CN102579422B - 黄酮类化合物在制备抗代谢性疾病药物中的用途 - Google Patents
黄酮类化合物在制备抗代谢性疾病药物中的用途 Download PDFInfo
- Publication number
- CN102579422B CN102579422B CN 201110001869 CN201110001869A CN102579422B CN 102579422 B CN102579422 B CN 102579422B CN 201110001869 CN201110001869 CN 201110001869 CN 201110001869 A CN201110001869 A CN 201110001869A CN 102579422 B CN102579422 B CN 102579422B
- Authority
- CN
- China
- Prior art keywords
- compound
- compounds
- insulin
- application
- glucose
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 239000003814 drug Substances 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims description 3
- 208000030159 metabolic disease Diseases 0.000 title abstract 2
- -1 flavonoids compound Chemical class 0.000 title description 9
- 230000001399 anti-metabolic effect Effects 0.000 title description 3
- 208000016097 disease of metabolism Diseases 0.000 title 1
- 229930003935 flavonoid Natural products 0.000 title 1
- 235000017173 flavonoids Nutrition 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 53
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 14
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 8
- 239000003472 antidiabetic agent Substances 0.000 claims abstract description 7
- BKOOMYPCSUNDGP-UHFFFAOYSA-N trimethyl-ethylene Natural products CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 claims description 7
- 230000001610 euglycemic effect Effects 0.000 claims description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 abstract description 40
- 102000004877 Insulin Human genes 0.000 abstract description 22
- 108090001061 Insulin Proteins 0.000 abstract description 22
- 241000699670 Mus sp. Species 0.000 abstract description 20
- 229940125396 insulin Drugs 0.000 abstract description 20
- 239000008280 blood Substances 0.000 abstract description 17
- 210000004369 blood Anatomy 0.000 abstract description 17
- 210000001789 adipocyte Anatomy 0.000 abstract description 16
- 230000004069 differentiation Effects 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 12
- 240000000249 Morus alba Species 0.000 abstract description 10
- 235000008708 Morus alba Nutrition 0.000 abstract description 9
- 206010022489 Insulin Resistance Diseases 0.000 abstract description 7
- 238000002474 experimental method Methods 0.000 abstract description 3
- 239000003524 antilipemic agent Substances 0.000 abstract 1
