CN102659888B - Cucurbitacin derivatives and preparation method thereof - Google Patents
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- CVKKIVYBGGDJCR-SXDZHWHFSA-N Cucurbitacin B Natural products CC(=O)OC(C)(C)C=CC(=O)[C@@](C)(O)[C@@H]1[C@@H](O)C[C@]2(C)C3=CC[C@@H]4C(C)(C)C(=O)[C@H](O)C[C@@]4(C)[C@@H]3CC(=O)[C@@]12C CVKKIVYBGGDJCR-SXDZHWHFSA-N 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- LNSXRXFBSDRILE-UHFFFAOYSA-N Cucurbitacin Natural products CC(=O)OC(C)(C)C=CC(=O)C(C)(O)C1C(O)CC2(C)C3CC=C4C(C)(C)C(O)C(O)CC4(C)C3(C)C(=O)CC12C LNSXRXFBSDRILE-UHFFFAOYSA-N 0.000 title description 20
- 150000001904 cucurbitacins Chemical class 0.000 title description 18
- PIGAXYFCLPQWOD-UHFFFAOYSA-N dihydrocucurbitacin I Natural products CC12C(=O)CC3(C)C(C(C)(O)C(=O)CCC(C)(O)C)C(O)CC3(C)C1CC=C1C2C=C(O)C(=O)C1(C)C PIGAXYFCLPQWOD-UHFFFAOYSA-N 0.000 title description 18
- 150000001901 cucurbitacin B derivatives Chemical class 0.000 claims abstract description 28
- IXQKXEUSCPEQRD-NRNCYQGDSA-N (2S,4R,23E)-2,16beta,20-trihydroxy-9beta,10,14-trimethyl-1,11,22-trioxo-4,9-cyclo-9,10-secocholesta-5,23-dien-25-yl acetate Chemical compound C([C@H]1[C@]2(C)C[C@@H](O)[C@@H]([C@]2(CC(=O)[C@]11C)C)[C@@](C)(O)C(=O)C=CC(C)(C)OC(=O)C)C=C2[C@H]1C[C@H](O)C(=O)C2(C)C IXQKXEUSCPEQRD-NRNCYQGDSA-N 0.000 claims abstract description 17
- IHTCCHVMPGDDSL-ZJNDIJRCSA-N Cucurbitacin A Natural products O=C([C@@](O)(C)[C@H]1[C@@H](O)C[C@]2(C)[C@]1(C)CC(=O)[C@]1(CO)[C@H]2CC=C2C(C)(C)C(=O)[C@H](O)C[C@@H]12)/C=C/C(OC(=O)C)(C)C IHTCCHVMPGDDSL-ZJNDIJRCSA-N 0.000 claims abstract description 17
- QZJJDOYZVRUEDY-UHFFFAOYSA-N Dihydrocucurbitacin B Natural products CC12C(=O)CC3(C)C(C(C)(O)C(=O)CCC(C)(C)OC(=O)C)C(O)CC3(C)C1CC=C1C2CC(O)C(=O)C1(C)C QZJJDOYZVRUEDY-UHFFFAOYSA-N 0.000 claims abstract description 17
- NDYMQXYDSVBNLL-LAMASETHSA-N (23E)-25-acetyloxy-2,16alpha,20-trihydroxy-9beta-methyl-19-nor-10alpha-lanosta-1,5,23-triene-3,11,22-trione Chemical compound C([C@H]1[C@]2(C)C[C@@H](O)[C@@H]([C@]2(CC(=O)[C@]11C)C)[C@@](C)(O)C(=O)C=CC(C)(C)OC(=O)C)C=C2[C@H]1C=C(O)C(=O)C2(C)C NDYMQXYDSVBNLL-LAMASETHSA-N 0.000 claims abstract description 12
- NDYMQXYDSVBNLL-UHFFFAOYSA-N (9beta,10alpha,16alpha,23E)-25-(acetyloxy)-2,16,20-trihydroxy-9-methyl-19-norlanosta-1,5,23-triene-3,11,22-trione Natural products CC12C(=O)CC3(C)C(C(C)(O)C(=O)C=CC(C)(C)OC(=O)C)C(O)CC3(C)C1CC=C1C2C=C(O)C(=O)C1(C)C NDYMQXYDSVBNLL-UHFFFAOYSA-N 0.000 claims abstract description 12
- IVGSDBLLLAUYTL-UHFFFAOYSA-N cucurbitacin E Natural products CC(=O)OC(C)(C)C=CC(=O)C(C)(O)C1C(O)CC2(C)C3CC=C4C(C=C(O)C(=O)C4(C)C)C3(C)CCC12C IVGSDBLLLAUYTL-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims description 27
- 239000007787 solid Substances 0.000 claims description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 150000001903 cucurbitacin E derivatives Chemical class 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 23
- 239000012044 organic layer Substances 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- 238000004440 column chromatography Methods 0.000 claims description 16
- 238000000746 purification Methods 0.000 claims description 16
- 238000004090 dissolution Methods 0.000 claims description 13
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 8
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 claims description 4
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 claims description 4
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- 239000011787 zinc oxide Substances 0.000 claims description 4
- 239000012230 colorless oil Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 claims 2
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims 2
- GZCGUPFRVQAUEE-VANKVMQKSA-N aldehydo-L-glucose Chemical compound OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)C=O GZCGUPFRVQAUEE-VANKVMQKSA-N 0.000 claims 2
- 230000000694 effects Effects 0.000 abstract description 9
- 230000001093 anti-cancer Effects 0.000 abstract description 4
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- 230000002588 toxic effect Effects 0.000 abstract description 2
- 230000002155 anti-virotic effect Effects 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- 238000001819 mass spectrum Methods 0.000 description 12
