CN102532092A - Natural product Bostrycin derivative I as well as preparation method and application thereof - Google Patents
Natural product Bostrycin derivative I as well as preparation method and application thereof Download PDFInfo
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- CN102532092A CN102532092A CN2012100125169A CN201210012516A CN102532092A CN 102532092 A CN102532092 A CN 102532092A CN 2012100125169 A CN2012100125169 A CN 2012100125169A CN 201210012516 A CN201210012516 A CN 201210012516A CN 102532092 A CN102532092 A CN 102532092A
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- bostrycin
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- verivate
- alkyl
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- ZQNOLGRKZRDRQO-XHSDSOJGSA-N bostrycin Chemical class O[C@@H]1[C@@H](O)[C@@](C)(O)CC2=C1C(O)=C1C(=O)C=C(OC)C(=O)C1=C2O ZQNOLGRKZRDRQO-XHSDSOJGSA-N 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 229930014626 natural product Natural products 0.000 title claims abstract description 27
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 15
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 12
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 7
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 7
- NCLWGURXHFTQGF-MGPLVRAMSA-N bostrycin Natural products COC1=CC(=O)c2c(O)c3C[C@H](O)[C@](C)(O)Cc3c(O)c2C1=O NCLWGURXHFTQGF-MGPLVRAMSA-N 0.000 claims description 39
- 150000001875 compounds Chemical class 0.000 claims description 38
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 238000006555 catalytic reaction Methods 0.000 claims description 11
- 230000000259 anti-tumor effect Effects 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 8
- 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 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- -1 3-methyl-2-butene aldehyde Chemical class 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- BKOOMYPCSUNDGP-UHFFFAOYSA-N trimethyl-ethylene Natural products CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 claims description 3
- 229920006324 polyoxymethylene Polymers 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims 1
- 208000026310 Breast neoplasm Diseases 0.000 claims 1
- 206010009944 Colon cancer Diseases 0.000 claims 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims 1
- 201000010989 colorectal carcinoma Diseases 0.000 claims 1
- 201000007270 liver cancer Diseases 0.000 claims 1
- 208000014018 liver neoplasm Diseases 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 17
- 230000000694 effects Effects 0.000 abstract description 5
- 238000011160 research Methods 0.000 abstract description 4
- 238000012360 testing method Methods 0.000 abstract description 4
- 210000004881 tumor cell Anatomy 0.000 abstract description 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 abstract 2
- 125000004417 unsaturated alkyl group Chemical group 0.000 abstract 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 abstract 1
- 230000005918 in vitro anti-tumor Effects 0.000 abstract 1
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 244000005700 microbiome Species 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241000233866 Fungi Species 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 150000002611 lead compounds Chemical class 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 235000015097 nutrients Nutrition 0.000 description 3
- 229930000044 secondary metabolite Natural products 0.000 description 3
- QGZCUOLOTMJILH-UHFFFAOYSA-N 2h-tetrazol-2-ium;bromide Chemical compound [Br-].C1=N[NH+]=NN1 QGZCUOLOTMJILH-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 240000002044 Rhizophora apiculata Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000000118 anti-neoplastic effect Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- MWWSFMDVAYGXBV-FGBSZODSSA-N (7s,9s)-7-[(2r,4s,5r,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydron;chloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-FGBSZODSSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZCWPHDXKEDBCER-UHFFFAOYSA-N 2,5-diphenyl-2h-tetrazol-2-ium;bromide Chemical compound [Br-].C1=CC=CC=C1C1=[NH+]N(C=2C=CC=CC=2)N=N1 ZCWPHDXKEDBCER-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- 241000286194 Alternaria eichhorniae Species 0.000 description 1
- 241000171735 Arthrinium phaeospermum Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 0 CC1(Cc2c(C)c(C(C(OC)=C3)=C)c4C3=O)O*OC1C(*)c2c4OC Chemical compound CC1(Cc2c(C)c(C(C(OC)=C3)=C)c4C3=O)O*OC1C(*)c2c4OC 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000368696 Nigrospora oryzae Species 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- WHHGLZMJPXIBIX-UHFFFAOYSA-N decabromodiphenyl ether Chemical compound BrC1=C(Br)C(Br)=C(Br)C(Br)=C1OC1=C(Br)C(Br)=C(Br)C(Br)=C1Br WHHGLZMJPXIBIX-UHFFFAOYSA-N 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000013461 design 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
- 229940079593 drug Drugs 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003592 new natural product Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000505 pernicious effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000009333 weeding Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a natural product Bostrycin derivative I as well as a preparation method and application thereof. The natural product Bostrycin derivative I has a structure shown in the general formula (1) in the specification, wherein X is a structure shown in the specification, C=O, S=O or C=S; R<1> is H, hydroxymethyl or alkyl; R<2> is H, C1-10 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or aralkyl; R<3> is H, C1-10 alkyl, substituted or un substituted phenyl, substituted or unsubstituted benzyl, or aralkyl; R<4> is H, straight-chain or branch-chain alkyl, unsaturated alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or aralkyl; R<5> is H, straight-chain or branch-chain alkyl, unsaturated alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or aralkyl; and R<6> is H, alkyl or phenyl. Results of primary pharmacological research ( in vitro anti-tumor cell test) prove that the natural product Bostrycin derivative has excellent tumor cell resistance activity, can be further used for researching and developing novel antitumor drugs.
