CN110330545A - 一种丹参酮iia衍生物tan20及其制备方法和应用 - Google Patents
一种丹参酮iia衍生物tan20及其制备方法和应用 Download PDFInfo
- Publication number
- CN110330545A CN110330545A CN201910363875.0A CN201910363875A CN110330545A CN 110330545 A CN110330545 A CN 110330545A CN 201910363875 A CN201910363875 A CN 201910363875A CN 110330545 A CN110330545 A CN 110330545A
- Authority
- CN
- China
- Prior art keywords
- tan20
- tanshinone iia
- fat
- derivative
- iia derivative
- 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.)
- Granted
Links
- AZEZEAABTDXEHR-UHFFFAOYSA-M sodium;1,6,6-trimethyl-10,11-dioxo-8,9-dihydro-7h-naphtho[1,2-g][1]benzofuran-2-sulfonate Chemical class [Na+].C12=CC=C(C(CCC3)(C)C)C3=C2C(=O)C(=O)C2=C1OC(S([O-])(=O)=O)=C2C AZEZEAABTDXEHR-UHFFFAOYSA-M 0.000 title claims abstract description 86
- 238000002360 preparation method Methods 0.000 title claims description 22
- AIGAZQPHXLWMOJ-UHFFFAOYSA-N tanshinone IIA Natural products C1=CC2=C(C)C=CC=C2C(C(=O)C2=O)=C1C1=C2C(C)=CO1 AIGAZQPHXLWMOJ-UHFFFAOYSA-N 0.000 claims abstract description 34
- 210000003486 adipose tissue brown Anatomy 0.000 claims abstract description 29
- 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 claims abstract description 28
- 239000008103 glucose Substances 0.000 claims abstract description 27
- 208000008589 Obesity Diseases 0.000 claims abstract description 23
- 235000020824 obesity Nutrition 0.000 claims abstract description 23
- HYXITZLLTYIPOF-UHFFFAOYSA-N Tanshinone II Natural products O=C1C(=O)C2=C3CCCC(C)(C)C3=CC=C2C2=C1C(C)=CO2 HYXITZLLTYIPOF-UHFFFAOYSA-N 0.000 claims abstract description 19
- 210000004369 blood Anatomy 0.000 claims abstract description 18
- 239000008280 blood Substances 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 18
- 208000001145 Metabolic Syndrome Diseases 0.000 claims abstract description 17
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims abstract description 17
- 229940079593 drug Drugs 0.000 claims abstract description 16
- 230000006872 improvement Effects 0.000 claims abstract description 10
- 230000002265 prevention Effects 0.000 claims abstract description 10
- 239000012190 activator Substances 0.000 claims abstract description 5
- 210000000636 white adipocyte Anatomy 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 206010012601 diabetes mellitus Diseases 0.000 claims description 8
- 229930183118 Tanshinone Natural products 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000002244 precipitate Substances 0.000 claims description 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 2
- 206010008111 Cerebral haemorrhage Diseases 0.000 claims description 2
- 206010020772 Hypertension Diseases 0.000 claims description 2
- 208000034189 Sclerosis Diseases 0.000 claims description 2
- 210000001367 artery Anatomy 0.000 claims description 2
- 201000005577 familial hyperlipidemia Diseases 0.000 claims description 2
- 208000023589 ischemic disease Diseases 0.000 claims description 2
- 208000019423 liver disease Diseases 0.000 claims description 2
- 208000010125 myocardial infarction Diseases 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 19