- -1 tetracyclic triterpenoids compound Chemical class 0.000 description 8
- 244000241257 Cucumis melo Species 0.000 description 7
- 238000011160 research Methods 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
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- 210000004185 liver Anatomy 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- ITMUUFDDBRYVNJ-VOKXYEOFSA-N (2S,4R)-2,16,20,25-tetrahydroxy-9beta,10,14-trimethyl-4,9-cyclo-9,10-seco-16alpha-cholest-5-ene-1,11,22-trione Chemical compound C([C@H]1[C@]2(C)C[C@@H](O)[C@@H]([C@]2(CC(=O)[C@]11C)C)[C@@](C)(O)C(=O)CCC(C)(O)C)C=C2[C@H]1C[C@H](O)C(=O)C2(C)C ITMUUFDDBRYVNJ-VOKXYEOFSA-N 0.000 description 2
- 208000005623 Carcinogenesis Diseases 0.000 description 2
- 235000009842 Cucumis melo Nutrition 0.000 description 2
- 206010023126 Jaundice Diseases 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
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- 231100000504 carcinogenesis Toxicity 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 229930182478 glucoside Natural products 0.000 description 2
- 229930182470 glycoside Natural products 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 239000003440 toxic substance Substances 0.000 description 2
- UZEAHFLEZWXHCE-UHFFFAOYSA-N 3-iodo-2-methylaniline Chemical compound CC1=C(N)C=CC=C1I UZEAHFLEZWXHCE-UHFFFAOYSA-N 0.000 description 1
- 241000218999 Begoniaceae Species 0.000 description 1
- 241000219193 Brassicaceae Species 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 240000001980 Cucurbita pepo Species 0.000 description 1
- 235000009852 Cucurbita pepo Nutrition 0.000 description 1
- 241000219104 Cucurbitaceae Species 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 241001112083 Elaeocarpaceae Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000466331 Hemsleya endecaphylla Species 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- 206010062717 Increased upper airway secretion Diseases 0.000 description 1
- 244000302512 Momordica charantia Species 0.000 description 1
- 235000009811 Momordica charantia Nutrition 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 241000013557 Plantaginaceae Species 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- ITMUUFDDBRYVNJ-UHFFFAOYSA-N Tetrahydrocucurbitacin I Natural products CC12C(=O)CC3(C)C(C(C)(O)C(=O)CCC(C)(O)C)C(O)CC3(C)C1CC=C1C2CC(O)C(=O)C1(C)C ITMUUFDDBRYVNJ-UHFFFAOYSA-N 0.000 description 1
- 206010053613 Type IV hypersensitivity reaction Diseases 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
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- ZYZJWAJOTPNVPI-ZVBSCDOUSA-N cucurbitane Chemical compound C([C@H]1[C@]2(C)CC[C@@H]([C@]2(CC[C@]11C)C)[C@H](C)CCCC(C)C)CC2[C@H]1CCCC2(C)C ZYZJWAJOTPNVPI-ZVBSCDOUSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a plurality of new derivatives of cucurbitacin B and cucurbitacin E, salts of the cucurbitacin B and the cucurbitacin E, and a preparation method of the new derivatives. The new derivatives and salts of the cucurbitacin B and the cucurbitacin E have common basic structure and substantially same properties with cucurbitacin B and cucurbitacin E; have good anti-cancer, anti-virus, anti-inflammatory and liver-protecting effects, and low toxic and side effects.
Description
Technical field
The present invention relates to the multiple derivative of cucurbitacin, be specifically related to the multiple derivative of Cucurbitacin B and E, also relate to the preparation method of these derivatives.
Background technology
Cucurbitacin (cucurbitacin) belongs to 19-methyl and appears at the class tetracyclic triterpenoids compound on C-9 position, mainly be distributed in cucurbitaceous plant, in the higher plants such as Cruciferae, scrophulariaceae, Begoniaceae, Elaeocarpaceae, Datiscaceceae and some macro fungis, be also found.The extract of cucurbit prime system cucurbitaceous plant muskmelon (Cucumis melo L.) muskmelon pedicel, cucurbitacin has multiple biological activity, has removing toxic substances heat-clearing, and dampness removing jaundice is the effective Chinese patent medicine that is used for the treatment of clinically chronic hepatitis and primary hepatocarcinoma.