Description
Technical field
The present invention relates to the discovery field of pharmaceutical chemistry, lead compound, be specifically related to one type of new natural product bostrycin verivate, its preparation method and purposes in the preparation antitumor drug through modifying.
Background technology
Bostrycin is a kind of pigment of redness, at first from Bostryconema alpespre cesati (Tetrahedron Lett. 58:6087,1968; Tetrahedron Lett. 58:6091,1968; Tetrahedron. separate obtaining 26:1339,1968), can suppress gram positive bacterium.Report (Sankyo Kenkyusho Nenpo. 21:165 subsequently again from Nigrospora oryzae; 1969), Fungus Arthrinium phaeospermum (Experientia. 31:783; 1975), Alternaria eichhorniae (Appl Environ Microbiol. 43:846; 1982) separate obtaining in, and find that it has weeding activity.2000; Jiang Guangce, Lin Yongcheng, Zhou Shining (Zhongshan University's journal (natural science edition); 39:68; 2000) separation obtains Bos trycin from South China Sea mangrove endogenetic fungus #1403 secondary metabolite, and cell in vitro poison test-results shows: Bostrycin all can effectively suppress growth of various tumor cell strains (CN1347865A; CN1850765A; CN1762961A; CN101544556A).
For a long time, human health and life in malignant tumour serious threat always.The sickness rate and the lethality rate of tumor disease rise year by year; Yet the specifics of treatment tumor disease especially at present the selectivity of antitumor clinical used cytotoxic drug not high cause to Normocellular pernicious killing and wounding, thereby limited the general applicability of such medicine.Therefore, seek and find that the new antitumor drug with high-efficiency low-toxicity is worldwide research focus.
Yet ball surface-area 70% is taken up an area of in the ocean, and abundant Biological resources are also being contained in the ocean when containing the abundant mineral and the energy.Marine microorganism in quantity or the variety aspect is all quite abundant.Because the living environment of marine microorganism is special, the compound of energy metabolism novel structure, and have good pharmacologically active has been found the compound of antitumor in a large number, treatment cardiovascular disorder, antibiotic, antiviral isoreactivity at present.According to the report of John professor at 2010 " Natural Product Reports ", found that the marine natural product new compound surpassed 1000 kinds first in 2008, marine microorganism is one of main source (accounting for 23%).In addition, marine microorganism is easy to gather and cultivate, and the meta-bolites that the artificial fermentation produces is purified easily, and cost is low, meets the resources development and utilization principle of Sustainable development, so the active compound that therefrom screens is more conducive to suitability for industrialized production.
Make full use of oceanic resources; With its effective constituent is that lead compound carries out structure of modification and composition optimizes; Design is synthetic to have the more compound of strong biological activity, is an effective way seeking new type antineoplastic medicine, and the present invention is a lead compound with South China Sea ocean mangrove endophytic fungus #1403 secondary metabolite Bos trycin; It is carried out structure of modification, and purpose is to seek the natural antitumor drug candidate of high-efficiency low-toxicity.
Summary of the invention
The contriver obtains the structure that compound Bostrycin has following IV by extraction separation in the South China Sea thalassiomycetes #1403 secondary metabolite.
