CN100478336C - Derivative of methyol series of andrographolide C15 - Google Patents
Derivative of methyol series of andrographolide C15 Download PDFInfo
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- CN100478336C CN100478336C CNB2006100173576A CN200610017357A CN100478336C CN 100478336 C CN100478336 C CN 100478336C CN B2006100173576 A CNB2006100173576 A CN B2006100173576A CN 200610017357 A CN200610017357 A CN 200610017357A CN 100478336 C CN100478336 C CN 100478336C
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- andrographolide
- deoxidation
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- BOJKULTULYSRAS-OTESTREVSA-N Andrographolide Chemical class C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1/[C@H](O)COC1=O BOJKULTULYSRAS-OTESTREVSA-N 0.000 title claims abstract description 14
- ASLUCFFROXVMFL-UHFFFAOYSA-N andrographolide Natural products CC1(CO)C(O)CCC2(C)C(CC=C3/C(O)OCC3=O)C(=C)CCC12 ASLUCFFROXVMFL-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 238000005886 esterification reaction Methods 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 29
- 239000004593 Epoxy Substances 0.000 claims description 9
- -1 aldehyde ketone Chemical class 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims 3
- 230000005494 condensation Effects 0.000 claims 1
- 238000009833 condensation Methods 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 13
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 238000000034 method Methods 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 4
- 238000010511 deprotection reaction Methods 0.000 abstract description 2
- 238000007259 addition reaction Methods 0.000 abstract 1
- 230000018044 dehydration Effects 0.000 abstract 1
- 238000006297 dehydration reaction Methods 0.000 abstract 1
- 230000032050 esterification Effects 0.000 abstract 1
- 125000000524 functional group Chemical group 0.000 abstract 1
- 230000007365 immunoregulation Effects 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 229930040373 Paraformaldehyde Natural products 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 229920002866 paraformaldehyde Polymers 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- 238000004896 high resolution mass spectrometry Methods 0.000 description 6
- 235000017550 sodium carbonate Nutrition 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 102100024295 Maltase-glucoamylase Human genes 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 108010028144 alpha-Glucosidases Proteins 0.000 description 4
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical class O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 235000015320 potassium carbonate Nutrition 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 150000008431 aliphatic amides Chemical class 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 150000004982 aromatic amines Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000005815 base catalysis Methods 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000006356 dehydrogenation reaction Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 125000004475 heteroaralkyl group Chemical group 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 150000002596 lactones Chemical class 0.000 description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- IFBHRQDFSNCLOZ-ZIQFBCGOSA-N 4-nitrophenyl alpha-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC1=CC=C([N+]([O-])=O)C=C1 IFBHRQDFSNCLOZ-ZIQFBCGOSA-N 0.000 description 2
- 241000746375 Andrographis Species 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 150000003934 aromatic aldehydes Chemical class 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- 150000002611 lead compounds Chemical class 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000008057 potassium phosphate buffer Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- DAXJNUBSBFUTRP-RTQNCGMRSA-N (8r,9s,10r,13s,14s)-6-(hydroxymethyl)-10,13-dimethyl-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthrene-3,17-dione Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(CO)C2=C1 DAXJNUBSBFUTRP-RTQNCGMRSA-N 0.000 description 1
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 1
- 244000118350 Andrographis paniculata Species 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- WTEVQBCEXWBHNA-UHFFFAOYSA-N Citral Natural products CC(C)=CCCC(C)=CC=O WTEVQBCEXWBHNA-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 1
- 241000594182 Sarcophaga sigma Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003509 anti-fertility effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000001741 anti-phlogistic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000002279 cholagogic effect Effects 0.000 description 1
- 229940043350 citral Drugs 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 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
- 229930004069 diterpene Natural products 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- WTEVQBCEXWBHNA-JXMROGBWSA-N geranial Chemical compound CC(C)=CCC\C(C)=C\C=O WTEVQBCEXWBHNA-JXMROGBWSA-N 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000004957 immunoregulator effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000002398 materia medica Substances 0.000 description 1
- 239000002547 new drug Substances 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
- SQYNKIJPMDEDEG-UHFFFAOYSA-N paraldehyde Chemical compound CC1OC(C)OC(C)O1 SQYNKIJPMDEDEG-UHFFFAOYSA-N 0.000 description 1
- 229960003868 paraldehyde Drugs 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
This invention discloses a method for synthesizing andrographolide C15-hydroxymethyl derivatives. The method comprises: utilizing andrographolide with abundant resources as a pilot compound, and performing dehydration, epoxidization, esterification and addition reactions to obtain the derivatives. The method has such advantages as simple process, mild reaction conditions, no need for functional group protection/deprotection, and high yield. The derivatives can inhibit the activity of alpha-glycosidase and have high immunoregulation activity.