Ancient Times in China just adopts Chinese medicine muskmelon (Cucumis melo L.) muskmelon pedicel to control jaundice, again can be emetic, eliminate the phlegm, for sputum place, eat.Start the establishment along with cucurbitacin chemical structure the sixties, abroad someone studies its antitumor action.Isolate the compositions such as Cucurbitacin B, E the domestic beginning of the seventies from Chinese medicine Muskmelon Base, and carried out the pharmacological researches such as antitumor, immunostimulant and anti-hepatitis.The pharmacological action of report has: cell toxicant and antitumous effect; Anti-chemical carcinogenesis; Protect the liver, antihepatitic activity; Improve immunologic function; To cardiovascular effect; Anti-inflammatory; Suppress the effect of hepatic fibroplasia; In addition can also move by stimulating gastrointestinal, can also practise contraception.
In our research, by the method for chemosynthesis, found some novel derivatives of Cucurbitacin B and E, these novel derivatives have and Cucurbitacin B, the basic the same effect of E, and the present invention has been born.
Summary of the invention
First object of the present invention is to provide the multiple novel derivative of Cucurbitacin B and E and their salt; Second object of the present invention is to provide the preparation method of the novel derivative of Cucurbitacin B and E.
The invention provides the novel derivative of six kinds of Cucurbitacin Bs, the novel derivative of six kinds of Cucurbitacin Es and their pharmacy acceptable salt,
The chemical structure of these novel derivatives is as follows:
The Cucurbitacin B derivative of formula I, by nuclear magnetic resonance technique, illustrate its structure and mass spectrum calculating compound molecular weight:
1H-NMR(400MHz,CDCl3)δ7.01(d,J=12Hz,1H),6.29(d,J=12Hz,1H),5.51(t,J=8.4Hz,1H),4.08(m,1H),3.23(m,1H),2.29-2.27(m,3H),2.16(m,1H),2.04-2.02(m,2H),1.86-1.71(m,6H),1.60-1.46(m,2H),1.47(s,6H),1.38(s,3H),1.31(s,6H),1.30(s,3H),1.14(t,J=8.4,3H),1.04(s,6H).MS 573[M+H]
+。
The Cucurbitacin B derivative of formula II, by nuclear magnetic resonance technique, illustrate its structure and mass spectrum calculating compound molecular weight:
1H-NMR(400MHz,CDCl3)δ7.01(d,J=12Hz,1H),6.29(d,J=12Hz,1H),5.51(t,J=8.4Hz,1H),4.08(m,1H),3.23(m,1H),2.29-2.27(m,3H),2.16(m,1H),2.04-2.02(m,2H),1.86-1.71(m,8H),1.60-1.46(m,2H),1.47(s,6H),1.38(s,3H),1.31(s,6H),1.30(s,3H),1.04(s,6H),0.9(t,J=8.4,3H).MS 587[M+H]
+。
The Cucurbitacin B derivative of formula III, by nuclear magnetic resonance technique, illustrate its structure and mass spectrum calculating compound molecular weight:
1H-NMR(400MHz,CDCl3)δ5.51(t,J=8.4Hz,1H),4.08(m,1H),3.23(m,1H),2.29-2.27(m,3H),2.16(m,1H),2.04-2.02(m,2H),1.86-1.71(m,12H),1.60-1.46(m,2H),1.47(s,6H),1.38(s,3H),1.31(s,6H),1.30(s,3H),1.14(t,J=8.4,3H),1.04(s,6H).MS 575[M+H]
+。
The Cucurbitacin B derivative of formula IV, by nuclear magnetic resonance technique, illustrate its structure and mass spectrum calculating compound molecular weight:
1H-NMR(400MHz,CDCl3)δ5.51(t,J=8.4Hz,1H),4.08(m,1H),3.23(m,1H),2.29-2.27(m,3H),2.16(m,1H),2.04-2.02(m,2H),1.86-1.71(m,12H),1.60-1.46(m,2H),1.47(s,6H),1.38(s,3H),1.31(s,6H),1.30(s,3H),1.04(s,6H),0.9(t,J=8.4,3H).MS 587[M+H]
+。
The Cucurbitacin B derivative of formula V, by nuclear magnetic resonance technique, illustrate its structure and mass spectrum calculating compound molecular weight:
1H-NMR(400MHz,CDCl3)δ7.01(d,J=12Hz,1H),6.29(d,J=12Hz,1H),5.51(t,J=8.4Hz,1H),5.03(m,1H),4.08(m,1H),3.79-3.49(m,5H),3.40(m,1H),2.85(m,1H),2.27-2.02(m,8H),1.85-1.69(m,4H),1.60-1.46(m,2H),1.47(s,6H),1.38(s,3H),1.31(s,6H),1.30(s,3H),1.04(s,6H).MS 721[M+H]
+。
