CN106883267A - VBE Oridonin derivatives and its preparation and application - Google Patents
VBE Oridonin derivatives and its preparation and application Download PDFInfo
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- CN106883267A CN106883267A CN201710095269.6A CN201710095269A CN106883267A CN 106883267 A CN106883267 A CN 106883267A CN 201710095269 A CN201710095269 A CN 201710095269A CN 106883267 A CN106883267 A CN 106883267A
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- vbe
- oridonin
- stand alone
- ome
- pharmaceutically acceptable
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- SDHTXBWLVGWJFT-XKCURVIJSA-N oridonin Chemical class C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12[C@@H](O)CCC(C)(C)[C@H]1[C@H](O)[C@@]3(O)OC2 SDHTXBWLVGWJFT-XKCURVIJSA-N 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 230000000694 effects Effects 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 26
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 6
- 230000000118 anti-neoplastic effect Effects 0.000 abstract description 2
- CAQAFLRZJHXSIS-UHFFFAOYSA-N oridonin Natural products CC1(C)C=CC(O)C23COC(O)(C(O)C12)C45C(O)C(CCC34)C(=C)C5=O CAQAFLRZJHXSIS-UHFFFAOYSA-N 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 238000011081 inoculation Methods 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241001646826 Isodon rubescens Species 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- 150000001241 acetals Chemical group 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229920005610 lignin Polymers 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- ONVABDHFQKWOSV-UHFFFAOYSA-N 16-Phyllocladene Natural products C1CC(C2)C(=C)CC32CCC2C(C)(C)CCCC2(C)C31 ONVABDHFQKWOSV-UHFFFAOYSA-N 0.000 description 1
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical class COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- HOSGXJWQVBHGLT-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical group N1C(=O)CCC2=CC(O)=CC=C21 HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical class CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 101150097381 Mtor gene Proteins 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102100023085 Serine/threonine-protein kinase mTOR Human genes 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- 241001643642 Viticis Species 0.000 description 1
- 150000004075 acetic anhydrides Chemical class 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 125000000567 diterpene group Chemical group 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- ONVABDHFQKWOSV-HPUSYDDDSA-N ent-kaur-16-ene Chemical compound C1C[C@H](C2)C(=C)C[C@@]32CC[C@@H]2C(C)(C)CCC[C@@]2(C)[C@@H]31 ONVABDHFQKWOSV-HPUSYDDDSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000002790 naphthalenes Chemical class 0.000 description 1
- RQKYHDHLEMEVDR-UHFFFAOYSA-N oxo-bis(phenylmethoxy)phosphanium Chemical compound C=1C=CC=CC=1CO[P+](=O)OCC1=CC=CC=C1 RQKYHDHLEMEVDR-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
- C07F9/65522—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring condensed with carbocyclic rings or carbocyclic ring systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a kind of VBE Oridonin derivatives or its pharmaceutically acceptable hydrate, including its stereoisomer or dynamic isomer.VBE Oridonin derivatives of the invention have antitumaous effect and preferably water solubility, can be used to prepare antineoplastic.The invention discloses its preparation method.
Description
Technical field
The present invention relates to the derivative of VBE Oridonins, and its application in pharmacy, belong to pharmaceutical technology field.
Background technology
Oridonin（oridonin）It is isolated a kind of kaurene from Labiatae Rabdosia plant Rabdosia rubescens
Diterpenes native compound.It has clearing heat and detoxicating, promoting blood circulation and removing blood stasis, anti-inflammation, it is antitumor the effects such as.As PTS,
It can suppress tumor cell proliferation, inducing cell apoptosis, and tumour cell signal path can be adjusted, and can remove thin
Intracellular free radical and suppression toxic substance mutagenized cell DNA etc..But, because Oridonin is water insoluble, limits it and facing
Application on bed.