- 230000001737 promoting effect Effects 0.000 abstract 1
- 230000001235 sensitizing effect Effects 0.000 abstract 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 16
- 239000008103 glucose Substances 0.000 description 16
- 101150110386 SLC2A4 gene Proteins 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 230000014509 gene expression Effects 0.000 description 9
- 230000006377 glucose transport Effects 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 7
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 229930003944 flavone Natural products 0.000 description 7
- 235000011949 flavones Nutrition 0.000 description 7
- 239000001963 growth medium Substances 0.000 description 7
- 210000002966 serum Anatomy 0.000 description 7
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 7
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 7
- 210000000577 adipose tissue Anatomy 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 239000002953 phosphate buffered saline Substances 0.000 description 6
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 230000004936 stimulating effect Effects 0.000 description 5
- 101710168309 CCAAT/enhancer-binding protein alpha Proteins 0.000 description 4
- 102100034808 CCAAT/enhancer-binding protein alpha Human genes 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 238000007410 oral glucose tolerance test Methods 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 4
- 101001062864 Homo sapiens Fatty acid-binding protein, adipocyte Proteins 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000218213 Morus <angiosperm> Species 0.000 description 3
- 101150023417 PPARG gene Proteins 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- 238000003304 gavage Methods 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000218231 Moraceae Species 0.000 description 2
- 108091006300 SLC2A4 Proteins 0.000 description 2
- 229940127003 anti-diabetic drug Drugs 0.000 description 2
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 230000024245 cell differentiation Effects 0.000 description 2
- 230000003915 cell function Effects 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- QSKWJTXWJJOJFP-UHFFFAOYSA-N chloroform;ethoxyethane Chemical compound ClC(Cl)Cl.CCOCC QSKWJTXWJJOJFP-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- CSCPPACGZOOCGX-WFGJKAKNSA-N deuterated acetone Substances [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 201000005577 familial hyperlipidemia Diseases 0.000 description 2