The Cucurbitacin B derivative of formula VI, by nuclear magnetic resonance technique, illustrate its structure and mass spectrum calculating compound molecular weight:
1H-NMR(400MHz,CDCl3)δ5.51(t,J=8.4Hz,1H),5.03(m,1H),4.08(m,1H),3.79-3.49(m,5H),3.40(m,1H),2.85(m,1H),2.27-2.02(m,12H),1.85-1.69(m,4H),1.60-1.46(m,2H),1.47(s, 6H),1.38(s,3H),1.31(s,6H),1.30(s,3H),1.04(s,6H).MS 723[M+H]
+。
The Cucurbitacin E derivative of formula X, by nuclear magnetic resonance technique, illustrate its structure and mass spectrum calculating compound molecular weight:
1H-NMR(400MHz,CDCl3)δ7.01(d,J=12Hz,1H),6.66(s,1H),6.29(d,J=12Hz,1H),5.51(t,J=8.4Hz,1H),3.23(m,1H),2.85(m,1H),2.29-2.27(m,3H),2.16(m,1H),2.04-2.02(m,2H),1.86-1.71(m,4H),1.60-1.46(m,2H),1.47(s,6H),1.38(s,3H),1.36(s,6H),1.30(s,3H),1.14(t,J=8.4,3H),1.04(s,6H).MS 571[M+H]
+。
The Cucurbitacin E derivative of formula XI, by nuclear magnetic resonance technique, illustrate its structure and mass spectrum calculating compound molecular weight:
1H-NMR(400MHz,CDCl3)δ7.01(d,J=12Hz,1H),6.66(s,1H),6.29(d,J=12Hz,1H),5.51(t,J=8.4Hz,1H),3.23(m,1H),2.85(m,1H),2.32-2.27(m,3H),2.16(m,1H),2.04-2.02(m,2H),1.86-1.71(m,6H),1.60-1.46(m,2H),1.47(s,6H),1.38(s,3H),1.36(s,6H),1.30(s,3H),1.04(s,6H),0.90(t,J=8.4,3H).MS 585[M+H]
+。
The Cucurbitacin E derivative of formula XII, by nuclear magnetic resonance technique, illustrate its structure and mass spectrum calculating compound molecular weight:
1H-NMR(400MHz,CDCl3)δ6.66(s,1H),5.51(t,J=8.4Hz,1H),3.23(m,1H),2.85(m,1H),2.29-2.27(m,3H),2.16(m,1H),2.04-2.02(m,2H),1.86-1.71(m,8H),1.60-1.46(m,2H),1.47(s,6H),1.38(s,3H),1.36(s,6H),1.30(s,3H),1.14(t,J=8.4,3H),1.04(s,6H).MS 573[M+H]
+。
The Cucurbitacin E derivative of formula XIII, by nuclear magnetic resonance technique, illustrate its structure and mass spectrum calculating compound molecular weight:
1H-NMR(400MHz,CDCl3)δ6.66(s,1H),5.51(t,J=8.4Hz,1H),3.23(m,1H),2.85(m,1H),2.32-2.27(m,3H),2.16(m,1H),2.04-2.02(m,2H),1.86-1.71(m,10H),1.60-1.46(m,2H),1.47(s,6H),1.38(s,3H),1.36(s,6H),1.30(s,3H),1.04(s,6H),0.90(t,J=8.4,3H).MS 585[M+H]
+。
The Cucurbitacin E derivative of formula XIV, by nuclear magnetic resonance technique, illustrate its structure and mass spectrum calculating compound molecular weight:
1H-NMR(400MHz,CDCl3)δ7.01(d,J=12Hz,1H),6.66(s,1H),6.29(d,J=12Hz,1H),5.51(t,J=8.4Hz,1H),5.03(m,1H),3.79-3.49(m,5H),3.40(m,1H),3.23(m,1H),2.85(m,1H),2.29-2.27(m,6H),2.16(m,1H),2.04-2.02(m,2H),1.86-1.71(m,4H),1.60-1.46(m,2H),1.47(s,6H),1.38(s,3H),1.36(s,6H),1.30(s,3H),1.04(s,6H).MS 719[M+H]
+。
The Cucurbitacin E derivative of formula XV, by nuclear magnetic resonance technique, illustrate its structure and mass spectrum calculating compound molecular weight:
1H-NMR(400MHz,CDCl3)δ6.66(s,1H),5.51(t,J=8.4Hz,1H),5.03(m,1H),3.79-3.49(m,5H),3.40(m,1H),3.23(m,1H),2.85(m,1H),2.29-2.27(m,10H),2.16(m,1H),2.04-2.02(m,2H),1.86- 1.71(m,4H),1.60-1.46(m,2H),1.47(s,6H),1.38(s,3H),1.36(s,6H),1.30(s,3H),1.04(s,6H).MS721[M+H]
+。
, formula II(B-2), formula III (B-3), formula IV(B-4 likes I(B-1)) Cucurbitacin B derivative and formula X(E-1), formula XI(E-2), formula XI(E-3), formula XIII(E-4) the synthetic route of Cucurbitacin E derivative as follows:
, Cucurbitacin B derivative formula VI(B-6) and formula XIV(E-5 likes V(B-5)), formula XV(E-6) the synthetic route of Cucurbitacin E derivative as follows:
Newfound above-mentioned six kinds of Cucurbitacin B derivatives and six kinds of Cucurbitacin E derivatives and their salt, owing to thering is common basic structure with Cucurbitacin B, E respectively, so character is also substantially the same with Cucurbitacin B, E, there is preferably anticancer, antiviral, anti-inflammatory and protect the liver dirty effect, and toxic side effect is lower.