- 210000001789 adipocyte Anatomy 0.000 abstract description 14
- 230000004060 metabolic process Effects 0.000 abstract description 14
- 238000000034 method Methods 0.000 abstract description 13
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 abstract description 8
- 229930186217 Glycolipid Natural products 0.000 abstract description 8
- 230000004913 activation Effects 0.000 abstract description 8
- 206010022489 Insulin Resistance Diseases 0.000 abstract description 7
- 230000003647 oxidation Effects 0.000 abstract description 6
- 238000007254 oxidation reaction Methods 0.000 abstract description 6
- 230000007246 mechanism Effects 0.000 abstract description 4
- 230000008844 regulatory mechanism Effects 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 37
- 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 description 28
- 210000000577 adipose tissue Anatomy 0.000 description 21
- 210000003470 mitochondria Anatomy 0.000 description 18
- 102000004877 Insulin Human genes 0.000 description 14
- 108090001061 Insulin Proteins 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 14
- 229940125396 insulin Drugs 0.000 description 14
- 102000015494 Mitochondrial Uncoupling Proteins Human genes 0.000 description 13
- 108010050258 Mitochondrial Uncoupling Proteins Proteins 0.000 description 13
- 230000006698 induction Effects 0.000 description 11
- 229940090044 injection Drugs 0.000 description 11
- 239000007924 injection Substances 0.000 description 11
- 238000002347 injection Methods 0.000 description 11
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- 238000012360 testing method Methods 0.000 description 8
- 235000009200 high fat diet Nutrition 0.000 description 7
- 230000002503 metabolic effect Effects 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 230000009977 dual effect Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 241000282693 Cercopithecidae Species 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 201000010063 epididymitis Diseases 0.000 description 4
- 239000006481 glucose medium Substances 0.000 description 4
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 4
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 4
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 4
- 210000000496 pancreas Anatomy 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 230000004580 weight loss Effects 0.000 description 4
- 238000001262 western blot Methods 0.000 description 4
- 102100036009 5'-AMP-activated protein kinase catalytic subunit alpha-2 Human genes 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 101000783681 Homo sapiens 5'-AMP-activated protein kinase catalytic subunit alpha-2 Proteins 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 108020005196 Mitochondrial DNA Proteins 0.000 description 3
- 210000000593 adipose tissue white Anatomy 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000036760 body temperature Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 230000000875 corresponding effect Effects 0.000 description 3
- 239000000975 dye Substances 0.000 description 3