Description
Technical field
The present invention relates to andrographolidume derivative, relate in particular to derivative of methyol series of andrographolide C 15.
Background technology
Rographolide (Andrographolide) is the diterpenes diterpenoids lactones compound that extracts in acanthaceous plant Herba Andrographis Andrographispaniculata (Bum.f.) Nees, be one of main component of Chinese medicine Herba Andrographis, have functions such as clearing heat and detoxicating, cool blood detumescence.Modern pharmacology studies show that, rographolide and derivative thereof have effects such as antiphlogistic antibacterial, anti-virus infection, antitumor, anti-cardiovascular disease, immunomodulatory, hepatic cholagogic and antifertility.The rographolide resource is extensive, and absorption is fast in animal body, drug effect is long, bioavailability is high, and does not have obvious toxic and side effects.In recent years, the research to rographolide has become the research focus that receives much attention.We are lead compound with the rographolide, and derivative of methyol series of andrographolide C 15 has been synthesized in design.This is to further development and use rographolide, and the Chinese materia medica modernization, the medicine of developing one's own intellectual property that promote China are significant.
Summary of the invention
The object of the invention is to prepare serial derivative of methyol series of andrographolide C 15, with the new drug of developing one's own intellectual property by the main active ingredient rographolide based on traditional Chinese medicine Herba Andrographis.
For realizing the object of the invention, technical scheme is as follows:
Derivative of methyol series of andrographolide C 15, represent with following general formula:
General formula 1 general formula 2 general formulas 3
General formula 1 expression 14-deoxidation-11, two methylol andrographolidume derivatives of 12-dehydrogenation-15-or 14-deoxidation-11, the two methylols-3 of 12-dehydrogenation-15-, 19-acetal ketone andrographolidume derivative or 14-deoxidation-11, the two methylols-3 of 12-dehydrogenation-15-, a kind of in the 19-esterification andrographolidume derivative; General formula 2 expression 14-deoxidations-11,12-dehydrogenation-8, two methylol andrographolidume derivatives of 17-epoxy-15-or 14-deoxidation-11,12-dehydrogenation-8, the two methylols-3 of 17-epoxy-15-, 19-acetal ketone andrographolidume derivative or 14-deoxidation-11,12-dehydrogenation-8, the two methylols-3 of 17-epoxy-15-, a kind of in the 19-esterification andrographolidume derivative; General formula 3 expression 14-deoxidations-11,12-dehydrogenation-15-replaces methylol andrographolidume derivative or 14-deoxidation-11,12-dehydrogenation-8,17-epoxy-15-replaces a kind of in the methylol andrographolidume derivative.R in the general formula 1
1, R
2Be hydrogen, COR
3And ring-type two hydroxy-protective groups are as CMe
2, CMePh, CHPh etc.; R
3Be the saturated or unsaturated alkyl of C1-16, aromatic base, aromatic alkyl, alkenyl, heteroaryl, groups such as heteroaralkyl.R in the general formula 2
1, R
2Be hydrogen, COR
3And ring-type two hydroxy-protective groups are as CMe
2, CMePh, CHPh etc.; R
3Be the saturated or unsaturated alkyl of C1-16, aromatic base, aromatic alkyl, alkenyl, heteroaryl, groups such as heteroaralkyl.R in the general formula 3
1, R
2Be two keys or epoxy bond; R
3Be the saturated or unsaturated alkyl of C1-16, aromatic base, aromatic alkyl, alkenyl, heteroaryl, groups such as heteroaralkyl.
