can inhibit HBV from infecting liver cells, which provides a good theoretical basis for the development of drugs for hepatitis B treatment.
而且，肝脏中除了NTCP之外，还有大量钠离子非依赖性胆酸盐转运蛋白，如有机阴离子转运蛋白家族(OATPs)，可以执行与NTCP相类似的功能，从血液中将胆酸盐转运到肝脏中，因此NTCP的缺失不会造成临床上的病变。基于此，抑制NTCP理论上应该不会引起明显的副作用。Moreover, in addition to NTCP, there are a large number of sodium ion-independent bile salt transporters in the liver, such as the organic anion transporter family (OATPs), which can perform similar functions to NTCP, transporting bile salt from the blood to the liver, so the absence of NTCP does not cause clinical lesions. Based on this, inhibiting NTCP should theoretically cause no significant side effects.
JamesE.Polli对胆酸衍生物进行研究发现，该类化合物具有NTCP抑制活性(InternationalJournalofPharmaceutics396(2010)111–118；JournalofPharmaceuticalSciences,2011.100(3),1184-1195)，2013年JamesE.Polli及其团队成员采用药效团模型和贝叶斯模型，对胆酸衍生物进行NTCP抑制剂的虚拟筛选，结果发现31个药物分子作为先导化合物分子，其中27个抑制剂是以前没有报道抑制NTCP活性的化合物，并且其中的几个抑制剂经过测活发现，分别具有抗真菌、抗高血脂、抗高血压等疗效(MolPharm.2013,10(3):1008–1019)。JamesE.Polli's research on cholic acid derivatives found that these compounds have NTCP inhibitory activity (International Journal of Pharmaceuticals 396 (2010) 111-118; Journal of Pharmaceutical Sciences, 2011.100 (3), 1184-1195), adopted by JamesE. Polli and his team members in 2013 Pharmacophore model and Bayesian model, virtual screening of NTCP inhibitors on bile acid derivatives, found 31 drug molecules as lead compound molecules, of which 27 inhibitors are compounds that have not been reported to inhibit NTCP activity before, and Several of the inhibitors were found to have anti-fungal, anti-hyperlipidemic, and anti-hypertensive effects (MolPharm. 2013, 10(3): 1008-1019).
本发明涉及的新型生物素-胆酸/熊去氧胆酸类化合物，具有很强的NTCP抑制活性，且该类化合物作为NTCP抑制剂，迄今尚未见有国内外的相关报道。本发明涉及的新型NTCP抑制剂，为抗胆汁酸转运药物的抗病毒、抗胆汁淤积及代谢调节作用指明了方向。The novel biotin-cholic acid/ursodeoxycholic acid compounds involved in the present invention have strong NTCP inhibitory activity, and as NTCP inhibitors, there have been no related reports at home and abroad so far. The novel NTCP inhibitor involved in the invention points out the direction for the antiviral, anticholestasis and metabolic regulation effects of anti-bile acid transport drugs.
发明内容:Invention content:
本发明的目的之一是，提供新型生物素-胆酸/熊去氧胆酸类钠离子牛磺胆酸共转运多肽抑制剂。One of the objectives of the present invention is to provide a novel biotin-cholic acid/ursodeoxycholic acid sodium ion taurocholic acid co-transport polypeptide inhibitor.
本发明的目的之二是，提供制备所述化合物的方法。The second object of the present invention is to provide a method for preparing the compound.
本发明的目的之三是，提供所述化合物在抑制NTCP中的应用。The third object of the present invention is to provide the application of said compound in inhibiting NTCP.
本发明的目的之四是，提供所述化合物为有效成份与药学上可接受的载体组成的药物组合物及其对NTCP的抑制作用。The fourth object of the present invention is to provide a pharmaceutical composition composed of the compound as an active ingredient and a pharmaceutically acceptable carrier and its inhibitory effect on NTCP.