（Ⅳ）
The used fungi 1403 of the present invention be preserved in Chinese typical culture collection center (CCTCC, in
State Wuhan University is in the school), preserving number is CCTCC NO:M201018, preservation day is April 23 calendar year 2001.
The purpose of this invention is to provide a kind of novel natural product Bostrycin derivatives I.
Another object of the present invention provides the preparation method of above-mentioned novel natural product Bostrycin verivate.
A purpose more of the present invention provides the purposes of novel natural product Bostrycin verivate in the preparation antitumor drug.
The novel natural product Bostrycin verivate of the present invention has the structure of formula (I):
Wherein: X=
or
or C=O; S=O; C=S;
R
1=H, methylol, alkyl;
R
2The alkyl of=H, C1-C10, replacement or unsubstituted phenyl, replacement or not substituted benzyl, aralkyl;
R
3The alkyl of=H, C1-C10, replacement or unsubstituted phenyl, replacement or not substituted benzyl, aralkyl;
R
4=H, direct-connected or branched-chain alkyl, undersaturated alkyl, replacement or unsubstituted phenyl, replacement or not substituted benzyl, aralkyl;
R
5=H, direct-connected or branched-chain alkyl, undersaturated alkyl, replacement or unsubstituted phenyl, replacement or not substituted benzyl, aralkyl;
R
6=H, alkyl, phenyl;
Natural product Bostrycin verivate of the present invention prepares through following method: employing Bostrycin is a raw material, and with 2, the reaction of 2-Propanal dimethyl acetal obtains compound under the catalysis of acid
1Under the catalysis of acid, obtain compound with 3-methyl-2-butene aldehyde reaction
2Under the catalysis of acid, obtain compound with polyformaldehyde reaction
3Under the catalysis of alkali, obtain compound with the solid phosgene reaction
4Under the catalysis of alkali, obtain compound with the thionyl chloride reaction
5
Above-claimed cpd of the present invention is through preliminary pharmaceutical research, and through anticancer experiment in vitro, wherein majority of compounds has shown good activity, has good antineoplastic activity, can develop to be novel natural antitumor medicine.
Preferred compound of the present invention has following compound
1,2,3,4,5Structure:
The compounds of this invention
1The preparation process following:
Compound
1Preparation technology comprise:
Bostrycin is under Catalyzed by p-Toluenesulfonic Acid, and with 2, the reaction of 2-Propanal dimethyl acetal obtains 5,10,11-trihydroxy-7
-methoxy-2,2,3a-trimethyl-3a, 4,11,11a-tetrahydroanthra [2,3-d] [1,3] dioxole-6,9-dione (compound
1).
The compounds of this invention
2The preparation process following:
Compound
2Preparation technology comprise:
Bostrycin obtains 5,10,11-trihydroxy-7-methoxy-with 3-methyl-2-butene aldehyde reaction under Catalyzed by p-Toluenesulfonic Acid
3a-methyl-2-(2-methylprop-1-enyl)-3a, 4,11,11a-tetrahydroanthra [2,3-d] [1,3] dioxole-6,9-dione (compound
2).
The compounds of this invention
3The preparation process following:
Compound
3Preparation technology comprise:
Bostrycin obtains 5 with polyformaldehyde reaction under Catalyzed by p-Toluenesulfonic Acid, 10-dihydroxy-11-(hydroxymethoxy)
-7-methoxy-3a-methyl-3a, 4,11,11a-tetrahydroanthra [2,3-d] [1,3] dioxole-6,9-dione (compound
3).
The compounds of this invention
4The preparation process following:
Compound
4Preparation technology comprise:
Bostrycin obtains 5,10,11-trihydroxy-7-methoxy-3a-Methyl with the solid phosgene reaction under to pyridine catalysis
-3a, 4,11,11a-tetrahydroanthra [2,3-d] [1,3] dioxole-2,6,9-trione (compound
4).
The compounds of this invention
5The preparation process following:
Natural product Bostrycin verivate involved in the present invention, preliminary pharmaceutical research (extracorporeal anti-tumor cell tests), the result shows that this compounds has good antitumor cell activity, can further develop to be novel antitumor drug.
Embodiment:
Further specify the present invention through embodiment below.Embodiment has provided synthetic, the dependency structure appraising datum and the compound activity data of representative new compound.Mandatory declaration, following embodiment is used to explain the present invention rather than limitation of the present invention.The simple modifications that essence according to the present invention is carried out the present invention all belongs to the present invention and requires the scope protected.