- 241000411851 herbal medicine Species 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 239000004026 insulin derivative Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000003753 real-time PCR Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000010839 reverse transcription Methods 0.000 description 2
- 229960004586 rosiglitazone Drugs 0.000 description 2
- 229930182733 sanggenol Natural products 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- FVFVNNKYKYZTJU-UHFFFAOYSA-N 6-chloro-1,3,5-triazine-2,4-diamine Chemical compound NC1=NC(N)=NC(Cl)=N1 FVFVNNKYKYZTJU-UHFFFAOYSA-N 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000030914 Fatty Acid-Binding Human genes 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 206010023379 Ketoacidosis Diseases 0.000 description 1
- 208000007976 Ketosis Diseases 0.000 description 1
- 241000301123 Morus cathayana Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- VRYALKFFQXWPIH-JYVPUZSJSA-N O=C([C@@]([C@@H](O)[C@H](O)[C@H](O)CO)([3H])[2H])[3H] Chemical compound O=C([C@@]([C@@H](O)[C@H](O)[C@H](O)CO)([3H])[2H])[3H] VRYALKFFQXWPIH-JYVPUZSJSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- NPGIHFRTRXVWOY-UHFFFAOYSA-N Oil red O Chemical compound Cc1ccc(C)c(c1)N=Nc1cc(C)c(cc1C)N=Nc1c(O)ccc2ccccc12 NPGIHFRTRXVWOY-UHFFFAOYSA-N 0.000 description 1
- 108010016731 PPAR gamma Proteins 0.000 description 1
- 102000000536 PPAR gamma Human genes 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 102000023732 binding proteins Human genes 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 230000023852 carbohydrate metabolic process Effects 0.000 description 1
- 235000021256 carbohydrate metabolism Nutrition 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000013211 curve analysis Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 108091022862 fatty acid binding Proteins 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000004190 glucose uptake Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 102000013415 peroxidase activity proteins Human genes 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属医药技术领域,涉及式(I)结构化合物的用途,具体涉及所述化合物(5aR,10aS)-5a,10a-二氢-1,3,8,10a-四羟基-2,5a-二(3-甲基-2-丁烯基)-11H-苯并呋喃[3,2-b][1]苯并吡喃-11-酮在治疗代谢性疾病中的用途。该化合物从黑桑中分离得到。实验证实,该化合物具有很强的促进脂肪细胞分化、增加糖尿病小鼠的胰岛素敏感性、降低血糖和血脂的作用,可进一步制成胰岛素增敏剂、降糖药物以及降脂药物应用于医药领域。