- 238000004043 dyeing Methods 0.000 description 3
- 210000000918 epididymis Anatomy 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000012894 fetal calf serum Substances 0.000 description 3
- 238000007446 glucose tolerance test Methods 0.000 description 3
- 210000004013 groin Anatomy 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 208000030159 metabolic disease Diseases 0.000 description 3
- 235000021590 normal diet Nutrition 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 239000010453 quartz Substances 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- HARGZZNYNSYSGJ-UHFFFAOYSA-N 1,2 dihydrotanshinquinone Natural products C1=CC2=C(C)C=CC=C2C(C(=O)C2=O)=C1C1=C2C(C)CO1 HARGZZNYNSYSGJ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- GVKKJJOMQCNPGB-JTQLQIEISA-N Cryptotanshinone Chemical compound O=C1C(=O)C2=C3CCCC(C)(C)C3=CC=C2C2=C1[C@@H](C)CO2 GVKKJJOMQCNPGB-JTQLQIEISA-N 0.000 description 2
- GVKKJJOMQCNPGB-UHFFFAOYSA-N Cryptotanshinone Natural products O=C1C(=O)C2=C3CCCC(C)(C)C3=CC=C2C2=C1C(C)CO2 GVKKJJOMQCNPGB-UHFFFAOYSA-N 0.000 description 2
- 102000017011 Glycated Hemoglobin A Human genes 0.000 description 2
- 108091023040 Transcription factor Proteins 0.000 description 2
- 102000040945 Transcription factor Human genes 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000023852 carbohydrate metabolic process Effects 0.000 description 2
- 230000006706 cellular oxygen consumption Effects 0.000 description 2
- 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 2
- 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 2
- 229960003957 dexamethasone Drugs 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 238000003364 immunohistochemistry Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000002438 mitochondrial effect Effects 0.000 description 2
- 230000036284 oxygen consumption Effects 0.000 description 2
- 238000003753 real-time PCR Methods 0.000 description 2
- 230000000241 respiratory effect Effects 0.000 description 2
- 230000001177 retroviral effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- XDUXBBDRILEIEZ-UHFFFAOYSA-N 6-(hydroxymethyl)-1,6-dimethyl-8,9-dihydro-7h-naphtho[1,2-g][1]benzofuran-10,11-dione Chemical compound O=C1C(=O)C2=C3CCCC(C)(CO)C3=CC=C2C2=C1C(C)=CO2 XDUXBBDRILEIEZ-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000000503 Collagen Type II Human genes 0.000 description 1
- 108010041390 Collagen Type II Proteins 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000058061 Glucose Transporter Type 4 Human genes 0.000 description 1
- 108010014663 Glycated Hemoglobin A Proteins 0.000 description 1
- 102100024594 Histone-lysine N-methyltransferase PRDM16 Human genes 0.000 description 1
- 101000686942 Homo sapiens Histone-lysine N-methyltransferase PRDM16 Proteins 0.000 description 1
- 101001123331 Homo sapiens Peroxisome proliferator-activated receptor gamma coactivator 1-alpha Proteins 0.000 description 1
- 102000007330 LDL Lipoproteins Human genes 0.000 description 1