Fruit of negundo lignin VBE（VBE-1 and VBE-2）It is the activity from fruit of negundo Fructus Viticis Negundo
Aryl dihydro naphthalenes lignin compound isolated in extract part Evn-50, being proved can be by suppressing Akt-
MTOR paths play antitumor action.VBE toxicity is low（LD50>2000mg/kg）, it is safe, to breast cancer, prostate cancer,
Liver cancer, oophoroma etc. have inhibitory action, and display has broad spectrum anticancer activity.But, it is metabolized rapidly in vivo, and half-life period is only
It is 69.3min, is inactivated after metabolism, and poorly water-soluble.Undesirable pharmacokinetic parameter becomes VBE as antineoplastic
The significant deficiency of thing.Research shows that the metabolism site of VBE is mainly 2- aldehyde radical, 6- hydroxyl and 4 '-position hydroxyl.In view of tool
Having has 1,3- dihydroxy fragments in the Oridonin structure of antitumor activity, and design is by VBE and Oridonin with acetal
Form is docked, and by 6- HM, while introducing water soluble functional group on 4 '-position hydroxyl of VBE, improves VBE
Metabolism, improve its water-soluble.VBE Oridonin derivatives discharge VBE and Oridonin through enzyme effect, dual anti-
Cancer.
The content of the invention
It is an object of the invention to provide a kind of VBE Oridonin derivatives or its pharmaceutically acceptable hydrate, bag
Its stereoisomer and dynamic isomer are included, it has preferably water-soluble and active anticancer.
Another object of the present invention is to provide above-mentioned VBE Oridonin derivatives or its pharmaceutically acceptable hydration
Thing, including its stereoisomer and dynamic isomer preparation method.
It is still another object of the present invention to provide above-mentioned VBE Oridonin derivatives or its pharmaceutically acceptable hydration
Thing, including its stereoisomer and dynamic isomer purposes.
The present invention will be described in detail below.
VBE Oridonin derivatives or its pharmaceutically acceptable hydrate that the present invention is provided, including its alloisomerism
Body and dynamic isomer, structure are as follows：
In formula, R1Each stand alone as OH, oxo oxygen acyl group, substituted oxygen acyl group；R2Each stand alone as H, OMe；R3Each stand alone as
H, OMe.
Described VBE Oridonin derivative concrete structure examples are as follows：
The preparation method of the above-claimed cpd that the present invention is also provided is shown below：
In formula, R1Each stand alone as OH, oxo, oxygen acyl group, substituted oxygen acyl group；R2Each stand alone as H, OMe；R3It is each independent
It is H, OMe.
VBE Oridonin derivatives of the invention or its pharmaceutically acceptable hydrate, including its stereoisomer and
Dynamic isomer, the effect with preferable water-soluble and treating cancer.
The present invention is further illustrated by following examples, but should be noted that the scope of the present invention is not implemented by these
Any limitation of example.
Specific embodiment
Embodiment 1
Compound（IIa）Preparation
N2Under, to the K of the VBE-1 and 276mg (2 mmol) of 356mg (1 mmol)2CO35mLDMF is added in mixture, is heated
To 70 DEG C, 1.0mL (1 mmol) Me is added dropwise2SO4, 2h is reacted, 30mL water is added, adjust pH7.0, ethyl acetate with 10%HCl solution
Extraction, saturated aqueous common salt removes DMF, is spin-dried for, column chromatography purifying, obtains Ia450.2mg, yield 87.4%.1H NMR（400MHz,
CDCl3)δ: 3.26 (dd, J=4.8, 14.6Hz, 1H), 3.33 (dd, J=4.8, 15.2Hz, 1H), 3.46 (s,
1H), 3.61 (q, J=5.2Hz, 1H), 3.66 (s, 3H), 3.84 (s, 3H), 3.92 (s,3H), 4.38 (
d, J=5.2Hz, 1H), 6.56 (d, J=8.0Hz, 1H), 6.65 (d, J=8.0Hz, 1H), 6.73 (s, 1H),
6.90 (s,1H),7.35 (s,1H), 9.50 (s,1H)。
N2Under, to 10mL acetonitriles are added in 370mg (1 mmol) Ia, it is cooled to -10 DEG C, plus 770mg (5 mmol) CCl4,
In in 30min add 0.38mL (2.1 mmol) DIPEAs and 12.6mg (0.1 mmol) DMAP, then at
0.4mL (1.4 mmol) dibenzyl phosphite is added dropwise in 30min, insulation reaction 1h adds the KH of 0.5mol/L2PO4Solution
4mL, is stirred at room temperature 5min, and decompression boils off acetonitrile, plus 5mL water, and ethyl acetate extraction, concentration, raffinate adds 15mL petroleum ether and stirrings,
White solid is separated out, compound IIa, yield 95% is obtained.1H NMR（400MHz,CDCl3)δ: 3.26 (dd, J=4.8,
14.6Hz, 1H), 3.33 (dd, J=4.8, 15.2Hz, 1H), 3.46 (s, 1H), 3.61 (q, J=5.2Hz,
1H), 3.66 (s, 3H), 3.84 (s, 3H), 3.92 (s,3H), 4.38 ( d, J=5.2Hz, 1H), 5.29
(s, 4H), 6.56 (d, J=8.0Hz, 1H), 6.65 (d, J=8.0Hz, 1H), 6.73 (s, 1H), 6.90 (s,
1H),7.19 (m,10H),7.35 (s,1H), 9.50 (s,1H)。
Embodiment 2
Compound（IIb）Preparation
Replace the VBE-1 of 356mg (1 mmol) with the VBE-2 of 356mg (1 mmol), other operations are obtained with embodiment 1
Compound IIb.