Description
技术领域
本发明属医药技术领域,涉及黄酮类化合物新的药物用途,具体涉及从黑桑中分离得到的黄酮类化合物的用途。尤其涉及化合物(5aR,10aS)-5a,10a-二氢-1,3,8,10a-四羟基-2,5a-二(3-甲基-2-丁烯基)-11H-苯并呋喃[3, 2-b][1]苯并吡喃-11-酮在提高胰岛素敏感性、治疗糖尿病和高脂血症方面的用途。
背景技术
近年来,由于生活水平的提高、饮食结构的改变、日趋紧张的生活节奏以及少动多坐的生活方式等诸多因素,全球糖尿病发病率增长迅速,糖尿病已经成为继肿瘤、心脑血管疾病之后第三大严重威胁人类健康的疾病。据世界卫生组织预计,到2025年,全球成人糖尿病患者人数将增至3亿。
2型糖尿病占总糖尿病的90%,其主要发病机制是胰岛素抵抗、胰岛β细胞功能衰竭和胰岛素分泌障碍。2型糖尿病病人多伴随有肥胖、高甘油三脂或高胆固醇血症,高血脂是胰岛素抵抗和胰岛β细胞功能紊乱的主要原因之一。糖尿病可导致多种急性和慢性并发症,如酮症酸中毒、心脑血管疾病、肾病等,对人类健康构成严重威胁。目前常用的降糖药有:胰岛素、磺脲类药物、非磺脲类胰岛素促分泌剂、双胍类降糖药、胰岛素增敏剂等,这几类降糖药作用快、疗效好、但毒副作用强,对肝、肾等器官损害,部分糖尿病人对胰岛素表现明显的抗药性。糖尿病为终身性疾病,需长期服药,因此,发现新的安全有效的抗糖尿病药物是目前社会的迫切需要。
脂肪组织是餐后葡萄糖吸收的主要部位,分化的脂肪细胞能高水平表达葡萄糖载体4(Glut4)。Glut4是一种糖蛋白,具有在胰岛素的作用下将葡萄糖转运至脂肪细胞内的功能。增加Glut4蛋白的表达量能增加脂肪组织对葡萄糖的转运,改善对胰岛素刺激的葡萄糖摄取的抵抗。糖尿病患者机体中Glut4表达减少、移位障碍,是胰岛素抵抗的主要原因,因此,寻找促进脂肪细胞分化、提高Glut4表达、增加胰岛素敏感性而促进葡萄糖转运的药物对治疗2型糖尿病具有重要的临床意义。我国有丰富的天然药物资源和悠久的应用中草药的历史,并且各少数民族在与疾病的斗争中积累了宝贵的民族药,这些都成为药物发现的重要源泉。
黑桑(Morus nigra Linn.)为桑科(Moraceae)桑属植物,原产伊朗,后传入我国,现在新疆喀什、阿克苏地区广泛栽培。黑桑在维吾尔医药中早已应用,俗称“药桑”,根皮和茎枝具有降血压、抗衰老、消炎止痛等功效。结构如式(I)所示的化合物桑根醇F(sanggenol F)是从黑桑中分离得到的(参考文献:傅大煦等,《黑桑的化学成分研究》,中草药,2005, 36 (9), 1296-1299)。另有文献报道,Fukai T. 等从桑属植物华桑(Morus cathayana Hemsl.)中首次分离得到如式(I)所示的化合物sanggenol F(Phytochemistry, 1997,
47(2), 273-280)。未见该化合物的生物活性研究报道。
发明内容
本发明的目的是提供黄酮类化合物新的药物用途,尤其涉及化合物(5aR,10aS)-5a,10a-二氢-1,3,8,10a-四羟基-2,5a-二(3-甲基-2-丁烯基)-11H-苯并呋喃[3, 2-b][1]苯并吡喃-11-酮在提高胰岛素敏感性、治疗糖尿病和高脂血症方面的用途。
本发明所述黄酮类化合物是从黑桑中分离得到的天然化合物。该黄酮类化合物具有如下式(I)的结构,
(I)
本发明所述的式(I)结构的化合物,尤其是化合物(5aR,10aS)-5a,10a-二氢-1,3,8,10a-四羟基-2,5a-二(3-甲基-2-丁烯基)-11H-苯并呋喃[3, 2-b][1]苯并吡喃-11-酮,经实验证实,其具有很强的促进脂肪细胞分化、增加Glut4蛋白的表达量而增加胰岛素敏感性和促进葡萄糖转运的作用,并具有降低血脂的功效,可进一步作为胰岛素增敏剂、降糖药物、降脂药物应用于医药领域。
本发明的黄酮类化合物是从黑桑中分离得到的天然化合物,通过如下方法制备:
将黑桑Morus nigra Linn.的茎枝粉碎后,用有机溶剂或/和水提取制备总提取物,所用的有机溶剂可采用醇类,如乙醇,甲醇等,其中优选95%(体积比)乙醇,将总提取物溶于水后,用石油醚萃取,取石油醚相,回收溶剂后干燥即得石油醚提取物;
将石油醚提取物进行硅胶柱色谱分离, 分别用石油醚、石油醚-丙酮梯度洗脱,其中石油醚-丙酮4∶1洗脱部分进行硅胶柱色谱分离, 以氯仿-***(5∶1) 洗脱, 然后再进行ODS柱色谱分离,以甲醇-水梯度洗脱,得到化合物 (5aR,10aS)-5a,10a-二氢-1,3,8,10a-四羟基-2,5a-二(3-甲基-2-丁烯基)-11H-苯并呋喃[3, 2-b][1]苯并吡喃-11-酮,用波谱方法鉴定其结构,如式()的结构。
本发明式()的化合物进行了体外脂肪细胞分化、葡萄糖转运和体内db/db小鼠糖代谢、脂代谢相关实验,结果表明,所述化合物(I)具有很强的促进脂肪细胞分化、增强胰岛素刺激的脂肪细胞葡萄糖转运而增加胰岛素敏感性的作用,并具有降血脂的作用,可作为胰岛素增敏剂、降血糖、降血脂药物及应用于医药领域。
进一步,本发明式(I)的化合物(5aR,10aS)-5a,10a-二氢-1,3,8,10a-四羟基-2,5a-二(3-甲基-2-丁烯基)-11H-苯并呋喃[3, 2-b][1]苯并吡喃-11-酮可作为药物的有效成分,制备抗代谢性疾病的药物。所述的药物是胰岛素增敏剂,降血糖药物或降血脂药物。
附图说明
图1为实施例2中本发明化合物(I)对3T3-L1前脂肪细胞分化作用的影响。