- 108010007622 LDL Lipoproteins Proteins 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 102100028960 Peroxisome proliferator-activated receptor gamma coactivator 1-alpha Human genes 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 108091006300 SLC2A4 Proteins 0.000 description 1
- 241001474728 Satyrodes eurydice Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000786103 Steatomys pratensis Species 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000879 anti-atherosclerotic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000002711 centrocyte Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- NKQPRNDTEUZYKT-UHFFFAOYSA-N cyclohex-5-ene-1,2,3,4-tetrone Chemical group O=C1C=CC(=O)C(=O)C1=O NKQPRNDTEUZYKT-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000011697 diabetes animal model Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 239000000469 ethanolic extract Substances 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 235000013410 fast food Nutrition 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000004459 forage Substances 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000004110 gluconeogenesis Effects 0.000 description 1
- 229940093181 glucose injection Drugs 0.000 description 1
- 108091005995 glycated hemoglobin Proteins 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 230000004957 immunoregulator effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008141 laxative Substances 0.000 description 1
- 230000002475 laxative effect Effects 0.000 description 1
- 230000004130 lipolysis Effects 0.000 description 1
- 230000002366 lipolytic effect Effects 0.000 description 1
- 238000007443 liposuction Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000013116 obese mouse model Methods 0.000 description 1
- 238000011623 obesity animal model Methods 0.000 description 1
- 238000007410 oral glucose tolerance test Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 238000007781 pre-processing Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000001044 red dye Substances 0.000 description 1
- 235000021067 refined food Nutrition 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000037351 starvation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 210000004003 subcutaneous fat Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
- C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Child & Adolescent Psychology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
本发明公开了一种丹参酮IIA衍生物TAN20,所述丹参酮IIA衍生物TAN20结构式如式(I)所示,其与丹参酮IIA相比,具有更好的改善糖脂代谢的效果,能降低血糖、改善糖耐量和消脂减肥能降低血糖、改善糖耐量和消脂减肥;所述丹参酮IIA衍生物TAN20促进脂肪细胞米色化以及活化棕色脂肪组织,增强有氧氧化及胰岛素敏感性的调控机制,不同于传统的改善肥胖及其相关代谢综合症的方法及机理,可作为白色脂肪细胞米色化促进剂和棕色脂肪激活剂,用于制备防治肥胖及相关代谢综合症的药物,具有较大的应用前景。
Description
技术领域
本发明涉及生物医药技术领域,更具体地,涉及一种丹参酮IIA衍生物TAN20及其制备方法,以及所述丹参酮IIA衍生物TAN20在制备防治肥胖及相关代谢综合症的药物中的应用。
背景技术
长期以来,肥胖发生的主导理论是“热量学说”,认为现代社会的人摄入的食物热量太多、消耗的太少,能量不平衡,多余的热量成为脂肪存储起来,导致体重增加乃至肥胖,而肥胖又可以产生糖尿病及许多相关代谢性疾病。按照这个理论,减肥的主要办法是减少热量的摄入、增加运动量。但现实是这种控制体重的效果欠佳,且易反复。而现今流行的手术抽脂减肥对机体毕竟会造成一定的创伤,并且可能存在潜在的并发症。另一方面,随着全球社会经济发展,越来越多的国家和地区进入富裕社会,糖尿病发病率及患者数目急剧升高。限制热量是预防肥胖的第一道防线,一旦发生糖脂代谢的异常,提高代谢效率和增加脂肪组织等主要代谢器官的能量消耗就显得尤为重要。