Embodiment
In conjunction with above-mentioned synthetic route, further set forth the present invention.
(1) B-1-1's is synthetic: by (559 milligrams of existing Cucurbitacin Bs, 1.0 mmoles) be dissolved in 10 ml methanol, then the lithium hydroxide aqueous solution (1 milliliter) that adds 1N, stirring at room 2 hours, concentrated, resistates dissolves with methylene dichloride, with soda lye wash, organic layer is dry concentrated, obtains 502 milligrams of white solids, yield 97.2%.
(2) B-1's is synthetic: by synthetic B-1-1(51.6 milligram, 0.1 mmole) be dissolved in 10 milliliters of methylene dichloride, then add pyridine (10 milligrams), add propionyl chloride (10 milligrams), room temperature reaction 2 hours, reacts complete again, reaction solution is with acid rinsing, organic layer is dry concentrated, and resistates column chromatography purification obtains 42 milligrams of white solids, yield 74%.
(3) E-1-1's is synthetic: by (557 milligrams of existing Cucurbitacin Es, 1.0 mmoles) be dissolved in 10 ml methanol, then the lithium hydroxide aqueous solution (1 milliliter) that adds 1N, stirring at room 2 hours, concentrated, resistates dissolves with methylene dichloride, with soda lye wash, organic layer is dry concentrated, obtains 498 milligrams of white solids, yield 96.8%.
(4) E-1's is synthetic: by synthetic E-1-1(51.4 milligram, 0.1 mmole) be dissolved in 10 milliliters of methylene dichloride, then add pyridine (10 milligrams), add propionyl chloride (10 milligrams), room temperature reaction 2 hours, reacts complete again, reaction solution is with acid rinsing, organic layer is dry concentrated, and resistates column chromatography purification obtains 47 milligrams of white solids, yield 83%.
(5) B-2's is synthetic: by synthetic B-1-1(51.6 milligram, 0.1 mmole) be dissolved in 10 milliliters of methylene dichloride, then add pyridine (10 milligrams), add butyryl chloride (10 milligrams), room temperature reaction 2 hours, reacts complete again, reaction solution is with acid rinsing, organic layer is dry concentrated, and resistates column chromatography purification obtains 45 milligrams of white solids, yield 77%.
(6) E-2's is synthetic: by synthetic E-1-1(51.4 milligram, 0.1 mmole) be dissolved in 10 milliliters of methylene dichloride, then add pyridine (10 milligrams), add butyryl chloride (11 milligrams), room temperature reaction 2 hours, reacts complete again, reaction solution is with acid rinsing, organic layer is dry concentrated, and resistates column chromatography purification obtains 50 milligrams of white solids, yield 86%.
(7) B-3's is synthetic: by compd B-1(57.2 milligram) be dissolved in 10 milliliters of ethanol, then add the palladium carbon of 0.3 gram 10%, nitrogen replacement, then hydrogen exchange, keep 2atm pressure, stirring reaction 1 hour, filters, concentrated, obtain 56.9 milligrams of white solids, yield 99%.
(8) B-4's is synthetic: by compd B-2(58.4 milligram) be dissolved in 10 milliliters of ethanol, then add the palladium carbon of 0.3 gram 10%, nitrogen replacement, then hydrogen exchange, keep 2atm pressure, stirring reaction 1 hour, filters, concentrated, obtain 55.2 milligrams of white solids, yield 94%.
(9) E-3's is synthetic: by compd E-1(57 milligram) be dissolved in 10 milliliters of ethanol, then add the palladium carbon of 0.3 gram 10%, nitrogen replacement, then hydrogen exchange, keep 2atm pressure, stirring reaction 1 hour, filters, concentrated, obtain 56.1 milligrams of white solids, yield 98.4%.
(10) E-4's is synthetic: by compd E-2(58.2 milligram) be dissolved in 10 milliliters of ethanol, then add the palladium carbon of 0.3 gram 10%, nitrogen replacement, then hydrogen exchange, keep 2atm pressure, stirring reaction 1 hour, filters, concentrated, obtain 56.5 milligrams of white solids, yield 97%.
(11) G-1's is synthetic: by (1.8 grams of glucose, 10 mmoles) be dissolved in 20 milliliters of acetone, then add (2.1 grams of 1,1-Propanal dimethyl acetals, 20 mmoles) and sulfuric acid (1), stirring at room 1 hour, is concentrated into the greatest extent, and resistates is with acetic acid ethyl dissolution, with water washing, organic layer is dry concentrated, obtains 2.13 grams of colorless oil, yield 82%.