图2为实施例3中本发明化合物(I)对胰岛素刺激的葡萄糖转运的影响。
图3为实施例4中本发明化合物(I)对db/db小鼠口服糖耐量(OGTT)的影响。
图4为实施例4中本发明化合物(I)对db/db小鼠OGTT曲线下面积的影响。
图5为实施例5中本发明化合物(I)对db/db小鼠胰岛素耐量(ITT)的影响。
图6为实施例5中本发明化合物(I)对db/db小鼠ITT曲线下面积的影响。
图7为实施例6中本发明化合物(I)对db/db小鼠脂肪组织基因aP2、C/EBPα、PPARg和Glut4表达水平的影响。
图8为实施例7中本发明化合物(I)对db/db小鼠血清甘油三酯(TG)、胆固醇(TC)水平的影响。
图1至图8中,* p < 0.05 and
** p < 0.01(与对照组相比)。
具体实施方式
下面结合具体实施实例对本发明作进一步阐述,但不限制本发明。
实施例 1 从黑桑中提取本发明化合物(I)
(1)提取:黑桑干燥茎枝粉碎后得粗粉2 公斤, 95%含水乙醇室温浸提三次,分别得到提取液8升、6升、4升,合并提取液,减压浓缩至干,得到浸膏204克。将此浸膏溶于水悬浮,用石油醚萃取,回收溶剂浓缩至干,得石油醚提取物47克。
(2)分离:将石油醚提取物47克进行硅胶柱色谱分离, 分别用石油醚、石油醚-丙酮(30∶1→20∶1→10∶1→9∶1→6∶1→4∶1)梯度洗脱,每个梯度用量3000毫升,收集流份,得到组分1~17份。石油醚-丙酮4∶1洗脱得到组分15~17,其中组分15(800毫克)经硅胶柱色谱分离, 氯仿-***(5∶1) 洗脱700毫升, 得到组分15.1~15.3;将组分15.2(450毫克)进行ODS柱色谱分离, 甲醇-水(7∶3→8∶2→9∶1) 梯度洗脱, 每个梯度用量500毫升,收集流份,甲醇-水(8∶2)流份得到化合物 (I)(5aR,10aS)-5a,10a-二氢-1,3,8,10a-四羟基-2,5a-二(3-甲基-2-丁烯基)-11H-苯并呋喃[3, 2-b][1]苯并吡喃-11-酮 201毫克。
(3)化合物(I)的理化性质及光谱数据如下述:分子式为C25H26O7;其性状为黄色无定形粉末;比旋光:[a]20 D
+165.6°(c 1.03, Me2CO);电子轰击质谱(质荷比):438 [M]+;核磁共振氢谱(500 MHz)数据(化学位移:ppm,偶合常数:Hz, 溶剂:氘代丙酮):δ 11.91(1H,s,OH-5),9.12(2H,br s,OH-7, 4′),7.35(1H,d,J = 8.2 Hz,H-6′),7.03(1H,br s,OH-3), 6.52(1H,dd,J = 1.6,8.2 Hz,H-5′),6.40(1H,d,J = 1.6 Hz,H-3′),5.92(1H,s,H-8), 5.25(1H,br t,J = 7.0 Hz,H-2″),5.19(1H,br t,J = 7.0 Hz,H-10),3.23 (2H,br d,J = 7.0 Hz,H2-1″),3.12(1H,br dd,J = 8.8,14.7 Hz,H-9a), 2.78(1H,br dd,J = 6.1,14.7 Hz,H-9b),1.73, 1.623(各3H,br s,H3-4″, 5″),1.615, 1.52 (各3H,br s,H3-12, 13);核磁共振碳谱(100 MHz)数据(化学位移:ppm,溶剂:氘代丙酮):d 188.2 s(C-4),166.6 s(C-7),162.7 s(C-5),161.6 s(C-8a),161.3 s(C-2¢),161.2 s(C-4¢),136.5 s(C-11),131.4 s(C-3¢¢),125.6 d(C-6¢),123.3 d(C-2¢¢),121.4 s(C-1¢),118.7 d(C-10),109.7 d(C-5¢),109.1 s(C-6),102.6 s(C-3),100.2 s(C-4a),99.5 d(C-3¢),95.3 s(C-8),91.8 s(C-2),31.9 t(C-9),25.8 q(C-13,5¢¢),21.5 t(C-1¢¢),18.1 q(C-12),17.8 q(C-4¢¢)。
实施例 2 本发明化合物(I)对3T3-L1前脂肪细胞分化的影响(油红染色法)
将3T3-L1细胞接种于48孔板,用含10% NCS(小牛血清)的高糖H-DMEM培养基培养。2天后改用含125 μM IBMX(3-异丁基-1-甲基黄嘌呤)、1μM Dex(***)、20 μg/ml Insulin(胰岛素)的10% FBS(胎牛血清)培养基诱导分化,并加入不同浓度的化合物(I)。分化2天后,分化细胞的培养基改用含20 μg/ml Insulin、10%的FBS和不同浓度化合物(I)的高糖H-DMEM培养基,每2天换液一次,连续换三次。细胞分化8天后弃培养基,用PBS(磷酸盐缓冲盐水)洗一次,每孔小心加入300 µl的10%***(终浓度为4%甲醛),37℃孵育15分钟。弃10%***,用PBS洗两次,吸干PBS,油红O 染色30分钟,弃上清,加入300 µl的PBS,拍照。结果证实本发明化合物(I)可剂量依赖性的增加3T3-L1细胞内脂滴的含量, 能明显促进3T3-L1细胞向脂肪细胞分化(如图1所示)。
实施例 3本发明化合物(I)对已分化3T3-L1脂肪细胞葡萄糖转运的影响