另外,与代谢综合症相关病症的最有效方法是多作锻炼,减肥和饮食控制。目前所有对抗代谢综合症方法的共同之处在于促进能量代谢,由此导致体内多余能量的最大消耗从而阻止能量积累。由于从加工食品和快餐中摄取的高卡路里,与不充分的锻炼相比,多余能量以脂肪的形式进行了累积,并由此变成了包括代谢紊乱的多种疾病的根本原因。有效的消除这些多余能量可考虑作为治疗代谢紊乱的方法。提高代谢活性对有效地消除多余能量至关重要。出于这一目的,一般认为必须抑制脂肪合成,抑制糖原异生,协助葡萄糖消耗,协助脂肪氧化,协助能量代谢中心细胞器线粒体的生物发生,以及活化参与代谢活化的因子。
丹参酮(Tanshinone)为丹参根部的乙醚或乙醇提取物,是丹参的主要脂溶性有效成分,含有邻苯二醌或对醌结构,具有很强的脂溶性,可在生物体内广泛分布,具有广泛的药理活性。丹参酮根据其不同的化学结构主要分为丹参酮I(tanshinone I,TSI)、丹参酮IIA(tanshinoneIIA,TAN2A或TSA)、丹参酮IIB(tanshinone B,TSB)、隐丹参酮(cryptotanshinone,CTS)、15,16-二氢丹参酮(15,16-dihydrotanshinone,DTS)等。其中,丹参酮IIA(PubChem CID:164676)活性最为突出,具有抗氧化、抗菌消炎和免疫调节活性。专利CN201110438937.3公开了用增强代谢活性的丹参衍生物治疗肥胖和代谢综合症的报道,具体公开了含有作为有效成分的丹参酮衍生物的预防和治疗代谢综合症的组合物能够通过提高AMPK的活性来预防和治疗肥胖和代谢综合症;专利CN200910145560.5公开了丹参酮IIA在制备治疗肥胖及胰岛素抵抗的药物中的应用。但是上述公开的丹参酮或其衍生物在改善糖脂代谢方面的效果不理想。
发明内容
本发明的目的在于克服现有技术的上述不足,提供一种丹参酮IIA衍生物TAN20,所述丹参酮IIA衍生物TAN20具有更好的改善糖脂代谢的效果,丹参酮IIA衍生物TAN20通过活化棕色脂肪以及促进白色脂肪米色化来改善糖脂代谢紊乱,能降低血糖、改善糖耐量和消脂减肥。
本发明的另一目的在于提供所述丹参酮IIA衍生物TAN20的制备方法。
本发明的再一目的在于提供所述丹参酮IIA衍生物TAN20在制备防治肥胖及相关代谢综合症的药物中的应用。
本发明的上述目的是通过以下技术方案给予实现的:
一种丹参酮IIA衍生物TAN20,所述丹参酮IIA衍生物TAN20的结构式如式(I)所示:
所述丹参酮IIA衍生物TAN20的制备方法,在反应容器中加入丹参酮IIA、4-甲砜基苯甲醛,加热混匀后,80~120℃反应10~30min,将反应液冷却至室温,调节溶液pH至6.5~7.5,得到淡黄色沉淀,过滤、层析、洗脱即得丹参酮IIA衍生物TAN20。
优选地,所述丹参酮IIA、4-甲砜基苯甲醛的摩尔比为34:51。
优选地,所述反应为微波反应。
优选地,所述反应为100℃反应20分钟。
优选地,所述pH为7.0。
本发明研究发现,丹参酮IIA衍生物TAN20有更好的改善糖脂代谢的效果,能降低血糖、改善糖耐量和消脂减肥能降低血糖、改善糖耐量和消脂减肥,所述丹参酮IIA衍生物TAN20促进脂肪细胞米色化以及活化棕色脂肪组织,增强有氧氧化及胰岛素敏感性的调控机制,不同于传统的改善肥胖及其相关代谢综合症的方法及机理,可用于进一步制备用于防治肥胖及相关代谢综合症的相关药物。
因此,本发明还请求保护所述丹参酮IIA衍生物TAN20在制备防治肥胖及相关代谢综合症的药物中的应用。
具体地,所述相关代谢综合症为肥胖症,糖尿病,动脉硬化,高血压,高脂血,肝病,脑溢血,心肌梗塞,局部缺血疾病和心血管疾病中的至少一种。
本发明还提供一种防治肥胖及相关代谢综合症的药物,所述药物含有作为有效成分的丹参酮IIA衍生物TAN20。
同时,所述丹参酮IIA衍生物TAN20的下列应用也在本发明保护范围内:
丹参酮IIA衍生物TAN20在制备降低血糖、改善糖耐量的制剂中的应用。
丹参酮IIA衍生物TAN20作为或在制备促进白色脂肪细胞米色化的制剂中的应用,具体为促进白色脂肪细胞转化成米色脂肪的制剂。
丹参酮IIA衍生物TAN20作为或在制备棕色脂肪活化剂中的应用,具体为提高棕色脂肪活性的制剂,即棕色脂肪激活剂。
同时,本发明进一步研究发现,丹参酮IIA衍生物TAN20是通过先磷酸化AMPK,进而上调PGC1a的表达,最终促进UCP1(解偶联蛋白1)的表达来调控棕色脂肪活化或者促进白色脂肪米色化的。
与现有技术相比,本发明具有以下有益效果:
本发明提供了一种丹参酮IIA衍生物TAN20,所述丹参酮IIA衍生物TAN20有更好的改善糖脂代谢的效果,能降低血糖、改善糖耐量和消脂减肥能降低血糖、改善糖耐量和消脂减肥,所述丹参酮IIA衍生物TAN20促进脂肪细胞米色化以及活化棕色脂肪组织,增强有氧氧化及胰岛素敏感性的调控机制,不同于传统的改善肥胖及其相关代谢综合症的方法及机理;可作为白色脂肪细胞米色化促进剂和棕色脂肪激活剂,用于制备防治肥胖及相关代谢综合症的药物,具有较大的应用前景。
附图说明
图1为丹参酮IIA衍生物TAN20的(A)结构图,结构鉴定的核磁共振(B)碳谱,(C)氢谱,(D)电喷雾质谱。
图2为丹参酮IIA衍生物TAN20降低肥胖小鼠体重,减小脂肪组织中组织细胞尺寸大小以及脂肪组织中FFA,TG的含量。还可以改善糖耐量(GTT)、胰岛素耐量(ITT),降低血糖含量和胰岛素水平。(A)丹参酮IIA及其衍生物TAN20的结构式,用二甲基亚砜(DMSO)或丹参酮2A/TAN20处理DIO小鼠(高脂喂养的肥胖小鼠模型)30天;(B)打药过程中对体重的监控;(C)日摄食量变化;(D)体温变化;(E)药物处理后葡萄糖耐量试验;(F)空腹血糖水平;(G)胰岛素耐量;(H)空腹胰岛素水平。
图3为丹参酮IIA衍生物TAN20降低肥胖猴体重,提高体温,改善葡萄糖耐量和胰岛素耐量,降低糖化血红蛋白水平,降低空腹胰岛素含量,减小脂滴大小及提高线粒体的数量。用DMSO,丹参酮IIA及其衍生物TAN20处理肥胖猴两周:(A)打药过程中对体重进行评估;(B)打药后测体温;(C)高低密度脂蛋白比值;(D)胆固醇;(E)肌酸磷酸激酶(CPK);(F)乳酸脱氢酶(LDH);(G)空腹血糖水平;(H)空腹血浆胰岛素水平;(I)葡萄糖耐量试验;(J)胰岛素耐受试验;(K)用透射电镜拍摄皮下脂肪组织的图像(L指脂滴,M指线粒体)。
图4为丹参酮IIA衍生物TAN20减小脂肪细胞中脂滴尺寸,提高还原当量NADH及增强能量ATP生成,增强线粒体呼吸容量。3T3-L1MBX细胞用丹参酮IIA以及其衍生物TAN20处理之后,检测相关指标。(A)3T3-L1MBX细胞油红染色;(B)3T3-L1MBX细胞透射电子显微镜图像;(C)3T3-L1MBX细胞线粒体Mitotracker染色;(D)药物处理后3T3-L1MBX细胞中的ATP水平;(E)3T3-L1MBX中的总NAD(NADt)和NADH产量;(F)3T3-L1MBX细胞中的OCR(氧耗速率)。
图5为丹参酮IIA衍生物TAN20促进棕色脂肪组织脂滴的消耗,对棕色脂肪相对比重没有显著影响,促进UCP1的表达,以及线粒体的产生,上调相应棕色脂肪Maker,相关转录因子,以及能量代谢相关分子,提高UCP1蛋白的表达。给予丹参酮2A/20两周后检测相关指标。(A)棕色脂肪组织(BAT)HE染色;(B)棕色脂肪组织UCP1蛋白的免疫组化;(C)药物处理后棕色脂肪组织占总体重的百分比;(D)药物处理后棕色脂肪组织线粒体mtDNA拷贝数;(D)棕色脂肪活化标志基因的相对表达量;(E)棕色脂肪与UCP1相关转录因子的相对表达量;(E)棕色脂肪线粒体与脂肪酸氧化相关基因的相对表达量;(H)Western-blot显示TAN20处理后棕色脂肪组织中的UCP1蛋白表达。