Beijing X is used in fusing point test
4Type micro melting point apparatus (TM is not proofreaied and correct).
1HNMR,
13C NMR is with U.S. Varian Inova-500 NB and Switzerland Bruker AVANCE AV-400NB,
TMS does interior mark.
Mass spectrum is measured with Thremo LCQ DECA XP LC-MS appearance and Thremo DSQ mass spectrograph.
Embodiment 1: compound
1Preparation
In the 25mL round-bottomed flask, add 50mg (0.149mmol) Bostrycin, 310mg (3.0mmol) 2,2-Propanal dimethyl acetal; 25.6mg (0.149mmol) tosic acid; The 10mL THF at room temperature reacts 20h, and TLC shows that raw material reaction is complete.Stopped reaction adds 10mL water, with dichloromethane extraction (50mL * 3), merges organic phase, and organic phase is water and saturated common salt water washing respectively, and anhydrous magnesium sulfate drying filters, and concentrates.Crude product is through purification by silica gel column chromatography, and eluent: V (methylene dichloride): V (sherwood oil)=1:1 gets the 48.5mg red solid, yield: 90%.mp：228-229℃；
1H?NMR（δ
H,?CDCI
3，400MHz）：13.18?(1H，s),?12.6?(1H，s),?6.18?(1H，s),?5.51(1H，d，
J=4?Hz),?4.41(1H,?d,?
J=4?Hz),?3.93?(3H，s),?3.41?(1H,?d,?
J=16?Hz),?2.72?(1H,?d,?
J=16Hz),?1.64?(3H，s),?1.40(3H，s),?1.03(3H，s)；EI（m/z）：376（M
+），361，318，301，289（100%），273，257，243。
Embodiment 2: compound
2Preparation
The reaction of Bostrycin and 3-methyl-2-butene, building-up process is with embodiment 1.Yield: 80%.mp：200-201℃；
1H?NMR（δ
H,?CDCI
3，400MHz）：13.09(1H，s),?12.53?(1H，s),?6.12?(1H，s),?5.50(1H，d，
J=7.6Hz),?5.45(1H,?d,?
J=2.5Hz),?4.79-4.62(1H,?m)，4.20(1H,?d,?
J=2.5Hz)，3.92?(3H，s),?3.51(1H,?d,?
J=16?Hz),?2.67?(1H,?d,?
J=16Hz)，1.67(3H，d，
J=1.2?Hz)，1.60(3H，d，
J=1.2?Hz)，1.57(3H，s)；EI（m/z）：402（M
+），387，318(100%)，301，289，271，257，243。
Embodiment 3: compound
3Preparation
The reaction of Bostrycin and Paraformaldehyde 96, building-up process is with embodiment 1.Yield: 24%.mp：233-234℃；
1H?NMR（δ
H,?CDCI
3，400MHz）；13.23(1H，s),?12.64?(1H，s),?6.17?(1H，s),?5.23(1H，d，
J=7.2Hz),?5.19(1H，d，
J=4.4Hz)，5.12(1H,?dd,?
J=7.5,1.6?Hz),?5.07(1H,?d,?
J=4.4?Hz)，5.04(1H,?d,?
J=7.2?Hz)，3.92(3H,?s)，3.63(1H,?d,?
J=7.5?Hz)，3.18(1H,?d,?
J=19.2?Hz)，2.69(1H,?dd,?
J=18.8,1.6?Hz)，1.50(3H,?s)；EI(m/z)：378（M
+），348，330，300(100%)，272，257，247，219。
Embodiment 4: compound
4Preparation
In the 25mL round-bottomed flask, add 100mg (0.298mmol) Bostrycin; 235mg (0.298mmol) pyridine, the 5mL methylene dichloride is under 0 ℃; The dichloromethane solution of 177mg (0.6mmol) solid phosgene is slowly dripped in the above-mentioned system reaction 30min.TLC shows that raw material reaction is complete.Stopped reaction slowly adds the 2mL saturated aqueous ammonium chloride, and 5mL water with dichloromethane extraction (50mL * 3), merges organic phase, and organic phase is used 2M hydrochloric acid, water and saturated common salt water washing respectively, and anhydrous magnesium sulfate drying filters, and concentrates.Crude product is through purification by silica gel column chromatography, and eluent: V (methylene dichloride): V (methyl alcohol)=100:0.5 gets the 30.2mg red solid, yield: 28%.mp：246-247℃；
1H?NMR（δ
H,?DMSO-d
6，400MHz）：13.14(1H，s),?12.32?(1H，s),?6.45?(1H，s),?6.20(1H，d，
J=4Hz),?5.33(1H，dd，
J=4，3.2?Hz)，4.88(1H,?d,?