将3T3-L1细胞接种于48孔板,分化培养方法与油红染色法相同,细胞分化8天后,弃去培养基,用无血清DMEM洗一遍,1ml/孔,加入含有0.1% BSA (牛血清清蛋白)的DMEM,300 µl/孔。37℃温育3-5h。弃去培养基,用HRP buffer洗一遍,加入HRP buffer(提前37℃温育,含有10 ng/ml 胰岛素),200 µl/孔,37℃温育15min。补加HRP buffer(含有2-deoxy-d-[1,2-3H]-glucose,终浓度稀释2000倍),100µl/孔,37℃温育10min。弃去板中所有液体,用冰冷的HRP buffer(300 µl /孔)洗一遍,吸掉,加入HRP buffer (400-500 μl/孔)再洗一遍,弃去。加入HRP buffer(含有0.1-0.5% TritonX-100),200μl/孔,过夜裂解。加入闪烁液 800µl/孔,检测。结果证实本发明化合物(I)能够剂量依赖性促进胰岛素刺激的葡萄糖转运而增强胰岛素的敏感性,其浓度为10 μM时,作用略强于降糖药物罗格列酮(Rosiglitazone)(如图2所示)。
实施例 4 本发明化合物(I)对db/db糖尿病小鼠口服糖耐量(OGTT)的影响
将8周龄的db/db小鼠按体重血糖分为两组:对照组(每天腹腔注射橄榄油,0.1ml/只)和给药组(每天腹腔注射橄榄油溶解的化合物(I),5 mg/kg, 0.1ml/只),每组6只,给药21天,第22天测口服糖耐量(OGTT):禁食12h,测对照组和给药组血糖、体重,根据体重灌胃葡萄糖(1g/kg)记为0时,灌胃后分别测60、90、120、150 min血糖。结果显示,给与本发明化合物(I)的db/db小鼠经口灌服葡萄糖后血糖低于对照组,曲线下面积明显小于对照组,说明本发明化合物(I)能提高db/db小鼠葡萄糖耐量(如图3和图4所示)。
实施例 5 本发明化合物(I)对db/db糖尿病小鼠胰岛素耐量(ITT)的影响
db/db小鼠给药18天(方法同上),第19天测胰岛素耐量(ITT):禁食6h,测对照组和给药组血糖、体重,根据体重腹腔注射胰岛素(1U/kg)记为0时,灌胃后分别测30、60、90、120 min血糖。结果显示,给与本发明化合物(I)的db/db小鼠在同样剂量胰岛素作用下,血糖明显低于对照组,说明本发明化合物(I)能提高db/db小鼠胰岛素敏感性(如图5和图6所示)。
实施例 6 本发明化合物(I)对db/db糖尿病小鼠脂肪组织基因表达水平的影响
db/db小鼠给与本发明化合物(I)三周后(方法同上),解剖,取脂肪组织,用TRIzol法抽提mRNA。100 mg组织加入1ml TRIzol,在旋涡震荡器上混匀后加入约1/5体积的氯仿,充分混匀后室温静置5 min;然后于4 °C,12000 rpm 离心15 min;将上清液转入1.5 ml离心管中,加入等体积的异丙醇,混匀后室温静置5 min;于4 °C,12000 rpm离心10 min;吸去上清液,向沉淀中加入2/5体积的70% 乙醇, 4 °C,12000 rpm离心15 min洗涤沉淀;吸去上清液,沉淀于室温自然晾干后加入适量RNase-free 的水,充分溶解沉淀;取1-2 ml稀释,测定OD 260, RNA浓度按以下公式计算:A260×40×稀释倍数(μg/μl)。用M-MLV逆转录酶把mRNA逆转录成cDNA,-80 °C冰箱保存待用。采用SYBR®Premix Ex
Taq™ II(Takara)对样品反转录产物进行实时荧光定量PCR分析。利用ABI 7500 Fast实时荧光定量PCR仪进行测定,同时做融解曲线判定引物质量,以β-actin为对照,计算aP2(脂肪组织脂肪酸结合蛋白)、C/EBPα(CAAT/ 增强子结合蛋白α)、PPARg(过氧化物体增殖剂活化受体g)和Glut4(葡萄糖载体4)的表达水平。结果显示,给与本发明化合物(I)的db/db小鼠脂肪细胞基因aP2、C/EBPα、PPARg和Glut4的表达明显高于对照组,说明本发明化合物(I)能提高db/db小鼠脂肪细胞基因aP2、C/EBPα、PPARγ和Glut4的表达, 在分子水平进一步证实本发明化合物(I)能促进脂肪细胞分化和葡萄糖的转运(如图7所示)。
实施例 7 本发明化合物(I)对db/db小鼠血清甘油三酯(TG)、胆固醇(TC)水平的影响
db/db小鼠给与本发明化合物(I)三周后(方法同上),尾静脉取血,离心,吸取上层血清,用甘油磷酸氧化酶-过氧化物酶法测血清TG含量,用胆固醇氧化酶-过氧化物酶法测血清TC含量。结果证实,本发明化合物(I)能降低db/db小鼠血清TG、TC的含量(如图8所示)。
上述实验结果表明,本发明化合物(I)具有明显促进脂肪细胞分化、提高Glut4的表达、增加胰岛素刺激的葡萄糖转运、提高糖尿病小鼠胰岛素敏感性、降低血糖、降低血脂的作用。因此,本发明化合物(I)可作为胰岛素增敏剂、降血糖药物和降血脂药物用于医药领域。
Claims (3)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN 201110001869 CN102579422B (zh) | 2011-01-06 | 2011-01-06 | 黄酮类化合物在制备抗代谢性疾病药物中的用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN 201110001869 CN102579422B (zh) | 2011-01-06 | 2011-01-06 | 黄酮类化合物在制备抗代谢性疾病药物中的用途 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201310168616.5A Division CN103393637B (zh) | 2011-01-06 | 2011-01-06 | 黄酮类化合物在制备抗代谢性疾病药物中的用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN102579422A CN102579422A (zh) | 2012-07-18 |