The method for preparing compound shown in the general formula 1: 14-deoxidation-11,12-dehydrogenation rographolide or 14-deoxidation-11,12-dehydrogenation-3,19-esterification rographolide or 14-deoxidation-11,12-dehydrogenation-3, a kind of and Paraformaldehyde 96 in the 19-acetal ketone rographolide be dissolved in the solvent under base catalysis 10～70 ℃ anti-
Should, 5～72 hours time, can obtain the andrographolidume derivative shown in the general formula 1.Wherein used alkali is yellow soda ash, salt of wormwood, and saleratus, sodium bicarbonate, triethylamine, pyridine, N, N-dimethyl aminopyridine, and a kind of in various aliphatic amide and the aromatic amine etc., its consumption is 0.2～50% mole.Wherein lactone/formaldehyde molar ratio is 1/2.5～1/9.
The preparation method of compound shown in the general formula 2: 14-deoxidation-11,12-dehydrogenation-8,17-epoxy rographolide or 14-deoxidation-11,12-dehydrogenation-3,19-esterification-8,17-epoxy rographolide or 14-deoxidation-11,12-dehydrogenation-8,17-epoxy-3, a kind of and Paraformaldehyde 96 in the 19-acetal ketone rographolide are dissolved in the solvent that 10～70 ℃ of reactions can obtain the andrographolidume derivative shown in the general formula 2 in 5～72 hours under base catalysis.Wherein used alkali is yellow soda ash, salt of wormwood, and saleratus, sodium bicarbonate, triethylamine, pyridine, N, N-dimethyl aminopyridine, and a kind of in various aliphatic amide and the aromatic amine etc., its consumption is 0.2～50% mole.Wherein lactone/formaldehyde molar ratio is 1/2.5～1/10.
The preparation method of compound shown in the general formula 3: 14-deoxidation-11,12-dehydrogenation rographolide or 14-deoxidation-11,12-dehydrogenation-8,17-epoxy rographolide are dissolved in the solvent can obtain the andrographolidume derivative shown in the general formula 3 with aldehyde ketone-20～20 ℃ of reactions under base catalysis; Wherein used alkali is yellow soda ash, salt of wormwood, and saleratus, sodium bicarbonate, triethylamine, pyridine, N, N-dimethyl aminopyridine, and various aliphatic amide and aromatic amine, its consumption are 0.2～50% mole; Wherein used aldehyde ketone is saturated or unsaturated aliphatic aldehyde, aromatic aldehyde, the assorted aromatic aldehyde of C1-16, such as paraldehyde, butyraldehyde-n, phenyl aldehyde, substituted benzaldehyde, furfural, replacement furfural, citral etc.; Wherein lactone/aldehyde ketone molar ratio is 1/1.1～1/6.
Preparation general formula 1, general formula 2, general formula 3 used solvents are methyl alcohol, ethanol, acetonitrile, a kind of in the tetrahydrofuran (THF) etc.
Beneficial effect of the present invention is as follows: 1, simple and convenient, the mild condition of rographolide C15 hydroxymethyl derivative preparation method provided by the present invention, do not need that the protective group deprotection directly prepares, the yield height, can prepare the rographolide series derivates easily.2, the serial andrographolidume derivative of tentative confirmation institute's synthetic of the present invention has cytotoxicity, immunoregulatory activity and alpha-glucosidase to suppress active external to a plurality of human cancer cell strains (being), for further screening active ingredients provides a large amount of new candidate compounds.3, the used lead compound of the present invention is the main component of natural traditional Chinese medicine plant, and is abundant in china natural resources, and very strong region resources advantage is arranged, and provides a new way for further developing rographolide.