Embodiment 3
The preparation of 1- oxo Oridonins
To 40mL acetone is added in 1.97g (5 mmol) Oridonin, at 0 DEG C, 6mLJone ' s reagents are slowly dropped into, risen to
Room temperature, reacts 2h, adds 0.4mL isopropanols, reacts 0.5h, adds 0.5gNaHCO3, 0.5h is reacted, add 50mL acetic acid second
Ester, filtering is concentrated under reduced pressure, and petroleum ether-acetone recrystallization obtains 1.69g solids, yield 85%.Mp220-222℃.ESI-MS
（m/z)：385.4([M+Na]+)。
Embodiment 4
The preparation of 1- acetoxyl group Oridonins
To addition 35mL acetone, 7mL dimethoxy propanes and 0.2g p-methyl benzenesulfonic acid in 1.97g (5 mmol) Oridonin,
It is heated to reflux 1h, plus 5%Na2CO3Solution 10mL terminating reactions, ethyl acetate extraction, concentration, column chromatography purifying obtains 7,14-
The Oridonin intermediate of acetal protection, yield 77.1%.
To added in the Oridonin intermediate that 7,14- acetal of above-mentioned 2.17g (5 mmol) is protected 20mL aceticanhydrides and
40mL pyridines, are heated to reflux 4h, cooling, the HOAc solution of addition 100mL80%, room temperature reaction 2days, decompression steams acetic acid,
And be continuously added methyl alcohol and take acetic acid and water out of, to drain, column chromatography purifying obtains 1- acetoxyl group Oridonins, yield 45%.1H
NMR（400MHz,CDCl3)δ: 1.13 (s,6H), 2.06 (s,3H), 3.20 (d, J=9.9Hz, 1H), 3.08
(dd, J=3.8, 10.4Hz, 1H), 4.28, 4.20 (d, J=11.2Hz, 2H), 4.24 (s, 1H), 4.62-
4.65 (m,1H), 5.50 (s,1H), 5.80 (s,1H), 6.10 (d, J=10.4Hz, 1H), 6.17 (s, 1H)。
Embodiment 5
Compound（1）Preparation
To addition 35mL acetone, 3.15g (5 mmol) compound IIa and 0.2g pairs in 1.97g (5 mmol) Oridonin
Toluenesulfonic acid, is heated to reflux 1h, plus 5%Na2CO3Solution 10mL terminating reactions, concentration, column chromatography purifying obtains IIIa, yield
72.5%, will 1.0g (1 mmol) IIIa add 20mLDMF in, add 0.18g 10%Pd/C, 50bar pressure under, room temperature hydrogenation
8h, filters Pd/C, is concentrated under reduced pressure, column chromatography purifying, obtains IVa, yield 90%.ESI-MS（m/z)：826.3([M]+), upwards
State and add 10mLDMF in 1g intermediate compound IVs a, stir, instill the ethanol solution of 1mol/LNaOH, keep reaction solution pH9.3, reaction
1h, decompression is steamed near and is done, plus 20mL acetone stirring 1h, and refrigerator stands 8h, and filtering, acetone washing is dry, obtains compound（1）, receive
Rate 97.2%.
Embodiment 6
Compound（2）Preparation
Replace 1.97g (5 mmol) Oridonin in embodiment 5 with 1.96g (5 mmol) 1- oxo Oridonins,
Other operations obtain compound with embodiment 5（2）.