图6为丹参酮IIA衍生物TAN20促进皮下脂肪组织脂滴的消耗,对棕色脂肪相对比重没有显著影响,促进UCP1的表达,以及线粒体的产生,上调相应棕色脂肪Maker,相关转录因子,以及能量代谢相关分子,提高UCP1蛋白的表达,给予丹参酮2A/20两周后检测相关指标。(A)皮下脂肪组织(scWAT)HE染色;(B)皮下脂肪组织UCP1蛋白的免疫组化;(C)Western-blot显示TAN20处理后皮下脂肪组织中的UCP1蛋白表达;(D)药物处理后皮下脂肪组织线粒体mtDNA拷贝数;(E)皮下脂肪组织米色化标志基因的相对表达量;(F)皮下脂肪组织米色化相关转录因子的相对表达量;(G)皮下脂肪组织线粒体与脂肪酸氧化相关基因的相对表达量;(H)Western-blot显示TAN20处理后皮下脂肪组织中UCP1蛋白的表达。
图7为丹参酮IIA衍生物TAN20通过诱导脂肪米色化改善代谢稳态的示意图。
具体实施方式
以下结合说明书附图和具体实施例来进一步说明本发明,但实施例并不对本发明做任何形式的限定。除非特别说明,本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明,以下实施例所用试剂和材料均为市购。
实施例1丹参酮IIA衍生物TAN20的合成
丹参酮IIA衍生物TAN20的合成,包括如下步骤:
在30毫升石英管中加入丹参酮IIA(102.1毫克,0.34毫摩尔),4-甲砜基苯甲醛(95.9毫克,0.51毫摩尔),乙酸铵5克和冰醋酸15毫升。将石英管在磁力搅拌器上加热搅拌10分钟,置于微波反应器中,100℃反应20分钟。结束后取出石英管,待其冷却至室温,将反应液加入200毫升烧杯,加入30毫升蒸馏水,用浓氨水将PH值调至7,将产生大量淡黄色沉淀。将其过滤,真空干燥得到淡黄色沉淀粗产品。将其用乙酸乙酯溶解,过100~200目硅胶柱层析。将石油醚和乙酸乙酯混合作为洗脱剂,将目标化合物洗脱下来。减压旋干得到淡黄色固体,产率为83.5%(以4-甲砜基苯甲醛计算)。TAN20的核磁共振谱,氢谱,质电喷雾谱结果见图1,表明成功制备得到了式(I)所示丹参酮IIA衍生物TAN20。上述反应的化学反应方程式如下所示:
实施例2丹参酮IIA衍生物TAN20的生物学功效
本实施例使用现有的丹参酮IIA和实施例1合成的丹参酮IIA衍生物TAN20进行糖脂代谢方面的相关研究。
一、试验方法
1、体内实验包括:高脂诱导肥胖/糖尿病动物模型、糖耐量测试(GTT)和胰岛素耐量测试(ITT)、腹腔注射、脂肪组织提取与分析等。
2、细胞实验包括:原代脂肪细胞的分离提取与诱导;免疫(荧光)细胞组织化学、线粒体染色示踪技术、线粒体呼吸容量检测(氧气消耗率OCR、NADH)。
3、生物大分子检测技术:免疫印迹(Western-blot)、实时定量PCR(qPCR)、ELISA、Oil-Red O染色示踪脂肪滴技术、脂肪酸检测技术、糖化血红蛋白检测。
4、附睾垫及腹股沟原代脂肪细胞(Primary adipocytes of the inguinal orepididymal)的分离提取与诱导:
首先在无菌的条件下分离老鼠的腹股沟、附睾垫,先用加了双抗的PBST将脂肪组织洗三遍,再用高压灭菌的剪刀将脂肪组织剪碎,以1:2的比例加入已用40μm过滤器过滤的二型胶原酶。在37℃,100转/分钟的条件下消化1小时左右。其中加上双抗,当脂肪组织都被消化好之后就可以用加了10%FBS的DMEM高糖培养基以1:1的比例加入消化液中已终止消化。以1500转/分钟的转速离心10分钟。弃上清后用新的培养基重悬细胞种版即可。诱导的过程:首先前两天加上诱导液1(加上1um/ML的IBMX;1um/ML的地塞米松(DEX);10ng/ML的胰岛素;10%胎牛血清(FBS);0.01%的双抗的DMEM高糖培养基),在用诱导液1诱导2天后换成诱导液2(加上10ng/ML的胰岛素;10%胎牛血清(FBS);0.01%的双抗的DMEM高糖培养基)诱导2~4天后换成诱导液3(10%胎牛血清(FBS);0.01%的双抗的DMEM高糖培养基)诱导2~4天后即可看见脂滴。此为诱导成功的原代脂肪细胞。此时其可以用于后续各种实验处理。
5、GTT,即糖耐量测试:肥胖/糖尿病或正常鼠预先处理后再空腹过夜达18小时后进行,静脉注射葡萄糖(4μl/g体重或1g葡萄糖/kg体重),尾静脉取血,在葡萄糖灌注后0,15,30,60,120分钟时间点用血糖测量仪测量血糖,然后以时间为横坐标、血糖浓度为纵坐标,绘制糖耐量曲线,反应血糖水平的变化趋势。
ITT,即胰岛素耐量测试:肥胖/糖尿病鼠预先处理后再饥饿6小时后进行,腹腔注射生理盐水稀释的0.5U/ml的重组胰岛素,每只肥胖/糖尿病鼠用量1U胰岛素/kg体重,然后在0,15,30,60,120分钟时间点用血糖测量仪测量血糖,以平均值作曲线,反应血糖水平变化趋势。
6、检测用丹参酮IIA衍生物TAN20处理动物或者细胞后糖、脂代谢的关键分子:采用Real-time PCR和/或Western-blot检测肝脏、脂肪(包括皮下脂肪,腹股沟脂肪,棕色脂肪)等组织器官的能量代谢AMPK;PGC1A等,胰岛素敏感性相关蛋白:pAKT,糖脂代谢GLUT4,米色化Maker:UCP1,PRDM16,TMEM16等相关指标,及控制糖、脂代谢的的情况,以此分析丹参酮IIA衍生物TAN20对糖、脂代谢系统的影响。证实丹参酮IIA衍生物TAN20能缓解胰岛素抵抗效应:通过空腹进行口服糖耐量试验(OGTT)和胰岛素耐量试验,观察丹参酮IIA衍生物TAN20是否可以降低肥胖动物糖耐量水平,以此判断能否具有缓解胰岛素抵抗的效应;观察丹参酮IIA衍生物TAN20能否降低肥胖动物eWAT,BAT实质重量及脂肪组织内脂类含量,以此判断TAN20能否干预脂肪代谢;通过HE染色观察脂肪组织中脂滴的改善情况以及通过油红染色观察脂肪细胞中脂肪的积累情况。
7、用透射电镜观察脂肪组织和脂肪细胞的脂滴大小以及线粒体的多少,用MitoTracker染色来观察线粒体在细胞上的数量。用mtDNA来定量脂肪组织和细胞中线粒体的扩增情况。
二、具体试验过程及结果如下:
1、采用二甲基亚砜(DMSO)溶解丹参酮IIA衍生物TAN20,腹腔注射肥胖小鼠,检测体重。
(1)建立了高脂饮食诱导的小鼠肥胖模型:小鼠为C57BL6,从中山大学动物实验中心购买。高脂饮食组采用脂肪含量为60%的饲料喂养,正常饮食组采用10%脂肪饲料作对照组,每周固定时间称量各组中每只动物的体重、活动情况、饲料的消耗等。
(2)用DMSO溶解的丹参酮IIA衍生物TAN20直接腹腔注射db/db肥胖糖尿病模型鼠:db/db鼠重新分组,5只/组,编为:DMSO注射组(DMSO),丹参酮IIA注射组(TAN2A)、丹参酮IIA衍生物TAN20注射组(TAN20)。小鼠的注射浓度为30mg/kg TAN2A/TAN20(溶于DMSO),每天注射一次。对照组老鼠每只注射相同体积的DMSO。