Embodiment
For can the present invention is described in detail better, it be as follows to give an actual example:
Embodiment 1: R shown in the preparation general formula 1
1=R
2Derivative during=H
14-deoxidation-11,12-dehydrogenation rographolide 100mg, Paraformaldehyde 96 10mg is dissolved in the 2ml methyl alcohol, adds 20mg yellow soda ash, and 65 ℃ were reacted 6 hours.After reaction finishes, add chloroform 6ml, add the silica gel suction filtration in the suction funnel and remove alkali in the system, concentration response system, column chromatography for separation get the 89mg faint yellow solid, yield 75%.Experimental data is as follows:
C
22H
32O
6，mp 106～108℃；IR 3394，2934，2873，1753，1654，1451，1388，1106，1080，1035，892，754cm
-1；
1HNMR(400MHz，CD
3COCD
3)7.35(1H，s)，6.90(1H，dd，J＝10.8，15.8Hz)，6.15(1H，d，15.8Hz)，4.76(1H，d，J＝1.7Hz)，4.66(1H，d，J＝4.5Hz)，4.51(1H，d，J＝1.7Hz)，4.30(2H，br)，4.13(1H，m)，3.80(4H，m)，3.42(1H，m)，3.33(1H，m)，3.0(1H，s)，2.41(2H，m)，2.06(1H，m)，1.80(1H，m)，1.73(2H，m)，1.47(1H，m)，1.45(1H，m)，1.31(1H，dd，J＝2.0，12.3Hz)，1.23(3H，s)，1.25(1H，m)，1.20(1H，m)，0.83(3H，s)；
13CNMR(100MHz，CDCl
3)：δ171.8，149.7，148.3，135.8，131.1，122.5，108.7，90.2，80.6，64.3，63.6，63.5，62.1，55.1，43.4，39.2，39.0，37.2，28.6，23.8，23.3，16.1；HR-MS m/z：[M+Na]
+415.2106，(calcd.415.2097)。
R shown in the embodiment 2 preparation general formulas 1
1, R
2Be the two hydroxyl protecting group CH of ring-type
2The time derivative
14-deoxidation-11,12-dehydrogenation-3,19-formal rographolide 100mg, Paraformaldehyde 96 15mg was dissolved in the 2ml ethanol, adds the 2mg triethylamine, in 45 ℃ of reactions 12 hours.After reaction finished, concentration response system and to wherein adding ethyl acetate 15ml was used dilute hydrochloric acid, saturated aqueous common salt, water washing successively, the organic phase anhydrous sodium sulfate drying, separate the faint yellow oily thing of 78mg, yield 70%.
Experimental data is as follows:
C
23H
32O
6；IR 3391，2935，2876，1748，1654，1448，1389，1108，1079，1033，890cm
-1；
1HNMR(400MHz，CDCl
3)7.11(1H，s)，6.90(1H，dd，J＝10.1，15.8Hz)，6.10(1H，d，15.8Hz)，4.92(1H，d，J＝6.3Hz)，4.80(1H，d，J＝6.3Hz)，4.79(1H，s)，4.54(1H，s)，4.03(1H，d，J＝11.3Hz)，3.87(2H，s)，3.86(2H，s)，3.50(1H，m)，3.44(1H，d，J＝11.3Hz)，2.46(1H，br)，2.33(1H，d，J＝10.1Hz)，2.24(1H，m)，2.05(1H，br)，1.76(1H，br)，1.60(2H，m)，1.41(3H，s)，1.27(2H，m)，1.11(1H，m)，0.93(3H，s).