CN102579422B true CN102579422B (zh) | 2013-08-21 |
Family
ID=46469033
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN 201110001869 Expired - Fee Related CN102579422B (zh) | 2011-01-06 | 2011-01-06 | 黄酮类化合物在制备抗代谢性疾病药物中的用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN102579422B (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105985306B (zh) * | 2015-02-15 | 2018-10-26 | 复旦大学 | 天然产物黄酮类化合物的全合成制备方法 |
KR101876805B1 (ko) * | 2016-10-18 | 2018-07-10 | 고려대학교 산학협력단 | 상지 주정 추출물을 함유하는 비만을 예방 또는 치료하기 위한 조성물 |
-
2011
- 2011-01-06 CN CN 201110001869 patent/CN102579422B/zh not_active Expired - Fee Related
Non-Patent Citations (2)
Title |
---|
傅大煦等.黑桑的化学成分研究.《中草药》.2005,第36卷(第9期),1296-1299. |
黑桑的化学成分研究;傅大煦等;《中草药》;20050930;第36卷(第9期);1296-1299 * |
Also Published As
Publication number | Publication date |
---|---|
CN102579422A (zh) | 2012-07-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102526165A (zh) | 一种红景天有效部位、其制备方法、其药物组合物及用途 | |
CN101791365A (zh) | 穿龙薯蓣提取物及其在制备抗自由基、降血脂药物中的应用 | |
CN102178741A (zh) | 具有降血糖作用的番石榴叶提取物及其制备方法与应用 | |
CN105232891B (zh) | 延龄草提取物及其中皂苷类化合物的制备方法及其在制备抗缺血性心脏病药物中的应用 | |
CN101401829A (zh) | 一种野金柴活性提取物及其制备方法和应用 | |
CN101836975A (zh) | 异戊烯基黄酮化合物作为胰脂肪酶抑制剂的用途 | |
CN102579422B (zh) | 黄酮类化合物在制备抗代谢性疾病药物中的用途 | |
CN103393637B (zh) | 黄酮类化合物在制备抗代谢性疾病药物中的用途 | |
CN103585192B (zh) | 一种通经草提取物的制备方法及其应用 | |
CN1989984B (zh) | 川芎有效组分、制备方法及其制剂与用途 | |
CN104523742A (zh) | 一种具有护肝和提高免疫作用的多糖组合物及其应用 | |
CN101156882B (zh) | 三七原人参二醇型皂苷制备方法 | |
CN102240293B (zh) | 刺囊酸在制备预防和治疗心血管疾病的药物中的应用 | |
CN101318946B (zh) | 化合物二聚兔耳风萜a及其制备方法和应用 | |
CN106928299A (zh) | 一类来源于地骨皮的化合物,其制法及在降糖方面的应用 | |
CN112592337A (zh) | 一种牛尾蒿黄酮类化合物及其制备方法和用途 | |
CN103142695B (zh) | 防治慢性肾小球疾病的药物组合物及其制法 | |
CN102670698B (zh) | 千斤拔提取物在制备防治糖尿病药物中的应用 | |
CN101284030B (zh) | 毛冬青药材、提取物或毛冬青制剂的质量控制方法 | |
CN110123827A (zh) | 一种治疗由代谢异常所致疾病的药物组合物及其制备方法和应用 | |
CN106692125A (zh) | 一种含野菊花提取物的抗糖尿病药物 | |
CN108864134A (zh) | 卡萨烷二萜衍生物及其含该衍生物的提取物的制备方法和应用 | |
CN104288169B (zh) | 一种黄酮苷类化合物及其制备方法和用途 | |
CN102824423A (zh) | 一种含白芍苷和牛蒡苷的药物组合物及应用 | |
CN101318966B (zh) | 二聚倍半萜类化合物及其制备方法和应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130821 |
|
CF01 | Termination of patent right due to non-payment of annual fee |