结果显示,丹参酮IIA衍生物TAN20注射肥胖鼠第2周即开始表现明显的体重减轻效果,实验结束后体重减轻幅度达到10%以上,而TAN2A组体重没有显著变化。HE染色显示能明显减小脂肪组织中组织细胞尺寸大小。并且葡糖糖耐量以及胰岛素耐量,空腹血糖,胰岛素含量等糖代谢相关数据也有所改善。并且TAN20组的都比TAN2A的效果显著。此部分的数据结果如图1所示。此外,丹参酮IIA衍生物TAN20注射肥胖小鼠后,线粒体生成增多,体温增加,能量代谢水平也相应的提高了,而且TAN20的效果比TAN2A更显著。此部分结果见图2。
2、丹参酮IIA衍生物TAN20直接注射到肥胖食蟹猴
采用二甲基亚砜(DMSO)溶解丹参酮IIA衍生物TAN20,腹腔注射肥胖食蟹猴,检测体重。
(1)建立了高脂饮食诱导的食蟹猴肥胖模型:猴子为食蟹猴,在广东省实验动物监测所饲养。高脂饮食组采用特定的高脂饲料喂养,正常饮食组采用普通饲料作对照组,每月固定时间称量各组中每只动物的体重、活动情况、饲料的消耗等。
(2)用DMSO溶解的丹参酮IIA衍生物TAN20直接腹腔注射高脂饮食诱导的肥胖猴:食蟹猴雄性鼠用高脂饮食喂养6个月后,肥胖食蟹猴重新分组,3只/组,编为:丹参酮IIA衍生物TAN20注射组(HFD-TAN20)、DMSO注射组(HFD-DMSO);食蟹猴的注射浓度为30mg/kgTAN20(溶于DMSO),每天注射一次;对照组食蟹猴每只注射相同体积的DMSO。丹参酮IIA衍生物TAN20注射肥胖组第1周即开始表现明显的体重减轻效果,实验结束后体重减轻幅度达到10%以上,HE染色显示能明显减小脂肪组织中细胞尺寸大小。并且葡糖糖耐量以及胰岛素耐量,空腹血糖,胰岛素含量等糖代谢相关数据也有所改善。此部分的数据结果如图3所示。
3、在细胞模型上进一步探讨丹参酮IIA衍生物TAN20对能量代谢的调控。
采用二甲基亚砜(DMSO)溶解丹参酮IIA及其衍生物TAN20,用30mg/kg的浓度处理诱导成脂肪细胞的3T3-L1细胞,检测能量代谢的相关指标
探讨了丹参酮IIA衍生物TAN20对脂肪细胞脂滴的影响,对线粒体生成的影响,对能量代谢的指标ATP及还原性氢的作用,以及对脂肪细胞氧耗速率的影响。发现丹参酮IIA衍生物TAN20可促进脂滴的分解,促进线粒体的生物产生,提高ATP和NADH的水平,促进细胞的氧耗。并且TAN20的效果要好于TAN2A。结果见图4所示。
4、在已有的动物实验的基础上进一步探讨丹参酮IIA衍生物TAN20调节糖脂代谢及能量代谢的机制。
(1)探讨了丹参酮IIA衍生物TAN20对棕色脂肪组织产热的影响:在棕色脂肪组织及原代棕色脂肪组织细胞上探讨丹参酮IIA衍生物TAN20对脂肪的代谢,线粒体的产生,棕色脂肪的活性的影响,发现丹参酮IIA衍生物TAN20可增加脂肪的消耗,促进线粒体的生物产生,提高棕色脂肪的活性。结果见图5所示。
(2)探讨了丹参酮IIA衍生物TAN20对白色脂肪组织米色化的影响:在皮下白色脂肪组织,附睾垫白色脂肪组织,及其相应的原代脂肪细胞上探讨丹参酮IIA衍生物TAN20对脂肪米色化,线粒体产生的影响,发现丹参酮IIA衍生物TAN20可增加脂肪的消耗,提高线粒体的生物产生,促进皮下或者内脏白色脂肪组织米色化。结果见图6所示。
Claims (9)
1.一种丹参酮IIA衍生物TAN20,其特征在于,所述丹参酮IIA衍生物TAN20的结构式如式(I)所示:
2.权利要求1所述丹参酮IIA衍生物TAN20的制备方法,其特征在于,在反应容器中加入丹参酮IIA、4-甲砜基苯甲醛,加热混匀后,80~120℃反应10~30min,将反应液冷却至室温,调节溶液pH至6.5~7.5,得到淡黄色沉淀,过滤、层析、洗脱即得丹参酮IIA衍生物TAN20。
3.根据权利要求2所述的制备方法,其特征在于,所述丹参酮IIA、4-甲砜基苯甲醛的摩尔比为34:51。
4.权利要求1所述丹参酮IIA衍生物TAN20在制备防治肥胖及相关代谢综合症的药物中的应用。
5.根据权利要求4所述的应用,其特征在于,所述相关代谢综合症为糖尿病,动脉硬化,高血压,高脂血,肝病,脑溢血,心肌梗塞,局部缺血疾病和心血管疾病中的至少一种。
6.一种防治肥胖及相关代谢综合症的药物,其特征在于,含有作为有效成分的丹参酮IIA衍生物TAN20。
7.权利要求1所述丹参酮IIA衍生物TAN20在制备降低血糖、改善糖耐量和消脂减肥的制剂中的应用。
8.权利要求1所述丹参酮IIA衍生物TAN20作为或在制备促进白色脂肪细胞米色化的制剂中的应用。
9.权利要求1所述丹参酮IIA衍生物TAN20作为或在制备棕色脂肪活化剂中的应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910363875.0A CN110330545B (zh) | 2019-04-30 | 2019-04-30 | 一种丹参酮iia衍生物tan20及其制备方法和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910363875.0A CN110330545B (zh) | 2019-04-30 | 2019-04-30 | 一种丹参酮iia衍生物tan20及其制备方法和应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110330545A true CN110330545A (zh) | 2019-10-15 |
CN110330545B CN110330545B (zh) | 2020-11-06 |
Family
ID=68140067
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910363875.0A Active CN110330545B (zh) | 2019-04-30 | 2019-04-30 | 一种丹参酮iia衍生物tan20及其制备方法和应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110330545B (zh) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101863894A (zh) * | 2010-06-01 | 2010-10-20 | 广东药学院 | 一种丹参酮ⅱa衍生物及其制备方法和应用 |
CN102304166A (zh) * | 2011-07-02 | 2012-01-04 | 中国科学院昆明植物研究所 | 丹参酮衍生物,其药物组合物及其在制药中的应用 |
CN102603861A (zh) * | 2012-02-25 | 2012-07-25 | 中国科学院昆明植物研究所 | 丹参酮衍生物及其药物组合物和其在医药中的用途 |
CN103232521A (zh) * | 2013-03-11 | 2013-08-07 | 常州大学 | 丹参酮咪唑类化合物、制备方法和用途 |
-
2019
- 2019-04-30 CN CN201910363875.0A patent/CN110330545B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101863894A (zh) * | 2010-06-01 | 2010-10-20 | 广东药学院 | 一种丹参酮ⅱa衍生物及其制备方法和应用 |