(12) B-5-1's is synthetic: by (559 milligrams of existing Cucurbitacin Bs, 1 mmole), synthetic G-1(260 milligram, 1 mmole), zinc oxide (81.5 milligrams, 1 mmole) is dissolved in 10 ml methanol, stirring at room one hour, be concentrated into the greatest extent, resistates, with acetic acid ethyl dissolution, washs with saturated brine, organic layer is dry concentrated, residuum, with column chromatography purification, obtains 624 milligrams of white solids, yield 78%.
(13) B-5's is synthetic: by synthetic B-5-1(400 milligram, 0.5 mmole) be dissolved in 10 milliliters of toluene, then add tosic acid (86 milligrams, 0.5 mmole), stirring at room 18 hours, react complete, in reaction solution, add saturated sodium bicarbonate aqueous solution washing, organic layer is dry concentrated, and resistates is with column chromatography purification, obtain 248 milligrams of white solids, yield 69%.
(14) E-5-1's is synthetic: by (556 milligrams of existing Cucurbitacin Es, 1 mmole), synthetic G-1(260 milligram, 1 mmole), zinc oxide (81.5 milligrams, 1 mmole) is dissolved in 10 ml methanol, stirring at room one hour, be concentrated into the greatest extent, resistates, with acetic acid ethyl dissolution, washs with saturated brine, organic layer is dry concentrated, residuum, with column chromatography purification, obtains 606 milligrams of white solids, yield 76%.
(15) E-5's is synthetic: by synthetic E-5-1(400 milligram, 0.5 mmole) be dissolved in 10 milliliters of toluene, then add tosic acid (86 milligrams, 0.5 mmole), stirring at room 18 hours, react complete, in reaction solution, add saturated sodium bicarbonate aqueous solution washing, organic layer is dry concentrated, and resistates is with column chromatography purification, obtain 240 milligrams of white solids, yield 67%.
(16) B-6's is synthetic: by compd B-5(72 milligram) be dissolved in 10 milliliters of ethanol, then add the palladium carbon of 0.3 gram 10%, nitrogen replacement, then hydrogen exchange, keep 2atm pressure, stirring reaction 1 hour, filters, concentrated, obtain 68.6 milligrams of white solids, yield 95%.
(17) E-6's is synthetic: by compd E-5(72 milligram) be dissolved in 10 milliliters of ethanol, then add the palladium carbon of 0.3 gram 10%, nitrogen replacement, then hydrogen exchange, keep 2atm pressure, stirring reaction 1 hour, filters, concentrated, obtain 69.8 milligrams of white solids, yield 97%.
The Cucurbitacin B novel derivative B-1 making, B-2, B-3, B-4, B-5, B-6 and Cucurbitacin E novel derivative E-1, E-2, E-3, E-4, E-5, E-6, function is identical with existing Cucurbitacin B, E respectively, the effect that has anticancer, antiviral, anti-inflammatory and protect the liver.In other words, the method for pharmacology of these Cucurbitacin Bs and E novel derivative of studying is with existing Cucurbitacin B, E, therefore be not repeated herein, the pharmacological action report of relevant existing Cucurbitacin B, E is specifically referring to following disclosed document:
1、Geissman,T.A.(1964).“New substances of plant origin”,Annu.Rev.Pharmacol.,4,305-316。
, Fang Xinde. the chemistry of cucurbitacine composition and bioactive progress [J]. foreign medical science: pharmacy fascicle, 1985,3:132.
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、Gallily R.et al.Further studies on the antitumor effect of cucubitacins.Cance Research.1962,22:1038。
, Han De five hippology favours etc. Cucurbitacin B is to experimental hepatitis and cirrhotic preventive and therapeutic effect [J]. Chinese Medical Journal, 1979,59 (4): 208.
、Jian Chao Chen,Ming Hua Chiu,Rui Lin Nie,Geoffrey A.Cordell and Samuel X.Qiu(2005),"Cucurbitacins and cucurbitane glycosides:structures and biological activities"Natural Product Reports,volume 22,pages 386-399。
、Chiy-Rong Chen,Yun-Wen Liao,Lai Wang,Yueh-Hsiung Kuo,Hung-Jen Liu,Wen-Ling Shih,Hsueh-Ling Cheng and Chi-I Chang(2010)."Cucurbitane Triterpenoids from Momordica charantia and Their Cytoprotective Activity in tert-Butyl Hydroperoxide-Induced Hepatotoxicity of HepG2 Cells".Chemical & pharmaceutical bulletin,volume 58,issue 12,pages 1639-1642。
、Jian-Chao Chen,Gao-Hong Zhang,Zhong-Quan Zhang,Ming-Hua Qiu,Yong-Tang Zheng,Liu-Meng Yang,Kai-Bei Yu(2008),"Octanorcucurbitane and Cucurbitane Triterpenoids from the Tubers of Hemsleya endecaphylla with HIV-1 Inhibitory Activity".J.Nat.Prod.volume 71,pages 153–155。
、Da-Cheng Wang,Hong-Yu Pan,Xu-Ming Deng,Hua Xiang,Hui-Yuan Gao,Hui Cai,and Li-Jun Wu(2007),"Cucurbitane and hexanorcucurbitane glycosides from the fruits of Cucurbita pepo cv dayangua".Journal of Asian Natural Products Research,volume 9,issue 6,pages 525–529.