13CNMR(100MHz，CDCl
3)：δ171.3，147.9，145.9，136.7，131.0，121.3，109.6，88.8，87.7，80.0，69.2，63.7，61.6，54.4，38.6，37.7，37.3，36.4，25.9，21.9，21.1，21.0，16.1；HR-MS m/z：[M+Na]
+427.2111，(calcd.427.2097)。
Embodiment 3: R shown in the preparation general formula 1
1=R
2Derivative during=OAc
14-deoxidation-11,12-dehydrogenation-3,19-acetic ester rographolide 100mg, Paraformaldehyde 96 10mg is dissolved in the 2ml methyl alcohol, adds 15mg yellow soda ash, and 25 ℃ were reacted 48 hours.After reaction finishes, add chloroform 6ml, add the silica gel suction filtration in the suction funnel and remove alkali in the system, concentration response system, column chromatography for separation get the 80mg faint yellow solid, yield 70%.Experimental data is as follows:
C
26H
36O
8，mp 108-110℃；IR 3438，2945，1761，1735，1644，1375，1245，1037，896cm
-1；
1HNMR(400MHz，CDCl
3)7.12(1H，s)，6.90(1H，dd，J＝10.4，16.0Hz)，6.11(1H，d，J＝15.6Hz)，4.80(1H，s)，4.60(1H，m)，4.50(1H，s)，4.38(1H，d，J＝11.6Hz)，4.15(1H，d，J＝11.6Hz)，3.87(2H，s)，3.86(2H，s)，2.46(1H，br)，2.34(1H，J＝10.0Hz)，2.06(1H，s)，2.05(1H，s)，2.04(1H，br)，1.88(1H，br)，1.69(2H，m)，1.57(2H，m)，1.33(1H，dd，J＝1.6，12.4Hz)，1.26(1H，m)，1.04(3H，s)，0.89(1H，m)；
13CNMR(100MHz，CDCl
3)：δ171.1，171.0，170.7，147，145.9，136.6，130.9，121.3，109.3，88.7，80.1，64.9，63.9，63.7，61.7，54.7，41.4，38.7，38.3，36.8，24.1，23.9，22.7，21.2，21.1，15.3；HR-MS m/z：[M+Na]
+499.2310(calcd.499.2308)。
Embodiment 4: R shown in the preparation general formula 2
1=R
2=H
Get 14-deoxidation-11,12-dehydrogenation-8,17-epoxy rographolide 100mg, Paraformaldehyde 96 15mg was dissolved in the 2ml methyl alcohol, adds 15mg yellow soda ash, in 20 ℃ of reactions 48 hours.After reaction finishes, add chloroform 6ml, add the silica gel suction filtration in the suction funnel and remove alkali in the system, concentration response system, column chromatography for separation get the 88mg faint yellow solid, yield 75%.Experimental data is as follows:
C
22H
32O
7，mp 126～128℃；IR 3399，2937，2868，1754，1453，1391，1263，1108，1037，887，819cm
-1；
1HNMR(400MHz，CD
3C0CD
3)7.30(1H，s)，6.48(1H，dd，J＝9.6，15.6Hz)，6.12(1H，d，J＝15.6Hz)，4.14(1H，d，J＝11.2Hz)，3.75(4H，m)，3.40(1H，dd，J＝4.4，11.6Hz)，3.35(1H，d，J＝11.0)，2.72(1H，dd，J＝1.2，4.4Hz)，2.51(1H，d，J＝4.8Hz)，2.20(1H，d，J＝10.0Hz)，1.85(2H，m)，1.78(1H，m)，1.69(1H，m)，1.58(1H，m)，1.47～1.38(2H，m)，1.23(3H，s)，1.19(1H，m)，1.16(1H，m)，0.98(1H，m)；
13CNMR(100MHz，CD
3COCD
3)：δ171.8，148.5，131.7，130.9，124.9，90.2，80.4，64.2，63.6，59.8，58.5，54.8，50.6，43.3，39.7，38.8，36.4，28.2，23.3，22.0，16.2.HR-MS m/z：[M+Na]
+421.2046(calcd.421.2046)。
Embodiment 5: R shown in shown in the preparation general formula 2
1, R
2Be the two hydroxyl protecting group CH of ring-type
2The time derivative
14-deoxidation-11,12-dehydrogenation-8,17-epoxy-3,19-formal rographolide 100mg, Paraformaldehyde 96 15mg was dissolved in the 2ml ethanol, adds the 5mg pyridine, in 60 ℃ of reactions 8 hours.After reaction finished, concentration response system and to wherein adding ethyl acetate 15ml was used dilute hydrochloric acid, saturated aqueous common salt, water washing successively, the organic phase anhydrous sodium sulfate drying, separate the yellowish solid of 82mg, yield 70%.