本发明所述化合物的结构如式(1)所示：The structure of the compound of the present invention is shown in formula (1):
本发明所述化合物(I)的合成方法是，通过生物素(II)与N,N-二取代二乙胺的缩合反应制备化合物(IV)，化合物(IV)溶解于二氯甲烷中，通入盐酸气体脱Boc保护基，制得化合物(V)，化合物(V)与胆酸或熊去氧胆酸反应制备相应的目标化合物(I)。The synthesis method of the compound (I) of the present invention is to prepare the compound (IV) through the condensation reaction of biotin (II) and N,N-disubstituted diethylamine, the compound (IV) is dissolved in dichloromethane, and the Adding hydrochloric acid gas to remove the Boc protecting group, the compound (V) is obtained, and the compound (V) is reacted with cholic acid or ursodeoxycholic acid to prepare the corresponding target compound (I).
附图说明：Description of drawings:
图1：化合物对NTCP活性检测结果Figure 1: The detection results of compounds on NTCP activity
其中：BCA：化合物I-1；BUDCA：化合物I-2Among them: BCA: Compound I-1; BUDCA: Compound I-2
具体实施方式：Detailed ways:
以下实施例仅为帮助本领域技术人员更好地理解本发明，但不以任何方式限制本发明。The following examples are only to help those skilled in the art better understand the present invention, but do not limit the present invention in any way.
《实施例1》N-Boc-N-甲基乙二胺-生物素(IV)的合成"Example 1" Synthesis of N-Boc-N-methylethylenediamine-biotin (IV)
将生物素(II,11.68g,47.82mM)，1.5eqHOBt(9.69g)，2.0eqEDCI(18.34g)加入25mL无水干燥的DMF中，电磁搅拌2h。然后加入2.0eqDIEA(15.78mL)和N-Boc-N-甲基乙二胺(III,10.0g,57.38mM)，搅拌过夜。加入500ml水淬灭。反应液用DCM(3×150mL)萃取，1NHCl(3×100mL)，1NNaOH(3×100mL)和饱和食盐水(2×100mL)洗涤。有机层用无水Mg2SO4干燥，过滤，旋干，得白色固体IV(14.52g)，产率：75.82％。Biotin (II, 11.68g, 47.82mM), 1.5eqHOBt (9.69g), 2.0eqEDCI (18.34g) were added to 25mL of anhydrous dry DMF, and electromagnetically stirred for 2h. Then 2.0eq DIEA (15.78mL) and N-Boc-N-methylethylenediamine (III, 10.0g, 57.38mM) were added and stirred overnight. Add 500ml of water to quench. The reaction solution was extracted with DCM (3×150 mL), washed with 1N HCl (3×100 mL), 1N NaOH (3×100 mL) and saturated brine (2×100 mL). The organic layer was dried with anhydrous Mg 2 SO 4 , filtered, and spin-dried to obtain white solid IV (14.52 g), yield: 75.82%.
《实施例2》N-甲基乙二胺-生物素的(V)合成"Example 2" (V) synthesis of N-methylethylenediamine-biotin
将IV(10.01g,25mM)溶于二氯甲烷(60mL)中，在室温下通干燥的盐酸气2.5h，继续搅拌1.5h。将反应液旋干，真空干燥，得白色固体V(8.34g)，产率：99.1％。Dissolve IV (10.01g, 25mM) in dichloromethane (60mL), pass dry hydrochloric acid gas at room temperature for 2.5h, and continue stirring for 1.5h. The reaction solution was spin-dried and vacuum-dried to obtain white solid V (8.34 g), yield: 99.1%.
《实施例3》CA-N-甲基乙二胺-生物素(I-1)的合成"Example 3" Synthesis of CA-N-methylethylenediamine-biotin (I-1)
将胆酸(2.04g,5mM)，1.5eqHOBt(1.08g)，2.0eqEDCI(1.98g)加入10mL无水干燥的DMF中，电磁搅拌2h。然后加入3.6eqDBU(2.79g)和V(1.52g,4.51mM)，搅拌过夜。Cholic acid (2.04g, 5mM), 1.5eqHOBt (1.08g), 2.0eqEDCI (1.98g) were added to 10mL of anhydrous and dried DMF, and electromagnetically stirred for 2h. Then 3.6eq DBU (2.79g) and V (1.52g, 4.51mM) were added and stirred overnight.