10、Dhong Hyun Lee,Gabriela B.Iwanski,and Nils H.Thoennissen “Cucurbitacin:Ancient Compound Shedding New Light on Cancer Treatment”The Scientific World.JOURNAL(2010)10,413–418
11、Yanmin Dong,Binbin Lu,Xiaoli Zhang,Jing Zhang,
Li Lai,Dali Li,YuanyuanWu,Yajuan Song,Jian Luo,
Xiufeng Pang,Zhengfang Yi,and Mingyao Liu
“Cucurbitacin E,a tetracyclic triterpenes compound from Chinese medicine,inhibits tumor angiogenesis through VEGFR2-mediated Jak2–STAT3 signaling pathway”Carcinogenesis vol.31no.12pp.2097–2104,2010
12, pct international patent open source literature WO 2007/116404A2 " CUCURBITACIN GLUCOSIDES AND USE THEREOF IN TREATING CANCER "
13、Yanyan Li,Qiushuang Sheng,Sijie Zhang,Zhe Lu,Jianbo Guo,Hui Xu,Yihui Deng“Feasibility of percutaneous administration of cucurbitacin B,an anticancer active substance isolated from cucurbitaceae plants
”Percutaneous administration of CuB/Asian Journal of Pharmaceutical Sciences 2010，5(4):152-160
14, american documentation literature US5925356 " METHOD OF ISOLATING CUCURBITACIN "
15、Meixia Zhang,PhD,Chunyan Sun,MD,Xiaolei Shan,MD,Xiaolin Yang,MD,Jesse Li-Ling,MD,PhD,and Yihui Deng,PhD“Inhibition of Pancreatic Cancer Cell Growth by Cucurbitacin B Through Modulation of Signal Transducer and Activator of Transcription 3Signaling”Pancreas & Volume 39,Number 6,August 2010
16、Yaowalak U-pratya,Usaneeporn Lueangamornnara,Weena Jiratchariyakul and Tanawan Kummalue “Immunosuppressive effects of Cucurbitacin B on
human peripheral blood lymphocytes”Journal of Medicinal Plants Research Vol.4(22),pp.2340-2347,18November，2010
17、Tehila Tannin-Spitz,Margalit Bergman,Shlomo Grossman “Cucurbitacin glucosides:Antioxidant and free-radical scavenging activities”Biochemical and Biophysical Research Communications 364(2007)181–186
18、Jose′M.Escandell,María-Carmen Recio,Rosa M.Giner，Salvador Ma′n～ez,Miguel Cerda′-Nicola′s,Irmgard Merfort,and Jose′-Luis Ríos
“Inhibition of Delayed-Type Hypersensitivity by Cucurbitacin R
through the Curbing of Lymphocyte Proliferation and Cytokine
Expression by Means of Nuclear Factor AT Translocation to
the Nucleus”THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol.332,No.2 。
Claims (10)
1. the Cucurbitacin B derivative that formula V or formula VI represent, or its pharmacy acceptable salt:
2. the method for the Cucurbitacin B derivative of preparation formula I or formula II, is characterized in that:
First, Cucurbitacin B is dissolved in methyl alcohol, then adds lithium hydroxide aqueous solution, stirring at room, concentrated, resistates dissolves with methylene dichloride, and with soda lye wash, organic layer is dry concentrated, the white solid that the formula VII of obtaining represents,
Then, the compound dissolution in formula VII, in methylene dichloride, is then added to pyridine, then add propionyl chloride, room temperature reaction, reacts complete, and reaction solution is with acid rinsing, organic layer is dry concentrated, and resistates column chromatography purification obtains white solid, is the Cucurbitacin B derivative of described formula I;
Or, the compound dissolution in formula VII, in methylene dichloride, is then added to pyridine, then adds butyryl chloride, room temperature reaction, reacts complete, and reaction solution is with acid rinsing, organic layer is dry concentrated, and resistates column chromatography purification obtains white solid, is the Cucurbitacin B derivative of described formula II.
3. the method for preparing the Cucurbitacin B derivative of formula III or formula IV, is characterized in that:
The Cucurbitacin B derivative of formula I is dissolved in ethanol, then adds palladium carbon, nitrogen replacement, then hydrogen exchange, keeps 2atm pressure, and stirring reaction filters, concentrated, obtains white solid, is the Cucurbitacin B derivative of described formula III;
Or, the Cucurbitacin B derivative of formula II is dissolved in ethanol, then add palladium carbon, nitrogen replacement, then hydrogen exchange, keeps 2atm pressure, and stirring reaction filters, concentrated, obtains white solid, is the Cucurbitacin B derivative of described formula IV.