J=2.8?Hz),?3.92(3H,?s)，3.54(1H,?d,?
J=14.4?Hz)，2.81(1H,?d,?
J=14.4?Hz)，1.76(3H，s)；EI(m/z)：362（M
+），318，300(100%)，282，254，229，216，201。
Embodiment 5: compound
5Preparation
The reaction of Bostrycin and thionyl chloride, building-up process is with embodiment 4.Yield: 15%.mp：193-194℃；
1H?NMR（δ
H,?DMSO-d
6，400MHz）：13.13(1H，s),?12.26?(1H，s),?6.45?(1H，s),?5.34(1H，d，
J=2.6?Hz),?5.16(1H，d，
J=2.6?Hz)，3.92(3H,?s)，3.56(1H,?d,?
J=16.8?Hz)，3.38(3H,?s)，2.71(1H,?d,?
J=16.8?Hz)，1.90(3H，s)；EI(m/z)：396(M
+)，364，332，315，303，286，273(100%)，257。
Embodiment 6: the test of extracorporeal anti-tumor cytoactive
1. material:
1.1 tetrazolium bromide (MTT): (3-(4 with the phosphate buffered saline buffer (PBS) of 0.01mol/L dissolving MTT; 5-dimethythiazol-z-yl) 2,5-diphenyl-tetrazolium bromide, SIGMA) final concentration 5mg/mL; Filtration sterilization, 4 ℃ keep in Dark Place after the packing.
1.2 the preparation of target cell: recovery and the cultivation of MCF-7 MCF-7 and MDA-MB-435, human lung cancer cell line A549 human hepatoma cell line HepG2, CCL188 HT-116.
A. from liquid nitrogen container, take out the cold pipe of depositing of MCF-7 MCF-7 and MDA-MB-435, human lung cancer cell line A549 human hepatoma cell line HepG2, CCL188 HT-116; Insert rapidly in 37 ℃ of water baths; Do not stop to shake and make it to dissolve rapidly, aseptic technique moves in the centrifuge tube;
B. add DMEM complete culture solution to 10 mL, the centrifugal 5min of 1000rmp abandons supernatant;
C. repeat above operation once;
D. move in the culturing bottle 5%CO after making the cell mixing with the piping and druming of DMEM complete culture solution
2, 37 ℃ of cultivations;
E. the observation of cell growing state is in time changed nutrient solution, divides bottle.
1.3 cell counting:
A. choose the logarithmic phase cell, trysinization, the DMEM perfect medium stops, and moves in the centrifuge tube, adds the DMEM perfect medium to 10mL;
B. get 10 μ L cell suspensions and splash in the tally one side groove, the TCS of microscopically counting four big lattice, divided by 4 takes advantage of 10
4, be every milliliter of contained cell count of nutrient solution;
C. adjust cell count to 1 * 10
5/ mL.
1.4 natural product Bostrycin derivative solution configuration:
Get natural product Bostrycin verivate and join in the DMEM perfect medium, adjustment concentration is 500 μ g/mL, ultrasonic emulsification, filtration sterilization, 4 ℃ of preservations.
2. TP
A. each hole of 96 orifice plates adds MCF-7 MCF-7 and MDA-MB-435, human lung cancer cell line A549 human hepatoma cell line HepG2, CCL188 HT-116 100 μ L (1 * 10
5/ mL), cultivate 4h for 37 ℃.
B. the study subject 100 μ L that add different concns, contrast adds DMEM perfect medium 100 μ L, continues to cultivate 48h..
C. add each 10 μ L of MTT (5mg/mL), continue to cultivate 4h.
D. remove nutrient solution, every hole adds DMSO 100 μ L, and the 5-10min that vibrates gently makes the particle dissolving.
E. enzyme linked immunological appearance 570nm measures every hole OD value down.
F. calculate inhibiting rate:
Tumor cell destruction %=[the average OD value that (the average OD value of average OD value-dosing group mensuration that control group is measured)/control group is measured] * 100%.