Experimental data is as follows:
C
23H
32O
7，mp 178-180℃；IR 3393，2939，2870，1754，1454，1389，1265，1106，1037，887，819cm
-1；
1HNMR(400MHz，CDCl
3)7.11(1H，s)，6.53(1H，dd，J＝9.8，15.6Hz)，6.13(1H，d，J＝15.6Hz)，4.94(1H，d，J＝6.3Hz)，4.82(1H，d，J＝6.3Hz)，4.05(1H，d，J＝11.3Hz)，3.8(4H.m)，3.50(2H，m)，2.82(1H，d，J＝3.9Hz)，2.57(1H，d，J＝4.0Hz)，2.24(1H，m)，2.20(1H，d，J＝9.8Hz)，1.90(2H，m)，1.60(2H，m)，1.48(2H，m)，1.43(3H，s)，1.14(1H，m)，1.08(3H，s)，1.02(1H，m)；
13CNMR(100MHz，CDCl
3)：δ171.0，146.9，131.5，130.3，124.2，88.6，87.6，79.4，68.9，63.6，59.0，58.3，53.9，51.2，38.9，37.5，36.9，35.3，31.5，25.8，20.2，16.0.HR-MS m/z：[M+Na]
+443.2050(calcd.443.2046)。
Embodiment 6: R shown in the preparation general formula 3
1, R
2=epoxy bond, R
3Derivative during=p-FPh
Get 14-deoxidation-11,12-dehydrogenation-8,17-epoxy rographolide 100mg, p-Fluorobenzenecarboxaldehyde 20mg is dissolved in the 2ml methyl alcohol, adds 6mg salt of wormwood, and 10 ℃ were reacted 72 hours.After reaction finished, concentration response system and to wherein adding ethyl acetate 15ml was used dilute hydrochloric acid, saturated aqueous common salt, water washing successively, the organic phase anhydrous sodium sulfate drying, separate the 112mg white solid, yield 79%.Experimental data is as follows:
C
27H
33FO
6，mp222～223℃；IR 3339，3076，2928，2859，1751，1604，1512，1221，1097，1039，838cm
-1；
1HNMR(400MHz，DMSO)7.38(2H，m)，7.34(1H，s)，7.16(2H，m)，6.3(1H，dd，J＝9.8，15.6Hz)，6.0(1H，d，J＝15.6Hz)，5.88(1H，d，J＝5.0Hz)，5.20(1H，d，J＝3.2Hz)，5.0(1H，d，4.7Hz)，4.84(1H，t，J＝4.6Hz)，4.14(1H，d，J＝4.7Hz)，3.84(1H，d8.8Hz)，3.33(1H，d，J＝8.8Hz)，3.20(1H，m)，2.623(1H，d，J＝4.7Hz)，2.13(1H，d，J＝9.8Hz)，1.7(2H，m)，1.57(3H，m)，1.30(2H，m)，1.10(3H，s)，1.07(2H，m)，0.89(3H，s)；
13CNMR(100MHz，DMSO)：δ171.4，162.6，160.2，146.6，136.9，130.7，128.7，128.6，123.4，114.6，114.4，83.9，78.4，71.4，62.6，58.1，58.1，53.3，49.5，42.2，38.5，37.7，35.3，27.1，23.0，21.4，15.4；HR-MS m/z：[M+Na]
+495.2173(calcd.495.2159)。
Alpha-glucosidase suppresses active mensuration: every hole adds the medicine of 40 μ l (primary dcreening operation is mixed with the solution that 0.25mM contains 10%DMSO with the 0.067M potassium phosphate buffer in 96 orifice plates; IC
50Measure to adopt the 0.067M potassium phosphate buffer to be mixed with-solution that contains 10%DMSO of series concentration gradient) and the alpha-glucosidase of 40 μ l 0.1u/ml (baker ' s yeast, U.S. Sigma company), behind 37 ℃ of insulation 40min, every hole adds 2.5mM reaction substrate p-nitrophenyl α-D glucoside (pNPG) 20 μ l, adds stop buffer 0.1M Na behind 37 ℃ of insulation 5min
2CO
3100 μ l are in 405nm colorimetric estimation OD value.Negative control replaces medicine with the 0.067M phosphate buffered saline buffer that contains 10%DMSO.Inhibiting rate=(1-medicine OD value/negative control OD value) * 100%, IC
50Obtain by mapping.
| Compound | Substituting group | Concentration | It is active that alpha-glucosidase suppresses |
| General formula 1 | R 1＝R 2＝H | 0.1mM | 45.0% (inhibiting rate) |
| General formula 1 | R 1，R 2＝CH 2(ring-type hydroxyl protecting group) | 0.1mM | 23.0% (inhibiting rate) |
| General formula 2 | R 1＝R 2＝OAc | 0.1mM | 15.4% (inhibiting rate) |
| General formula 3 | R 1，R 2Be epoxy bond, R 3＝p-FPh | 0.1mM | 17.49% (inhibiting rate) |
Claims (5)
1, derivative of methyol series of andrographolide C 15, it is characterized in that, has general formula 1 structure, general formula 1 expression 14-deoxidation-11, two methylol andrographolidume derivatives of 12-dehydrogenation-15-or 14-deoxidation-11, the derivative or the 14-deoxidation-11 of the two methylol rographolides of 12-dehydrogenation-15-and aldehyde ketone condensation, 12-dehydrogenation-15-pair of methylols-3, a kind of in the 19-esterification andrographolidume derivative;
General formula 1
R in the general formula 1
1, R
2Be hydrogen, COR
3And the two hydroxy-protective groups of ring-type; R
3Be the C1-16 saturated alkyl.
2, derivative of methyol series of andrographolide C 15 as claimed in claim 1 is characterized in that, the two hydroxy-protective groups of ring-type are CMe
2, CMePh or CHPh.
3, derivative of methyol series of andrographolide C 15, it is characterized in that having general formula 2 structures, general formula 2 expression 14-deoxidations-11,12-dehydrogenation-8, two methylol andrographolidume derivatives of 17-epoxy-15-or 14-deoxidation-11,12-dehydrogenation-8, the two methylols-3 of 17-epoxy-15-, 19-acetal ketone andrographolidume derivative or 14-deoxidation-11,12-dehydrogenation-8, the two methylols-3 of 17-epoxy-15-, a kind of in the 19-esterification andrographolidume derivative;
R in the general formula 2
1, R
2Be hydrogen, COR
3And the two hydroxy-protective groups of ring-type; R
3Be the C1-16 saturated alkyl.
4, derivative of methyol series of andrographolide C 15 as claimed in claim 3 is characterized in that, the two hydroxy-protective groups of ring-type are CMe
2, CMePh or CHPh.
5, derivative of methyol series of andrographolide C 15 is characterized in that, has general formula 3 structures, general formula 3 expression 14-deoxidations-11,12-dehydrogenation-15-substituted-andrographolide derivative or 14-deoxidation-11,12-dehydrogenation-8, a kind of in 17-epoxy-15-substituted-andrographolide derivative;
General formula 3
R in the general formula 3
1, R
2Be two keys or epoxy bond; R
3Be C1-16 saturated alkyl, aromatic base or aromatic alkyl.
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| CN1978437A (en) * | 2005-12-07 | 2007-06-13 | 郑州大学 | Andrographolide C15 substituted series derivates and their preparing method |
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| CN1978437A (en) * | 2005-12-07 | 2007-06-13 | 郑州大学 | Andrographolide C15 substituted series derivates and their preparing method |
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| Title |
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| 穿心莲内酯衍生物设计合成与抗肿瘤活性研究. 徐海伟.中国优秀博硕士学位论文全文数据库. 2004 * |
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