4. the method for the Cucurbitacin B derivative of preparation formula V, is characterized in that:
(1) glucose is dissolved in acetone, then adds 1,1-Propanal dimethyl acetal and sulfuric acid, stirring at room, is concentrated into the greatest extent, and resistates is with acetic acid ethyl dissolution, and with water washing, organic layer is dry concentrated, the colorless oil that the formula VIII of obtaining represents,
(2) compound in Cucurbitacin B, formula VIII, zinc oxide are dissolved in methyl alcohol, stirring at room, is concentrated into the greatest extent, resistates is with acetic acid ethyl dissolution, and with saturated brine washing, organic layer is dry concentrated, residuum is with column chromatography purification, the white solid that the formula IX of obtaining represents
(3) by the compound dissolution in formula IX in toluene, then add tosic acid, stirring at room, react complete, in reaction solution, add saturated sodium bicarbonate aqueous solution washing, organic layer is dry concentrated, resistates is with column chromatography purification, obtain white solid, be the Cucurbitacin B derivative of described formula V
5. the method for the Cucurbitacin B derivative of preparation formula VI, is characterized in that:
The Cucurbitacin B derivative of formula V is dissolved in ethanol, then adds palladium carbon, nitrogen replacement, then hydrogen exchange, keeps 2atm pressure, and stirring reaction filters, concentrated, obtains white solid, is the Cucurbitacin B derivative of described formula VI,
6. the Cucurbitacin E derivative that formula XIV or formula XV represent, or its pharmacy acceptable salt:
7. the method for the Cucurbitacin E derivative of preparation formula X or formula XI, is characterized in that:
First, Cucurbitacin E is dissolved in methyl alcohol, then adds lithium hydroxide aqueous solution, stirring at room, concentrated, resistates dissolves with methylene dichloride, and with soda lye wash, organic layer is dry concentrated, the white solid that the formula XVI of obtaining represents,
Then, the compound dissolution in formula XVI, in methylene dichloride, is then added to pyridine, then add propionyl chloride, room temperature reaction, reacts complete, and reaction solution is with acid rinsing, and organic layer is dry concentrated, and resistates column chromatography purification obtains the Cucurbitacin E derivative of described formula X;
Or, the compound dissolution in formula XVI, in methylene dichloride, is then added to pyridine, add butyryl chloride, room temperature reaction, reacts complete again, reaction solution is with acid rinsing, and organic layer is dry concentrated, and resistates column chromatography purification obtains the Cucurbitacin E derivative of described formula XI.
8. the method for the Cucurbitacin E derivative of preparation formula XII or formula XIII, is characterized in that:
The Cucurbitacin E derivative of formula X is dissolved in ethanol, then adds palladium carbon, nitrogen replacement, then hydrogen exchange, keeps 2atm pressure, and stirring reaction filters, concentrated, obtains the Cucurbitacin E derivative of described formula XII;
Or, the Cucurbitacin E derivative of formula XI is dissolved in ethanol, then add palladium carbon, nitrogen replacement, then hydrogen exchange, keeps 2atm pressure, and stirring reaction filters, concentrated, obtains the Cucurbitacin E derivative of described formula XIII.
9. the method for the Cucurbitacin E derivative of preparation formula XIV, is characterized in that:
(1) glucose is dissolved in acetone, then adds 1,1-Propanal dimethyl acetal and sulfuric acid, stirring at room, is concentrated into the greatest extent, and resistates is with acetic acid ethyl dissolution, and with water washing, organic layer is dry concentrated, obtains the colorless oil that described formula VIII represents,
(2) compound in Cucurbitacin E, formula VIII, zinc oxide are dissolved in methyl alcohol, stirring at room, is concentrated into the greatest extent, resistates is with acetic acid ethyl dissolution, and with saturated brine washing, organic layer is dry concentrated, residuum is with column chromatography purification, the white solid that the formula XVII of obtaining represents
(3) by the compound dissolution in formula XVII in toluene, then add tosic acid, stirring at room, react complete, in reaction solution, add saturated sodium bicarbonate aqueous solution washing, organic layer is dry concentrated, resistates, with column chromatography purification, obtains the Cucurbitacin E derivative of described formula XIV
10. the method for the Cucurbitacin E derivative of preparation formula XV, is characterized in that:
The Cucurbitacin E derivative of formula XIV is dissolved in ethanol, then adds palladium carbon, nitrogen replacement, then hydrogen exchange, keeps 2atm pressure, and stirring reaction filters, concentrated, obtains the Cucurbitacin E derivative of described formula XV,
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| CN104892713B (en) * | 2015-04-16 | 2016-08-17 | 中国农业科学院蔬菜花卉研究所 | The preparation method of cucurbitacin C and the like and application |
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| CN116768955A (en) * | 2022-03-09 | 2023-09-19 | 中国科学院上海药物研究所 | Cucurbitacin B derivative and preparation method and application thereof |
| CN115414369B (en) * | 2022-08-30 | 2023-09-15 | 中国农业大学 | Application of cucurbitacin C in preparation of medicines for preventing or treating inflammatory bowel disease |
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