G. with the logarithm mapping of inhibiting rate, try to achieve IC to drug level
50Value:
With lgc is X-coordinate, and inhibiting rate is an ordinate zou, tries to achieve IC
50Value.
Table
1Be the extracorporeal anti-tumor cytoactive result of The compounds of this invention.
Table
1
EPI (Pharmorubicin
) be U.S. Pharmacia Company products
Claims (10)
1. natural product Bostrycin verivate
I, it is characterized in that having the structure of logical formula I,
Wherein: X=
;
; C=O; S=O or C=S;
R
1=H, methylol, alkyl;
R
2The alkyl of=H, C1-C10, replacement or unsubstituted phenyl, replacement or not substituted benzyl, aralkyl;
R
3The alkyl of=H, C1-C10, replacement or unsubstituted phenyl, replacement or not substituted benzyl, aralkyl;
R
4=H, direct-connected or branched-chain alkyl, undersaturated alkyl, replacement or unsubstituted phenyl, replacement or not substituted benzyl, aralkyl; R
5=H, direct-connected or branched-chain alkyl, undersaturated alkyl, replacement or unsubstituted phenyl, replacement or not substituted benzyl, aralkyl; R
6=H, alkyl, phenyl.
2. the preparation method of the said natural product Bostrycin of claim 1 verivate 1; The structural formula of natural product Bostrycin verivate 1 is as follows; Its preparation method is that employing Bostrycin is a raw material; With 2, the reaction of 2-Propanal dimethyl acetal obtains corresponding compounds under the catalysis of acid;
3. the preparation method of the said natural product Bostrycin of claim 1 verivate 2; The structural formula of natural product Bostrycin verivate 2 is as follows; Its preparation method is that employing Bostrycin is a raw material, under the catalysis of acid, obtains corresponding compounds with 3-methyl-2-butene aldehyde reaction;
4. the preparation method of the said natural product Bostrycin of claim 1 verivate 3; The structural formula of natural product Bostrycin verivate 3 is as follows; Its preparation method is that employing Bostrycin is a raw material, under the catalysis of acid, obtains corresponding compounds with polyformaldehyde reaction;
5. the preparation method of the said natural product Bostrycin of claim 1 verivate 4; The structural formula of natural product Bostrycin verivate 4 is as follows; Its preparation method is that employing Bostrycin is a raw material, under the catalysis of alkali, obtains corresponding compounds with the solid phosgene reaction;
?
6. the preparation method of the said natural product Bostrycin of claim 1 verivate 5; The structural formula of natural product Bostrycin verivate 5 is as follows; Its preparation method is that employing Bostrycin is a raw material, under the catalysis of alkali, obtains corresponding compounds with the thionyl chloride reaction;
7. like claim 2,3 or 4 described preparing methods, it is characterized in that said acid is tosic acid.
8. like claim 5 or 6 described preparing methods, it is characterized in that said alkali is pyridine or 4-(N, N-dimethyl-) EL-970.
9. the application of the said natural product Bostrycin of claim 1 verivate in the preparation antitumor drug.
10. application as claimed in claim 9 is characterized in that said antitumor be anti-breast cancer, lung cancer, liver cancer or colorectal carcinoma.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1850765A (en) * | 2006-05-26 | 2006-10-25 | 中山大学 | Quinone compounds, and their preparing method and antitumour use |
| CN1962961A (en) * | 2006-10-26 | 2007-05-16 | 大连海事大学 | Method for preparing polythiophene composite film on stainless steel surface |
| CN101544556A (en) * | 2008-06-06 | 2009-09-30 | 中山大学 | Quinone compound Bostrycin, preparation method thereof and anti-tumor application thereof |
-
2012
- 2012-01-16 CN CN2012100125169A patent/CN102532092A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1850765A (en) * | 2006-05-26 | 2006-10-25 | 中山大学 | Quinone compounds, and their preparing method and antitumour use |
| CN1962961A (en) * | 2006-10-26 | 2007-05-16 | 大连海事大学 | Method for preparing polythiophene composite film on stainless steel surface |
| CN101544556A (en) * | 2008-06-06 | 2009-09-30 | 中山大学 | Quinone compound Bostrycin, preparation method thereof and anti-tumor application thereof |
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