Embodiment 7
Compound（3）Preparation
Replace 1.97g (5 mmol) the Rabdosia rubescens first in embodiment 5 with 2.18g (5 mmol) 1- acetoxyl group Oridonins
Element, other operations obtain compound with embodiment 5（3）.
Embodiment 8
Compound（4）Preparation
Replace 3.15g (5 mmol) the compound IIa in embodiment 5 with 3.15g (5 mmol) compound IIb, other operations
With embodiment 5, compound（4）.
Embodiment 9
Compound（5）Preparation
Replace 3.15g (5 mmol) the compound IIa in embodiment 6 with 3.15g (5 mmol) compound IIb, other operations
With embodiment 6, compound（5）.
Embodiment 10
Compound（6）Preparation
Replace 3.15g (5 mmol) the compound IIa in embodiment 7 with 3.15g (5 mmol) compound IIb, other operations
With embodiment 7, compound is obtained（6）.
Embodiment 11
VBE Oridonin derivative antitumor activities
ICR kind mouse, male and female half and half, body weight 18-22g.It is grouped at random by body weight, mouse is divided into tumour negative control group,
VBE-1 and Oridonin positive controls（20mg/Kg.d）, VBE Oridonin derivatives（20mg/Kg.d）Dosage group,
Every group each 10, in addition to VBE-1 and Oridonin group, remaining every group starts oral gastric infusion in inoculation previous week,
Negative control group gives a certain amount of physiological saline.Aseptic aspiration is inoculated with H22The ascites of the knurl kind mouse of 8 days, it is dilute with physiological saline
Release 10 times, 0.02% Yihong（Trypan blue）Dyeing, is added drop-wise to after being counted on cell counting count board, adjusts cell concentration to 2.0*106Individual/
ML, in inoculation, every 0.2mL under mouse hind leg armpit.Each group is administered next day after inoculation, continuous 9 days, puts to death within the 10th day small
Mouse, plucks knurl and weighs, and tumor killing effect is judged with inhibiting rate.
Tumour inhibiting rate（%）= （Control group knurl weight-experimental group knurl weight）/ control group knurl weight * 100%
Result shows, compared with VBE-1 and Oridonin, VBE Oridonin derivatives are to rat liver cancer 22（H22）Have
Obvious inhibiting effect（Table 1）.
Claims (5)
1. a kind of VBE Oridonin derivatives or its pharmaceutically acceptable hydrate, including its stereoisomer and mutually variation
Structure body, is shown below：
In formula, R1Each stand alone as OH, oxo, acyloxy, substituted oxygen acyl group；R2Each stand alone as H, OMe；R3It is each independent
It is H, OMe.
2. VBE Oridonin derivatives or its pharmaceutically acceptable hydrate according to right 1, including its alloisomerism
Body and dynamic isomer, it is characterised in that in formula, R1Each stand alone as OH, oxo, oxygen acyl group, substituted oxygen acyl group；R2Each
Stand alone as H, OMe；R3Each stand alone as H, OMe.
3. VBE Oridonin derivatives or its pharmaceutically acceptable hydrate according to right 1, including its alloisomerism
Body and dynamic isomer, it is characterised in that：The instantiation of the compound includes following various：
4. VBE Oridonin derivatives according to claim 1 or its pharmaceutically acceptable hydrate, including it is three-dimensional
Isomers and dynamic isomer, its preparation method are comprised the following steps：
In formula, R1Each stand alone as OH, oxo, oxygen acyl group, substituted oxygen acyl group；R2Each stand alone as H, OMe；R3It is each independent
It is H, OMe.
5. VBE Oridonin derivatives or its pharmaceutically acceptable hydrate according to right 1, including its alloisomerism
Body and dynamic isomer, the effect with preferable water-soluble and treating cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710095269.6A CN106883267B (en) | 2017-02-22 | 2017-02-22 | VBE Oridonin derivative and its preparation and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710095269.6A CN106883267B (en) | 2017-02-22 | 2017-02-22 | VBE Oridonin derivative and its preparation and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106883267A true CN106883267A (en) | 2017-06-23 |
| CN106883267B CN106883267B (en) | 2019-03-29 |
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| CN110627833A (en) * | 2019-11-03 | 2019-12-31 | 石家庄学院 | Oridonin derivative and preparation and application thereof |
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