加入500ml水淬灭。反应液分别用DCM(3×30mL)萃取，1NHCl(3×30mL)，1NNaOH(3×30mL)，和饱和食盐水(2×40mL)洗涤。有机层用无水Mg2SO4干燥，过滤，旋干，得黄色油状液体，用硅胶柱纯化得I-1白色固体(1.76g)，产率：51.2％。Add 500ml of water to quench. The reaction solution was extracted with DCM (3×30 mL), washed with 1N HCl (3×30 mL), 1N NaOH (3×30 mL), and saturated brine (2×40 mL), respectively. The organic layer was dried with anhydrous Mg 2 SO 4 , filtered, and spin-dried to obtain a yellow oily liquid, which was purified by a silica gel column to obtain I-1 as a white solid (1.76 g), yield: 51.2%.
《实施例4》UDCA-N-甲基乙二胺-生物素(I-2)的合成《Example 4》The synthesis of UDCA-N-methylethylenediamine-biotin (I-2)
将熊去氧胆酸(2.99g,7.61mM),1.5eqHOBt(1.64g),2.0eqEDCI(3.01g)加入10mL无水干燥的DMF中，电磁搅拌2h。然后加入3.6eqDBU(4.24g)和V(2.32g,6.87mM)，搅拌过夜。加入100mL水淬灭。反应液分别用DCM(3×30mL)萃取，1NHCl(3×30mL)，1NNaOH(3×30mL)，和饱和食盐水(2×40mL)洗涤。有机层用无水Mg2SO4干燥，过滤，旋干，得黄色油状液体，用硅胶柱纯化得白色固体I-2(2.35g)，产率：45.8％。Add ursodeoxycholic acid (2.99g, 7.61mM), 1.5eqHOBt (1.64g), 2.0eqEDCI (3.01g) into 10mL of anhydrous dry DMF, and stir for 2h. Then 3.6eq DBU (4.24g) and V (2.32g, 6.87mM) were added and stirred overnight. Add 100 mL of water to quench. The reaction solution was extracted with DCM (3×30 mL), washed with 1N HCl (3×30 mL), 1N NaOH (3×30 mL), and saturated brine (2×40 mL), respectively. The organic layer was dried with anhydrous Mg 2 SO 4 , filtered, and spin-dried to obtain a yellow oily liquid, which was purified by a silica gel column to obtain a white solid I-2 (2.35 g), yield: 45.8%.
《实施例5》生物活性检测结果《Example 5》biological activity detection result
NTCP的主要生理功能是运输胆酸，可以用抑制NTCP的胆酸转运效率来检测化合物对NTCP的抑制作用。鼠肝脏实质细胞高表达NTCP后，采用H3摄入法测定化合物对NTCP的抑制作用。用缓冲液配制H3标记的牛磺胆酸至10μM，并将不同浓度的I-1或I-2与其混合，同时处理细胞10分钟，然后弃去培养液，用不含H3标记的牛磺胆酸3次清洗细胞，然后裂解细胞进行H3的测定。结果见图1，表明I-1和I-2均能够很明显地抑制NTCP的活性。The main physiological function of NTCP is to transport bile acid, and the inhibitory effect of compounds on NTCP can be detected by inhibiting the bile acid transport efficiency of NTCP. After rat liver parenchymal cells highly expressed NTCP, the inhibitory effect of compounds on NTCP was determined by H3 uptake method. Prepare H3-labeled taurocholic acid to 10 μM with buffer, mix different concentrations of I-1 or I-2 with it, and treat cells for 10 minutes at the same time, then discard the culture medium, and use taurocholic acid without H3-labeled The cells were washed with acid three times, and then the cells were lysed for the determination of H3. The results are shown in Figure 1, indicating that both I-1 and I-2 can obviously inhibit the activity of NTCP.
初步研究结果表明，新型生物素-胆酸/熊去氧胆酸化合物具有良好的NTCP抑制活性，作为一类具有潜力的NTCP抑制剂值得进行更深入的研究与开发，为抗胆汁酸转运药物的抗病毒作用指明了研究方向。Preliminary research results show that the new biotin-cholic acid/ursodeoxycholic acid compound has good NTCP inhibitory activity. As a class of potential NTCP inhibitors, it is worthy of further research and development. The antiviral effect points out the research direction.
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| CN115490745A (en) * | 2022-09-24 | 2022-12-20 | 昆明理工大学 | Ginsenoside Rh 4-biotin active molecular probe and preparation method and application thereof |
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