CN102304166A (zh) * | 2011-07-02 | 2012-01-04 | 中国科学院昆明植物研究所 | 丹参酮衍生物,其药物组合物及其在制药中的应用 |
CN102603861A (zh) * | 2012-02-25 | 2012-07-25 | 中国科学院昆明植物研究所 | 丹参酮衍生物及其药物组合物和其在医药中的用途 |
CN103232521A (zh) * | 2013-03-11 | 2013-08-07 | 常州大学 | 丹参酮咪唑类化合物、制备方法和用途 |
Non-Patent Citations (2)
Title |
---|
张瑶华: "《上海市增补基本药物用药手册》", 31 May 2011, 上海交通大学出版社第一版 * |
郑康帝: "丹参酮ⅡA咪唑类衍生物的微波辅助合成及其抗肿瘤作用机制", 《中国优秀硕士学位论文全文数据库医药卫生科技辑》 * |
Also Published As
Publication number | Publication date |
---|---|
CN110330545B (zh) | 2020-11-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Shi et al. | Beneficial effects of Monascus purpureus NTU 568-fermented products: a review | |
Lozoya-Meckes et al. | Is the Tecoma stans infusion an antidiabetic remedy? | |
Lo et al. | Anti-hyperglycemic activity of natural and fermented Cordyceps sinensis in rats with diabetes induced by nicotinamide and streptozotocin | |
Zafar et al. | 4-Hydroxyisoleucine: a potential new treatment for type 2 diabetes mellitus | |
CN108653276B (zh) | 一种3-芳基香豆素类化合物的应用 | |
Zhou et al. | Astragaloside IV inhibits protein tyrosine phosphatase 1B and improves insulin resistance in insulin-resistant HepG2 cells and triglyceride accumulation in oleic acid (OA)-treated HepG2 cells | |
Sanae et al. | Green asparagus (Asparagus officinalis) prevented hypertension by an inhibitory effect on angiotensin-converting enzyme activity in the kidney of spontaneously hypertensive rats | |
Zhang et al. | Naringenin exhibits the protective effect on cardiac hypertrophy via EETs-PPARs activation in streptozocin-induced diabetic mice | |
JP3069686B2 (ja) | フラバノン類含有組成物 | |
Maghrani et al. | Effects of an aqueous extract of Triticum repens on lipid metabolism in normal and recent-onset diabetic rats | |
CN105012329B (zh) | 一种用于治疗二型糖尿病的药物 | |
Lan et al. | Effects of Portulaca oleracea on insulin resistance in rats with type 2 diabetes mellitus | |
KR102118059B1 (ko) | 발효생강 추출물을 포함하는 대사성 질환 예방 또는 치료용 약학 조성물 | |
MacKenzie et al. | Sutherlandia frutescens limits the development of insulin resistance by decreasing plasma free fatty acid levels | |
CN110330545A (zh) | 一种丹参酮iia衍生物tan20及其制备方法和应用 | |
KR20090091615A (ko) | 근육세포에서 포도당 흡수를 증가시키는 데이츄 추출물과이로부터 분리한 4h-크로멘-4-온 유도체 | |
Yu et al. | Atractylodin alleviates cancer anorexia-cachexia syndrome by regulating NPY through hypothalamic Sirt1/AMPK axis-induced autophagy | |
Mahmoudi et al. | Effects of pioglitazone on the lipid profile, serum antioxidant capacity, and UCP1 gene expression in mouse brown adipose tissue | |
CN109985045A (zh) | 桦木酸作为瘦素增敏剂制备治疗瘦素抵抗相关药物的用途 | |
CN102040603B (zh) | 溴化n-邻甲氧羰基苄基四氢小檗碱及其治疗高血脂症的用途 | |
CN111544440A (zh) | 地奥司明及组合物在制备抗肥胖的产品方面中的应用 | |
TWI825706B (zh) | 用於調解代謝疾病之副乾酪乳桿菌醱酵薑黃 | |
CN112546033B (zh) | 大黄素及其三甲氧基衍生物在制备抗糖脂代谢紊乱药物中的应用 | |
Yang et al. | Corni Fructus extracts ameliorate Streptozotocin-Induced diabetes in mice via regulating AMPK/ACC/CPT-1 signaling pathway | |
Çakır | The Effect of Royal Jelly on Irisin in Experimentally Diabetic Rats |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |