CN105237504A - Myricetin nitrogen-containing derivative, preparation method and uses thereof - Google Patents
Myricetin nitrogen-containing derivative, preparation method and uses thereof Download PDFInfo
- Publication number
- CN105237504A CN105237504A CN201510621302.5A CN201510621302A CN105237504A CN 105237504 A CN105237504 A CN 105237504A CN 201510621302 A CN201510621302 A CN 201510621302A CN 105237504 A CN105237504 A CN 105237504A
- Authority
- CN
- China
- Prior art keywords
- trimethoxyphenyl
- chromene
- dimethoxy
- base
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- PCOBUQBNVYZTBU-UHFFFAOYSA-N myricetin Natural products OC1=C(O)C(O)=CC(C=2OC3=CC(O)=C(O)C(O)=C3C(=O)C=2)=C1 PCOBUQBNVYZTBU-UHFFFAOYSA-N 0.000 title abstract description 5
- 235000007743 myricetin Nutrition 0.000 title abstract description 5
- 229940116852 myricetin Drugs 0.000 title abstract description 5
- 150000001875 compounds Chemical group 0.000 claims abstract description 26
- DCYOADKBABEMIQ-OWMUPTOHSA-N myricitrin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1OC1=C(C=2C=C(O)C(O)=C(O)C=2)OC2=CC(O)=CC(O)=C2C1=O DCYOADKBABEMIQ-OWMUPTOHSA-N 0.000 claims abstract description 7
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical class OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 6
- 150000003934 aromatic aldehydes Chemical class 0.000 claims abstract description 6
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical class CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 claims abstract description 6
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Chemical class O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 claims abstract description 3
- 238000006482 condensation reaction Methods 0.000 claims abstract description 3
- 239000002994 raw material Substances 0.000 claims abstract description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical class OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims abstract 2
- 150000003335 secondary amines Chemical class 0.000 claims abstract 2
- KJXSIXMJHKAJOD-LSDHHAIUSA-N Ampelopsin Natural products C1([C@@H]2[C@H](C(C3=C(O)C=C(O)C=C3O2)=O)O)=CC(O)=C(O)C(O)=C1 KJXSIXMJHKAJOD-LSDHHAIUSA-N 0.000 claims description 92
- KQILIWXGGKGKNX-UHFFFAOYSA-N dihydromyricetin Natural products OC1C(=C(Oc2cc(O)cc(O)c12)c3cc(O)c(O)c(O)c3)O KQILIWXGGKGKNX-UHFFFAOYSA-N 0.000 claims description 51
- 230000015572 biosynthetic process Effects 0.000 claims description 43
- 238000003786 synthesis reaction Methods 0.000 claims description 43
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 29
- 239000001301 oxygen Substances 0.000 claims description 27
- 229910052760 oxygen Inorganic materials 0.000 claims description 27
- 239000000047 product Substances 0.000 claims description 27
- OFLXLNCGODUUOT-UHFFFAOYSA-N acetohydrazide Chemical compound C\C(O)=N\N OFLXLNCGODUUOT-UHFFFAOYSA-N 0.000 claims description 26
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 26
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 16
- -1 substituted-phenyl Chemical group 0.000 claims description 16
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 13
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 12
- 230000002829 reductive effect Effects 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 9
- 229940079593 drug Drugs 0.000 claims description 9
- 239000012065 filter cake Substances 0.000 claims description 9
- 238000001953 recrystallisation Methods 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- 238000000967 suction filtration Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 239000006185 dispersion Substances 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 238000010189 synthetic method Methods 0.000 claims description 5
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 claims description 4
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 claims description 4
- 229940126208 compound 22 Drugs 0.000 claims description 4
- 229940125833 compound 23 Drugs 0.000 claims description 4
- 229940125846 compound 25 Drugs 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 238000011275 oncology therapy Methods 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 claims description 3
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 claims description 3
- 125000003368 amide group Chemical group 0.000 claims description 3
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 238000005352 clarification Methods 0.000 claims description 3
- 229940125961 compound 24 Drugs 0.000 claims description 3
- 229940125851 compound 27 Drugs 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 238000010792 warming Methods 0.000 claims description 3
- 150000001299 aldehydes Chemical class 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 238000009833 condensation Methods 0.000 claims 1
- 230000005494 condensation Effects 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 12
- 201000011510 cancer Diseases 0.000 abstract description 8
- 230000005764 inhibitory process Effects 0.000 abstract description 3
- 239000002246 antineoplastic agent Substances 0.000 abstract 1
- 229940041181 antineoplastic drug Drugs 0.000 abstract 1
- 159000000032 aromatic acids Chemical class 0.000 abstract 1
- 230000007062 hydrolysis Effects 0.000 abstract 1
- 238000006460 hydrolysis reaction Methods 0.000 abstract 1
- 231100000053 low toxicity Toxicity 0.000 abstract 1
- DCYOADKBABEMIQ-FLCVNNLFSA-N myricitrin Natural products O([C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](C)O1)C1=C(c2cc(O)c(O)c(O)c2)Oc2c(c(O)cc(O)c2)C1=O DCYOADKBABEMIQ-FLCVNNLFSA-N 0.000 abstract 1
- 229960003506 piperazine hexahydrate Drugs 0.000 abstract 1
- AVRVZRUEXIEGMP-UHFFFAOYSA-N piperazine;hexahydrate Chemical class O.O.O.O.O.O.C1CNCCN1 AVRVZRUEXIEGMP-UHFFFAOYSA-N 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 49
- 230000000694 effects Effects 0.000 description 28
- 238000000034 method Methods 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 230000006907 apoptotic process Effects 0.000 description 11
- 230000000259 anti-tumor effect Effects 0.000 description 10
- 238000011160 research Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 206010006187 Breast cancer Diseases 0.000 description 7
- 208000026310 Breast neoplasm Diseases 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 239000011734 sodium Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- 206010005003 Bladder cancer Diseases 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 230000006698 induction Effects 0.000 description 4
- 201000007270 liver cancer Diseases 0.000 description 4
- 208000014018 liver neoplasm Diseases 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 230000000452 restraining effect Effects 0.000 description 4
- 102000003952 Caspase 3 Human genes 0.000 description 3
- 108090000397 Caspase 3 Proteins 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 108010002687 Survivin Proteins 0.000 description 3
- 102000000763 Survivin Human genes 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 3
- 230000024245 cell differentiation Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 239000013642 negative control Substances 0.000 description 3
- 201000002528 pancreatic cancer Diseases 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 201000005112 urinary bladder cancer Diseases 0.000 description 3
- 241000219428 Fagaceae Species 0.000 description 2
- IKMDFBPHZNJCSN-UHFFFAOYSA-N Myricetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC(O)=C(O)C(O)=C1 IKMDFBPHZNJCSN-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 241000219094 Vitaceae Species 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000005779 cell damage Effects 0.000 description 2
- 208000037887 cell injury Diseases 0.000 description 2
- 238000005336 cracking Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- IYRMWMYZSQPJKC-UHFFFAOYSA-N kaempferol Chemical compound C1=CC(O)=CC=C1C1=C(O)C(=O)C2=C(O)C=C(O)C=C2O1 IYRMWMYZSQPJKC-UHFFFAOYSA-N 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000000877 morphologic effect Effects 0.000 description 2
- 230000004660 morphological change Effects 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- 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
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- ZWDVQMVZZYIAHO-UHFFFAOYSA-N 2-fluorobenzaldehyde Chemical compound FC1=CC=CC=C1C=O ZWDVQMVZZYIAHO-UHFFFAOYSA-N 0.000 description 1
- XRHGYUZYPHTUJZ-UHFFFAOYSA-N 4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-N 0.000 description 1
- BBYDXOIZLAWGSL-UHFFFAOYSA-N 4-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C=C1 BBYDXOIZLAWGSL-UHFFFAOYSA-N 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 241000208838 Asteraceae Species 0.000 description 1
- 101150012716 CDK1 gene Proteins 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 102000008178 Cyclin B1 Human genes 0.000 description 1
- 108010060385 Cyclin B1 Proteins 0.000 description 1
- UBSCDKPKWHYZNX-UHFFFAOYSA-N Demethoxycapillarisin Natural products C1=CC(O)=CC=C1OC1=CC(=O)C2=C(O)C=C(O)C=C2O1 UBSCDKPKWHYZNX-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000220485 Fabaceae Species 0.000 description 1
- 230000004668 G2/M phase Effects 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010064912 Malignant transformation Diseases 0.000 description 1
- 206010051141 Myeloblastoma Diseases 0.000 description 1
- SVTVEQWDTAUYBA-UHFFFAOYSA-N N1CCNCC1.O.O.O.O.O.O.N1CCNCC1 Chemical compound N1CCNCC1.O.O.O.O.O.O.N1CCNCC1 SVTVEQWDTAUYBA-UHFFFAOYSA-N 0.000 description 1
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 1
- 102000038030 PI3Ks Human genes 0.000 description 1
- 108091007960 PI3Ks Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 241001122767 Theaceae Species 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 201000001531 bladder carcinoma Diseases 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000025084 cell cycle arrest Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 239000012627 chemopreventive agent Substances 0.000 description 1
- 229940124443 chemopreventive agent Drugs 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 210000004292 cytoskeleton Anatomy 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000001339 epidermal cell Anatomy 0.000 description 1
- 229960003265 epirubicin hydrochloride Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 description 1
- 235000008777 kaempferol Nutrition 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 230000036212 malign transformation Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002398 materia medica Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- UXOUKMQIEVGVLY-UHFFFAOYSA-N morin Natural products OC1=CC(O)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 UXOUKMQIEVGVLY-UHFFFAOYSA-N 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- INAAIJLSXJJHOZ-UHFFFAOYSA-N pibenzimol Chemical compound C1CN(C)CCN1C1=CC=C(N=C(N2)C=3C=C4NC(=NC4=CC=3)C=3C=CC(O)=CC=3)C2=C1 INAAIJLSXJJHOZ-UHFFFAOYSA-N 0.000 description 1
- 229960005141 piperazine Drugs 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 235000020095 red wine Nutrition 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 201000008261 skin carcinoma Diseases 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000005760 tumorsuppression Effects 0.000 description 1
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 1
- 230000004862 vasculogenesis Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The present invention relates to a myricetin nitrogen-containing derivative, a preparation method and uses thereof, wherein the compound structure is represented by the following general formula (III) in the specification. According to the present invention, myricitrin, halogenated alkane, secondary amine, piperazine hexahydrate, aromatic acid, substituted aromatic acid, ethylbromoacetate, hydrazine hydrate, aromatic aldehyde and substituted aromatic aldehyde are adopted as raw materials, and substitution, hydrolysis and condensation reaction are performed to synthesize a series of myricetin nitrogen-containing derivatives; and the class of the compounds have characteristics of good cancer cell inhibition and low toxicity, and can be used for preparation of anti-cancer drugs. The formula (III) is defined in the specification.
Description
Technical field
The present invention relates to have antitumous effect containing ampelopsin nitrogen analog derivative and preparation method and purposes.
Background technology
Ampelopsin (3', 4', 5', 3,5,7-quercetagetin alcohol, Myricetin), ampelopsin be present in widely Fagaceae (
fagaceae), pulse family (
leguminosae), herald spring (
pfimulaceae), Vitaceae (
vitaceae), composite family (
compositae) etc. in plant, ampelopsin is present in our daily edible fruit usually, vegetables and and beverage in, such as: tea and red wine etc.There are some researches show: ampelopsin has anticancer, anti-oxidant (Ong, K.C.; Khoo, H.E.Biologicaleffectsofmyricetin [J] .GeneralPharmacology:TheVascularSystem, 1997,29 (2): 121-126), antiviral (Ono, K.; Nakane, H.; Fukushima, M.; Etal.Differentialinhibitoryeffectsofvariousflavonoidsont heactivitiesofreversetranscriptaseandcellularDNAandRNApo lymerases [J] .EuropeanJournalofBiochemistry; 1990; 190 (3): 469-476), anti-inflammatory (Lee, Y.S.; Choi; E.M.MyricetininhibitsIL-1 β-inducedinflammatorymediatorsinSW982humansynovialsarcomac ells [J] .InternationalImmunopharmacology; 2010; 10 (7): 812-814), antibacterial (El-Gammal, A.A.; Mansour, R.Antimicrobialactivitiesofsomeflavonoidcompounds [J] .Zentralblattf ü rMikrobiologie, 1986,141 (7): 561-565) the multiple pharmacologically active such as.
At present its research in antitumour activity is more, to mankind's kinds of tumor cells have obvious restraining effect (Zhang Xiujuan, Huang Qingling, Ji Yubin. ampelopsin pharmacology activity research progress [J]. Tianjin pharmacy, 2008,20 (5): 57-60).Modern medicine proves that ampelopsin all has effect in multiple stages of tumor development, comprises the propagation of tumour cell, the differentiation of inducing tumor cell and apoptosis, and the generation of Tumor suppression and transfer.Because ampelopsin has Antitumor test extensively, low to normal cytotoxicity, the effect of energy strengthening immunity simultaneously, therefore in the field of antineoplastic medicaments of development of new, the derivative of ampelopsin and ampelopsin obtains increasing concern.
2007, Lee (K.W.; Kang, N.J.; Rogozin, E.A.; Etal.Myricetinisanovelnaturalinhibitorofneoplasticcelltr ansformationandMEK1 [J] .Carcinogenesis, 2007,28 (9): 1918-1927) find that ampelopsin is 10 in concentration
μto JP6P under mol/L
+the malignant transformation of mouse epidermal cells and propagation have obvious restraining effect, and its mechanism blocks MEK/ERK/AP-1 signal path; The activity of all right methionine(Met) of ampelopsin and Akt, affects the restructuring of myeloblastoma actin cytoskeleton, contains into the morphological change that myeloma cells is caused by pHGF in transfer process, thus suppress it to shift, its IC
50value is 6
μmol/L (Labb é, D.; Provencal, M.; Lamy, S.; Etal.Theflavonolsquercetin, kaempferol, andmyricetininhibithepatocytegrowthfactor-inducedmedullo blastomacellmigration [J] .TheJournalofnutrition, 2009,139 (4): 646-652).
2009, Zhang Li waits quietly (Zhang Lijing, Liu Zhiguo, Meng great Li, Xia Mingyu. Cortex Myricae Rubrae extract and ampelopsin anti-tumor activity [J]. Shenyang Pharmaceutical University's journal, 2009,26 (4): 307-311) extracorporeal anti-tumor research is carried out to ampelopsin monomeric compound, research shows: ampelopsin all has obvious cytotoxicity to HeLa Cells, human melanoma A375-S2 cell, MCF-7 Human Breast Cancer Cells and human hepatoma HepG2 cell, ampelopsin obviously suppresses the propagation of HeLa cell, induction HeLa natural death of cerebral cells.
2010, (the Zhang Xiujuan such as Zhang Xiujuan, reach the clouds, Yu Hua, Ji Yubin. the research [J] of myricetin induction people HepG-2 cell line Apoptosis mechanism. CHINA JOURNAL OF CHINESE MATERIA MEDICA, 2010,35 (8): 1046-1050) ampelopsin has been inquired into people liver cancer HepG-2 Developing restraint and apoptosis-induced Function and its mechanisms, research shows: ampelopsin has obvious restraining effect to the growth of people's HepG-2 cell line, and has dose-dependently, IC
50for 58.6617mg/L; After ampelopsin effect 72h, HepG-2 cell presents typical cells apoptosis feature, and cell-cycle arrest is in the G2/M phase, and apoptosis rate is up to 64.73%.2011, (Zhang, the X. such as Zhang; Zou, Z.; Xu, C.; Etal.MyricetininducesG2/MphasearrestinHepG2cellsbyinhibi tingtheactivityofthecyclinB/Cdc2complex [J] .MolMedReport, 2011,4:273-277) further study the mechanism of action of ampelopsin to liver cancer cell, find that ampelopsin is the level by reducing Cdc2 and Cyclin B1 in liver cancer cell, thus suppress the growth and breeding of liver cancer cell.
2010, (the Wei such as Wei Wei, W., EffectsofmyricetinontheapoptosisofbladdercancercellBIU-8 7 [J] .JournalofChongqingMedicalUniversity, 2010,35 (12): 1791-1793) have studied the mechanism of ampelopsin induction bladder cancer cell line BIU-87 apoptosis, by cultivator bladder cancer cell line BIU-87, add the interference of different concns ampelopsin, observation of cell morphological change under inverted microscope; And utilize MTT and Hoechst33258 staining to detect ampelopsin to the impact of bladder cancer cell line BIU-87 apoptosis; The change of gene participating in apoptosis survivin and caspase-3 transcriptional level is detected afterwards with RT-PCR, immunoblotting detects the expression of survivin and caspase-3, result shows: ampelopsin can induce transitional cell bladder carcinoma cell line BIU-87 apoptosis, and obviously suppress the transcript and expression of survivin, there is rise effect to caspase-3 simultaneously.
2011, (Phillips, the P. such as Phillips; Sangwan, V.; Borja-Cacho, D.; Etal.Myricetininducespancreaticcancercelldeathviatheindu ctionofapoptosisandinhibitionofthephosphatidylinositol3-kinase (PI3K) signalingpathway [J] .Cancerletters, 2011,308 (2): 181-188) have studied ampelopsin to pancreatic cancer cell in vivo with external effect.Research finds, ampelopsin is 25
μmol/L ~ 200
μmol/L is that dosage suppresses AktL phosphorylation according to patience, can reduce the kinase whose activity of PI3, and the outer apoptosis of pancreatic cancer cell of inductor is dead; In vivo, ampelopsin is by treating pancreatic neoplasm to the abatement of tumour and the transfer of cancer cells.
2011, (Kang, the N.J. such as Kang; Jung, S.K.; Lee, K.W.; Etal.Myricetinisapotentchemopreventivephytochemicalinski ncarcinogenesis [J] .AnnalsoftheNewYorkAcademyofSciences, 2011,1229 (1): 124-132) have studied the restraining effect of ampelopsin to mouse skin cancer cells, research finds: ampelopsin is by weakening UV-B, the expression of induction COX-2, thus suppress skin carcinoma apoptosis; By the vasculogenesis that action target bacteriostatic action PI3-K induces, therefore, ampelopsin is the chemopreventive agent of a promising anticancer growth.
Summary of the invention
The object of the invention is to the nitrogenous analog derivative of ampelopsin of a series of novel structure of design and synthesis, this compounds is based on natural product Myricitroside, a series of ampelopsin derivative has been synthesized by structural modification, show through antitumour activity test, ampelopsin derivative is compared antitumour activity with ampelopsin and existing commercial medicament EpirubicinHydrochloride and is significantly improved, and the cytotoxicity of ampelopsin derivative to breast cancer cell (MDA-MB-231) is less, this compounds can be used as the medicine of anticancer.Prepared ampelopsin nitrogenous analog derivative structure is represented by following general formula (III):
R
3for (1) phenyl or substituted-phenyl; (2) heterocyclic radical comprises pyridyl, furyl, thienyl, pyrryl;
Substituted-phenyl is containing one or more methyl, ethyl, methoxyl group, oxyethyl group, n-propyl, sec.-propyl, trifluoromethyl, nitro, amido on phenyl ring.
In content of the present invention, substituted-phenyl can be on phenyl ring containing one or more methyl, ethyl, methoxyl group, oxyethyl group,
N-propyl, sec.-propyl, trifluoromethyl, nitro, amido.
In content of the present invention, compound has anti-tumor activity, and feature has good activity to human breast cancer cell (MDA-MB-231), and purposes is preparing the application in cancer therapy drug.
The preparation method of general formula of the present invention (III) compound is that be substituted, be hydrolyzed and condensation reaction synthesis target product, its synthetic route is with Myricitroside, halogenated alkane, ethyl bromoacetate, hydrazine hydrate, aromatic aldehyde and substituted aroma aldehyde for raw material:
Synthetic method is as follows:
The first step: the preparation of 3-hydroxyl-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone
Myricitroside and K is added in round-bottomed flask
2cO
3be dissolved in DMF, after stirring, drip methyl iodide slowly,
Stirring at room temperature a few hours, after stopped reaction, with water-dispersion, be extracted with ethyl acetate, merging filtrate, merge organic phase, concentrating under reduced pressure, is then dissolved in dehydrated alcohol by enriched material, be warming up to backflow, after solution clarification, under backflow, add concentrated hydrochloric acid, the yellow solid that has slowly is separated out, and continues reaction 2h, cooling, refrigerator is placed and is spent the night, and filters, obtains crude product, do not need purifying, be directly used in next step reaction
Second step: the preparation of 3-fluoroacetic acid ethyl ester-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone
The product of the first step is added successively, K in there-necked flask
2cO
3and anhydrous propanone, after stirring at room temperature is even, drip ethyl bromoacetate, drip and finish, back flow reaction a few hours, after stopped reaction, be cooled to room temperature, pour in frozen water after concentrated, crystallization, suction filtration, filter cake chloroform/water recrystallization obtains target product,
The preparation of the 3rd step: 2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base) acethydrazide
In there-necked flask, add the product of second step successively, 80% hydrazine hydrate and dehydrated alcohol, back flow reaction, TCL point plate is followed the tracks of, until react completely, after concentrating under reduced pressure removes a large amount of solvent, cooling, has precipitation to produce and separates out, suction filtration, filter cake dehydrated alcohol recrystallization obtains target product
4th step: the preparation of ampelopsin acylhydrazone
Product and the aromatic aldehyde of the 3rd step is added successively in there-necked flask, with anhydrous alcohol solution, the acetic acid of instillation catalytic amount, stirring heating refluxes, and TLC point plate is followed the tracks of, until react completely, concentration of reaction solution, cooling, has a large amount of Precipitations, suction filtration, filter cake dehydrated alcohol recrystallization obtains target product.
This step is applicable to the synthesis of the nitrogenous analog derivative of all above-mentioned target compound ampelopsin.
Route of the present invention and preparation method have synthesized and have proved that the compound of antitumous effect is as follows:
Compound 22:2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base)-N'-(2-luorobenzyl) acethydrazide
Compound 23:2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base)-N'-(4-methylbenzilidene) acethydrazide
Compound 24:2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base)-N'-(pyridine-2-methylene) acethydrazide
Compound 25:2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base)-N'-(furans-2-methylene) acethydrazide
Compound 26:2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base)-N'-((3 methyl thiophene-2-base) methylene radical) acethydrazide
Compound 27:N'-((1H-pyrroles-2-base) methylene radical)-2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base) acethydrazide
The nitrogenous analog derivative of ampelopsin of the present invention's synthesis has good antitumour activity, can be used for preparing cancer therapy drug.
Accompanying drawing explanation
Fig. 1: compound (9-18) is setting under concentration the breast cancer cell MDA-MB-231 effect Morphology Effects of 24,48,72 hours.
Fig. 2: compound (19-27) is setting under concentration the breast cancer cell MDA-MB-231 effect Morphology Effects of 24,48,72 hours.
27 the nitrogenous analog derivatives of ampelopsin that the present invention relates to all have good inhibit activities to target tumor, positive drug to the toxicity of tumour cell obviously too large (making the whole broken cracking of cell), and the compound of this experiment synthesis is substantially very little to target cell damage, this inhibit activities is mainly reflected in the propagation (cell quantity obviously tails off compared with the control) of T suppression cell, or Cell differentiation inducing activity (draws from morphological observation, cell is while reduced number, cell there occurs distortion, but damage is not clearly), so these medicines have inhibit activities very to target tumor, be worth furtheing investigate further.
Embodiment
This concrete embodiment is only explanation of the invention; but do not limit the present invention; the timely personnel in this area can make to this embodiment the amendment not having creative contribution as required after reading this specification sheets, as long as but the protection being all subject to patent law in right of the present invention.
Embodiment one, 3-(3-(diethyl amino-1-base) propoxy-)-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone (compound 1)
(1) synthesis of 3-hydroxyl-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone
In round-bottomed flask, add Myricitroside 2.32g (5mmol) be dissolved in 11.06g in 60mLDMF (16mmol) K
2cO
3
After stirring 10min, add 10mL (32mmol) methyl iodide slowly, stirring at room temperature 60h, filtering-depositing, and wash by ethyl acetate, merging filtrate, filtrate is poured in 100mL water, be extracted with ethyl acetate three times, merge organic phase, concentrating under reduced pressure, then enriched material is dissolved in the dehydrated alcohol of 30mL, be warming up to backflow, after solution clarification, 8mL concentrated hydrochloric acid is added under backflow, the yellow solid that has slowly is separated out, continue reaction 2h, cooling, refrigerator is placed and is spent the night, filter, obtain crude product A, crude product A does not need purifying, be directly used in next step reaction.
(2) synthesis of 3-(3-bromine propoxy-)-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone
Product A 1.17g (3mmol) and 1.66g (12mmol) K of previous step is added in round-bottomed flask
2cO
3after dissolving with the DMF of 30mL, add 2.42g (12mmol) 1,3-dibromopropane, at room temperature react 12h, ethyl acetate is that developping agent point plate follows the tracks of reaction, after stopped reaction, with the water-dispersion of 50mL, with extraction into ethyl acetate 3 times, each 25ml, obtains the HCl that organic phase uses 1N successively, saturated NaHCO
3, after the saturated NaCl aqueous solution washs 2 times respectively, combined ethyl acetate layer, boils off solvent with after anhydrous sodium sulfate drying, with reduced pressure chromatography (sherwood oil: ethyl acetate=2:1, V/V), obtains intermediate B 1.
(3) synthesis of target compound 3-(3-(diethyl amino-1-base) propoxy-)-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone:
The product B 10.25g (0.5mmol) of previous step is added, anhydrous K in round-bottomed flask
2cO
30.14g (1mmol), and 25mLDMF, add 0.70g (1mmol) diethylamine after stirring 10min, at room temperature react 24h, with (chloroform: methyl alcohol=5:1, V/V) for reaction followed the tracks of by developping agent point plate, after stopped reaction, 50mL water-dispersion is added, be extracted with ethyl acetate three times, each 25ml, merges the HCl of organic phase 1N, saturated NaHCO
3, after the saturated NaCl aqueous solution washs 2 times respectively, combined ethyl acetate layer, boils off solvent with after anhydrous sodium sulfate drying, with reduced pressure chromatography (chloroform: methyl alcohol=10:1, V/V), obtains target product.
Embodiment two, 5,7-dimethoxy-3-(4-(pyrrolidin-1-yl) butoxy)-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone (compound 7)
(1) synthesis of 3-hydroxyl-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone
As embodiment one (1) condition and method synthesis.
(2) synthesis of 3-(4-bromine butoxy)-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone
As embodiment one (2) condition and method synthesis, difference is the Isosorbide-5-Nitrae-dibromobutane adding 2.56g.
The synthesis of (3) 5,7-dimethoxy-3-(4-(pyrrolidin-1-yl) butoxy)-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone:
As embodiment one (3) condition and method synthesis, difference is the tetramethyleneimine adding 0.68g.
Utilize similar synthetic method, the part of having synthesized is as follows containing the structure of Heterocyclylalkyl class ampelopsin derivative:
Embodiment three, 5,7-dimethoxy-3-(4-(piperazine-1-base) butoxy)-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-
(1) synthesis of 3-hydroxyl-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone
As embodiment one (1) condition and method synthesis.
(2) synthesis of 3-(4-bromine butoxy)-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone
As embodiment two (2) condition and method synthesis.
The synthesis of (3) 5,7-dimethoxy-3-(4-(piperazine-1-base) butoxy)-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone:
The product 1.05g (2mmol) of previous step is added, anhydrous K in round-bottomed flask
2cO
31.38g (10mmol), and 50mLDMF, add 1.94g (10mmol) piperazine hexahydrate piperazine after stirring 10min, at room temperature react 24h, with (chloroform: methyl alcohol=5:1, V/V) for reaction followed the tracks of by developping agent point plate, after stopped reaction, add 50mL water-dispersion, be extracted with ethyl acetate three times, merge the HCl of organic phase 1N, saturated NaHCO
3, after the saturated NaCl aqueous solution washs 2 times respectively, combined ethyl acetate layer, boils off solvent with after anhydrous sodium sulfate drying, with reduced pressure chromatography (chloroform: methyl alcohol=15:1, V/V), obtains target product.
Embodiment four, 3-(4-(4-(4-fluoro benzoyl) piperazine-1-base) butoxy)-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone (compound 12)
(1) synthesis of 3-hydroxyl-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone
As embodiment one (1) condition and method synthesis.
(2) preparation of 3-(4-bromine butoxy)-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone
As embodiment two (2) condition and method synthesis.
The synthesis of (3) 5,7-dimethoxy-3-(4-(piperazine-1-base) butoxy)-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone
As embodiment three (3) condition and method synthesis.
(4) synthesis of 3-(4-(4-(4-fluoro benzoyl) piperazine-1-base) butoxy)-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone:
In round-bottomed flask, under condition of ice bath, add parafluorobenzoic acid 0.046g (0.33mmoL) and HATU0.137g (0.36mmoL), the triethylamine adding 1mL after dissolving with the dry DCM of 10mL stirs 30min together under ice bath, then ice bath is removed, the product 0.159g (0.3mmoL) adding the 3rd step at room temperature reacts 12h, TLC follows the tracks of reaction extremely without considerable change (developping agent: chloroform: methyl alcohol=5:1, V/V), after stopped reaction, wash reaction solution with water 3 times, each 20mL, decompression removing DCM after anhydrous sodium sulfate drying, then reduced pressure chromatography is separated (chloroform: methyl alcohol=10:1, V/V), obtain target product.
Embodiment five, 3-(4-(4-(4-chlorobenzene formacyl) piperazine-1-base) butoxy)-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone (compound 13)
(1) synthesis of 3-hydroxyl-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone
As embodiment one (1) condition and method synthesis.
(2) 3-oxygen (4-bromobutyl)-3
', 4
', 5,5
', the preparation of 7-pentamethoxyl ampelopsin
As embodiment two (2) condition and method synthesis.
The synthesis of (3) 5,7-dimethoxy-3-(4-(piperazine-1-base) butoxy)-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone
As embodiment three (3) condition and method synthesis.
(4) synthesis of 3-(4-(4-(4-chlorobenzene formacyl) piperazine-1-base) butoxy)-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone:
As embodiment three (4) condition and method synthesis, difference is the Chlorodracylic acid adding 0.052g.
Utilize similar synthetic method, the structure of the derivative of the part piperazine acidamide ampelopsin synthesized is as follows:
Embodiment six, 2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base)-N'-(2-luorobenzyl) acethydrazide (compound 22)
(1) synthesis of 3-hydroxyl-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone
As embodiment one (1) condition and method synthesis.
(2) preparation of 3-fluoroacetic acid ethyl ester-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone
The product 1.17g (3mmol) of the first step is added successively, anhydrous K in there-necked flask
2cO
30.5g (3.6mmol) and anhydrous propanone 30mL, after stirring at room temperature 30min, drip ethyl bromoacetate 0.4mL (3.6mmol), drip and finish, back flow reaction 24h, is cooled to room temperature, pour into after concentrating under reduced pressure in frozen water, crystallization, suction filtration, filter cake chloroform/water recrystallization obtains target product.
(3) preparation of 2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base) acethydrazide
The product 1.42g (3mmol) of second step is added successively in there-necked flask, 80% hydrazine hydrate 0.66mL (10mmol) and dehydrated alcohol 30mL, stir lower back flow reaction 2h, TCL point plate is followed the tracks of, until react completely, and a large amount of solvent of decompression removing, cooling, crystallization, suction filtration, filter cake dehydrated alcohol recrystallization obtains target product.
(4) synthesis of 2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base)-N'-(2-luorobenzyl) acethydrazide:
The product 0.15g (0.33mmol) of the 3rd step is added successively in there-necked flask, o fluorobenzaldehyde 0.045g (0.36mmol), 25mL dehydrated alcohol and catalytic amount acetic acid, stirring heating backflow 2h, TLC point plate is followed the tracks of, until react completely, concentration of reaction solution, cooling, crystallization, suction filtration, filter cake dehydrated alcohol recrystallization obtains target product.
Embodiment seven, 2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base)-N'-(4-methylbenzilidene) acethydrazide (compound 23)
(1) synthesis of 3-hydroxyl-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone
As embodiment one (1) condition and method synthesis.
(2) preparation of 3-fluoroacetic acid ethyl ester-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone
As embodiment six (2) condition and method synthesis.
(3) preparation of 2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base) acethydrazide
As embodiment six (3) condition and method synthesis.
(4) synthesis of 2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base)-N'-(4-methylbenzilidene) acethydrazide:
As embodiment six (4) condition and method synthesis, difference is the p-tolyl aldehyde adding 0.044g.
Utilize similar synthetic method, the structure of the part ampelopsin acylhydrazone of having synthesized is as follows:
The spectral data of the nitrogenous analog derivative of ampelopsin of synthesis is as follows:
2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base)-N'-(2-luorobenzyl) acethydrazide (compound 22)
Yellow solid, productive rate: 78.4%, m.p.136 ~ 138 DEG C; IR (KBr, cm
-1):
ν max1699,1683,1620,1604,1558,1417,1361,1246,1207,1124,1109,1012,819;
1hNMR (500MHz, CDCl
3) δ: 3.92-3.99 (m, 15H, 5 × OCH
3), 4.35 (s, 2H, CH
2), 6.40 (d,
j=2.3Hz, 1H, H-6), 6.54 (d,
j=2.3Hz, 1H, H-8), 7.07 (
j=18.9Hz, 1H), 7.16 (t,
j=14.9Hz, 1H), 7.22 (overlappings, 2H, H-2 ', H-6 '), 7.35 (q,
j=20.6Hz, 1H), 8.15 (t,
j=13.7Hz, 1H), 9.65 (s, 1H, NH), 12.35 (s, 1H, N=CH);
13cNMR (125MHz, CDCl
3) δ: 174.7 (C-4), 165.6 (C=O), 164.7 (C-7), 161.1 (C-9), 160.6 (C), 159.1 (C-2), 154.2 (C-5), 153.6 (C-3 ', C-5 '), 142.6 (CH), 141.3 (C-4 '), 140.8 (C-3), 132.0 (CH), 127.6 (CH), 124.8 (C-1 '), 124.4 (CH), 121.8 (C), 115.7 (CH), 108.8 (C-10), 105.7 (C-6 ', C-2 '), 96.5 (C-6), 92.7 (C-8), 73.2 (OCH
2), 61.2 (4 '-OCH
3), 56.6 (7-OCH
3), 56.5 (3 ', 5 '-OCH
3), 56.0 (8-OCH
3); MS (ESI, m/z): 567.3 [M+H]
+, 589.2 [M+Na]
+.
2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base)-N'-(4-methylbenzilidene) acethydrazide (compound 23)
Pale solid, productive rate: 82.3%, m.p.152 ~ 154 DEG C; IR (KBr, cm
-1):
ν max1699,1683,1620,1604,1558,1506,1417,1354,1247,1219,1124,1109,1011,819;
1hNMR (500MHz, CDCl
3) δ: 2.36 (s, 3H, CH
3), 3.92-3.99 (m, 15H, 5 × OCH
3), 4.35 (s, 2H, CH
2), 6.40 (d,
j=2.3Hz, 1H, H-6), 6.54 (d,
j=2.3Hz, 1H, H-8), 7.19 (d,
j=8Hz, 2H, 2CH), 7.21 (overlappings, 2H, H-2 ', H-6 '), 7.71 (d,
j=8Hz, 2H, CH), 8.35 (s, 1H, NH), 12.10 (s, 1H, N=CH);
13cNMR (125MHz, CDCl
3) δ: 174.7 (C-4), 165.2 (C=O), 164.9 (C-7), 161.1 (C-9), 159.1 (C-2), 154.2 (C-5), 153.6 (C-3 ', C-5 '), 149.5 (C), 141.5 (C-4 '), 140.8 (C-3), 131.1 (C), 129.6 (CH), 129.4 (CH), 128.5 (CH), 127.9 (CH), 124.8 (C-1 '), 108.8 (C-10), 105.7 (C-6 ', C-2 '), 96.5 (C-6), 92.8 (C-8), 73.3 (OCH
2), 61.2 (4 '-OCH
3), 56.7 (7-OCH
3), 56.5 (3 ', 5 '-OCH
3), 56.0 (8-OCH
3), 21.7 (CH
3); MS (ESI, m/z): 563.3 [M+H]
+, 585.3 [M+Na]
+.
2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base)-N'-(pyridine-2-ylmethyl) acethydrazide (compound 24)
Faint yellow solid, productive rate: 55.6%, m.p.176 ~ 178 DEG C; IR (KBr, cm
-1):
ν max1699,1683,1602,1588,1506,1417,1361,1244,1211,1126,1012,819;
1hNMR (500MHz, CDCl
3) δ: 3.92-3.99 (m, 15H, 5 × OCH
3), 4.36 (s, 2H, CH
2), 6.40 (d,
j=2.3Hz, 1H, H-6), 6.53 (d,
j=2.3Hz, 1H, H-8), 7.22 (overlappings, 2H, H-2 ', H-6 '), 7.27 (t,
j=13.3Hz, 1H), 7.71 (t,
j=15.4Hz, 1H), 8.20 (d,
j=8Hz, 1H), 8.53 (s, 1H, NH), 8.62 (d,
j=4.6Hz, 1H), 12.53 (s, 1H, N=CH);
13cNMR (125MHz, CDCl
3) δ: 174.7 (C-4), 165.9 (C=O), 164.8 (C-7), 161.2 (C-9), 159.1 (C-2), 154.1 (C-5), 153.6 (C-3 ', C-5 '), 153.3 (C), 149.6 (CH), 149.4 (CH), 141.4 (C-4 '), 140.8 (C-3), 136.4 (CH), 127.6 (CH), 124.8 (C-1 '), 121.3 (CH), 108.8 (C-10), 105.7 (C-6 ', C-2 '), 96.5 (C-6), 92.7 (C-8), 73.2 (OCH
2), 61.2 (4 '-OCH
3), 56.6 (7-OCH
3), 56.5 (3 ', 5 '-OCH
3), 56.0 (8-OCH
3); MS (ESI, m/z): 550.3 [M+H]
+, 572.2 [M+Na]
+.
2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base)-N'-(furans-2-methylene) acethydrazide (compound 25)
Pale solid, productive rate: 73.2%, m.p.172 ~ 174 DEG C; IR (KBr, cm
-1):
ν max1699,1683,1608,1558,1506,1417,1359,1246,1217,1126,1066,1014,819;
1hNMR (500MHz, CDCl
3) δ: 3.92-3.99 (m, 15H, 5 × OCH
3), 4.32 (s, 2H, CH
2), 6.41 (d,
j=2.3Hz, 1H, H-6), 6.48 (q,
j=5.1Hz, 1H, CH), 6.54 (d,
j=2.3Hz, 1H, H-8), 6.86 (d,
j=3.4Hz, 1H, CH), 7.20 (overlappings, 2H, H-2 ', H-6 '), 7.51 (d,
j=1.15Hz, 1H, CH), 8.30 (s, 1H, NH), 12.25 (s, 1H, N=CH);
13cNMR (125MHz, CDCl
3) δ: 174.8 (C-4), 165.2 (C=O), 164.9 (C-7), 161.1 (C-9), 159.1 (C-2), 154.2 (C-5), 153.6 (C-3 ', C-5 '), 149.5 (C), 144.7 (CH), 141.5 (C-4 '), 140.8 (C-3), 138.8 (CH), 124.8 (C-1 '), 113.3 (CH), 111.9 (CH), 108.8 (C-10), 105.7 (C-6 ', C-2 '), 96.6 (C-6), 92.8 (C-8), 73.3 (OCH
2), 61.2 (4 '-OCH
3), 56.7 (7-OCH
3), 56.5 (3 ', 5 '-OCH
3), 56.0 (8-OCH
3); MS (ESI, m/z): 539.3 [M+H]
+, 561.2 [M+Na]
+.
2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base)-N'-((3 methyl thiophene-2-base) methylene radical) acethydrazide (compound 26)
Pale solid, productive rate: 65.9%, m.p.132 ~ 134 DEG C; IR (KBr, cm
-1):
ν max1699,1681,1620,1606,1558,1506,1417,1354,1246,1217,1126,1107,1064,1010,816;
1hNMR (500MHz, CDCl
3) δ: 2.42 (s, 3H, CH
3), 3.92-3.99 (m, 15H, 5 × OCH
3), 4.32 (s, 2H, CH
2), 6.41 (d,
j=2.3Hz, 1H, H-6), 6.54 (d,
j=2.3Hz, 1H, H-8), 6.84 (d,
j=5.15Hz, 1H, CH), 7.21 (overlappings, 2H, H-2 ', H-6 '), 7.28 (d,
j=5.15Hz, 1H, CH), 8.63 (s, 1H, NH), 12.08 (s, 1H, N=CH);
13cNMR (125MHz, CDCl
3) δ: 174.7 (C-4), 164.9 (C=O), 164.9 (C-7), 161.1 (C-9), 159.1 (C-2), 154.1 (C-5), 153.6 (C-3 ', C-5 '), 144.1 (C), 141.4 (C-4 '), 140.8 (C-3), 140.5 (C), 132.5 (CH), 130.5 (CH), 128.0 (CH), 124.8 (C-1 '), 108.8 (C-10), 105.7 (C-6 ', C-2 '), 96.5 (C-6), 92.8 (C-8), 73.3 (OCH
2), 61.2 (4 '-OCH
3), 56.7 (7-OCH
3), 56.5 (3 ', 5 '-OCH
3), 56.0 (8-OCH
3), 14.2 (CH
3); MS (ESI, m/z): 569.2 [M+H]
+, 591.2 [M+Na]
+.
N'-((1H-pyrroles-2-base) methylene radical)-2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base) acethydrazide (compound 27)
Pale solid, productive rate: 72.4%, m.p.135 ~ 137 DEG C; IR (KBr, cm
-1):
ν max1699,1681,1620,1602,1558,1506,1417,1354,1244,1213,1126,1107,1039,1006,815;
1hNMR (500MHz, CDCl
3) δ: 3.92-4.00 (m, 15H, 5 × OCH
3), 4.32 (s, 2H, CH
2), 6.25 (d,
j=2.3Hz, 1H, H-6), 6.41 (d,
j=2.3Hz, 1H, H-8), 6.54 (m; 2H, 2CH), 6.91 (s, 1H; CH), 7.21 (overlappings, 2H, H-2 '; H-6 '), 8.23 (s, 1H, NH); 9.54 (s, 1H, NH); 12.11 (s, 1H, N=CH);
13cNMR (125MHz, CDCl
3) δ: 174.8 (C-4), 165.2 (C=O), 164.9 (C-7), 161.0 (C-9), 159.1 (C-2), 154.1 (C-5), 153.6 (C-3 ', C-5 '), 141.4 (C-4 '), 140.8 (C-3), 140.8 (CH), 127.2 (C), 124.8 (C-1 '), 124.3 (CH), 114.8 (CH), 109.8 (CH), 108.8 (C-10), 105.7 (C-6 ', C-2 '), 96.5 (C-6), 92.8 (C-8), 73.2 (OCH
2), 61.2 (4 '-OCH
3), 56.7 (7-OCH
3), 56.5 (3 ', 5 '-OCH
3), 56.0 (8-OCH
3); MS (ESI, m/z): 538.3 [M+H]
+, 560.2 [M+Na]
+. embodiment eight, compound are tested the in-vitro multiplication inhibit activities of cancer cells MDA-MB-231, A549, PC-3, HeLa and SiHa
The DMEM of human breast cancer cell MDA-MB-231 10%FBS cultivates, and the RPMI1640 of human lung cancer cell A549, human prostata cancer PC-3, proliferating epidermal cancer cells HeLa and human cervical cancer 1 squamous cell carcinoma SiHa 10%FBS cultivates, 37 DEG C, 5%CO
2saturated humidity incubator in cultivate, within 2 days, change a nutrient solution, within 4-6 days, pass once generation.The vegetative period cell of taking the logarithm is experimental subjects.Cell 0.025% trypsin contains 0.5mMEDTA) digestion process.20mM compound dissolution in DMSO as storing solution.Before use, directly desired concn is diluted to substratum.Negative control group adds the DMSO with medicine same volume, and positive controls adds with tested medicine with the Farmorubine Hydrochloride of concentration and Gefitinib.DMSO ultimate density in treatment agent is no more than 0.1% (v/v).
To take the logarithm cell in vegetative period, after 0.025% tryptic digestion, be resuspended in DMEM or the RPMI1640 substratum containing 10%FBS, with 4.5 × 10
4the final concentration of individual/mL is inoculated on 96 well culture plates, every hole 100
μl, the rightmost side one is classified as blank group, and adding acellularly has serum DMEM or RPMI1640 substratum, is placed in 37
oc, 5%CO
2saturated humidity incubator in cultivate.Sop up substratum after 24h, adding has blood serum medium, every hole 200 containing different concns medicine
μl, the every hole of blank group adds 200
μl perfect medium processes the requirement of experiment time respectively, removes supernatant, adds 100
μthe MTT of L/well concentration 0.5mg/mL.100 are added again after cultivating 4h
μl/well 10% SDS.At 37 DEG C, 10h makes crystallisate fully dissolve rear taking-up, and 5min is swung in microseism, and 30min under placement room temperature, surveys OD value, and calculate cytoactive, inhibiting rate and P value under A595 wavelength.
With the concentration of medicine or treatment time for transverse axis, OD value or inhibiting rate are the longitudinal axis, curve plotting.Every concentration of specimens repeats six holes, and each experiment in triplicate, is averaged as net result.
Experimental result carries out variance analysis with SPSS software, is significant difference during P<0.05, is that difference is extremely remarkable during p<0.01.The inhibiting rate calculation formula of cell proliferation is as follows:
Table 1 ampelopsin nitrogen containing derivative is to the in-vitro multiplication inhibit activities of breast cancer cell MDA-MB-231
Note: * compound has significant difference (P < 0.05) to MDA-MB-231 inhibiting rate and negative control group (DMSO) inhibiting rate difference analysis under setting concentration.
Table 2 ampelopsin nitrogen containing derivative is to the in-vitro multiplication inhibit activities (10 of A549, PC-3, HeLa and SiHa cancer cells
μm)
Note: * compound is 10 in concentration
μsignificant difference (P < 0.05) is had to cancer cells A549, PC-3, HeLa and SiHa inhibiting rate and negative control group (DMSO) inhibiting rate difference analysis under M.
Show from the data of table 1 and accompanying drawing, above compound all has good inhibit activities to target tumor MDA-MB-231, wherein the inhibit activities of compound 25 is compared with positive drug Farmorubine Hydrochloride, positive drug is higher than at same dosage and action time, it is worth mentioning that most that positive drug to the toxicity of tumour cell obviously too large (making the whole broken cracking of cell), new compound synthesized by this patent is substantially very little to target cell damage, this inhibit activities is mainly reflected in the propagation (cell quantity obviously tails off compared with the control) of T suppression cell, or (from morphological observation, we are not difficult to find Cell differentiation inducing activity, cell is while reduced number, cell there occurs distortion, but damage is not clearly), can find out from the data of table 2, the synthesized nitrogenous analog derivative of ampelopsin also has good inhibition to cancer cells such as A549, PC-3, HeLa and SiHa, the inhibition of part of compounds is better than positive control medicament, shows that this series compound can be used as cancer therapy drug and further studies.
Claims (5)
1. the nitrogenous analog derivative of ampelopsin, is characterized in that structure is represented by following general formula (III):
R
3for (1) phenyl or substituted-phenyl; (2) pyridyl, furyl, thienyl, pyrryl;
Substituted-phenyl is containing one or more methyl, ethyl, methoxyl group, oxyethyl group, n-propyl, sec.-propyl, trifluoromethyl, nitro, amido on phenyl ring.
2. the nitrogenous analog derivative of ampelopsin according to claim 1, is characterized in that described compound is as follows:
Compound 22:2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base)-N'-(2-luorobenzyl) acethydrazide
Compound 23:2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base)-N'-(4-methylbenzilidene) acethydrazide
Compound 24:2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base)-N'-(pyridine-2-methylene) acethydrazide
Compound 25:2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base)-N'-(furans-2-methylene) acethydrazide
Compound 26:2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base)-N'-((3 methyl thiophene-2-base) methylene radical) acethydrazide
Compound 27:N'-((1H-pyrroles-2-base) methylene radical)-2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base) acethydrazide.
3., according to the nitrogenous analog derivative of the ampelopsin described in claim 1 or 2, it is characterized in that affiliated compound is preparing the application in cancer therapy drug.
4. according to the preparation method of the nitrogenous analog derivative of ampelopsin described in claim 1, it is characterized in that the preparation method of general formula (III) compound is for raw material with Myricitroside, halogenated alkane, secondary amine, aromatic acid, substituted aroma acid, ethyl bromoacetate, hydrazine hydrate, aromatic aldehyde and substituted aroma aldehyde, be substituted, be hydrolyzed and condensation reaction synthesis target product, its synthetic route is:
The reaction scheme of compound formula (III)
。
5. the preparation method of the nitrogenous analog derivative of ampelopsin according to claim 4, it is characterized in that being substituted, be hydrolyzed and
Condensation is synthesized, and the synthetic method of general formula (III) is:
The first step: the preparation of 3-hydroxyl-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone
Myricitroside and K is added in round-bottomed flask
2cO
3be dissolved in DMF, after stirring, drip methyl iodide slowly,
Stirring at room temperature a few hours, after stopped reaction, with water-dispersion, be extracted with ethyl acetate, merging filtrate, merge organic phase, concentrating under reduced pressure, is then dissolved in dehydrated alcohol by enriched material, be warming up to backflow, after solution clarification, under backflow, add concentrated hydrochloric acid, the yellow solid that has slowly is separated out, and continues reaction 2h, cooling, refrigerator is placed and is spent the night, and filters, obtains crude product, do not need purifying, be directly used in next step reaction
Second step: the preparation of 3-fluoroacetic acid ethyl ester-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromene-4-ketone
The product of the first step is added successively, K in there-necked flask
2cO
3and anhydrous propanone, after stirring at room temperature is even, drip ethyl bromoacetate, drip and finish, back flow reaction a few hours, after stopped reaction, be cooled to room temperature, pour in frozen water after concentrated, crystallization, suction filtration, filter cake chloroform/water recrystallization obtains target product,
The preparation of the 3rd step: 2-((5,7-dimethoxy-4 '-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromene-3-base) oxygen base) acethydrazide
In there-necked flask, add the product of second step successively, 80% hydrazine hydrate and dehydrated alcohol, back flow reaction 2h, TCL point plate is followed the tracks of, until react completely, after concentrating under reduced pressure removes a large amount of solvent, cooling, has precipitation to produce and separates out, suction filtration, filter cake dehydrated alcohol recrystallization obtains target product
4th step: the preparation of ampelopsin acylhydrazone
Product and the aromatic aldehyde of the 3rd step is added successively in there-necked flask, with anhydrous alcohol solution, the acetic acid of instillation catalytic amount, stirring heating backflow 2h, TLC point plate is followed the tracks of, until react completely, concentration of reaction solution, cooling, has a large amount of Precipitations, suction filtration, filter cake dehydrated alcohol recrystallization obtains target product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510621302.5A CN105237504B (en) | 2014-01-22 | 2014-01-22 | Nitrogenous analog derivative of myricetin and its preparation method and application |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410028019.7A CN103804335B (en) | 2014-01-22 | 2014-01-22 | Nitrogenous analog derivative of a kind of myricetin and its production and use |
| CN201510621302.5A CN105237504B (en) | 2014-01-22 | 2014-01-22 | Nitrogenous analog derivative of myricetin and its preparation method and application |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410028019.7A Division CN103804335B (en) | 2014-01-22 | 2014-01-22 | Nitrogenous analog derivative of a kind of myricetin and its production and use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105237504A true CN105237504A (en) | 2016-01-13 |
| CN105237504B CN105237504B (en) | 2018-07-06 |
Family
ID=50701771
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410028019.7A Expired - Fee Related CN103804335B (en) | 2014-01-22 | 2014-01-22 | Nitrogenous analog derivative of a kind of myricetin and its production and use |
| CN201510621302.5A Expired - Fee Related CN105237504B (en) | 2014-01-22 | 2014-01-22 | Nitrogenous analog derivative of myricetin and its preparation method and application |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410028019.7A Expired - Fee Related CN103804335B (en) | 2014-01-22 | 2014-01-22 | Nitrogenous analog derivative of a kind of myricetin and its production and use |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN103804335B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106674216A (en) * | 2016-12-21 | 2017-05-17 | 贵州大学 | Myricetin derivative containing thiadiazole thioether structure and preparation method thereof |
| CN106699718A (en) * | 2016-12-28 | 2017-05-24 | 佳木斯大学 | Myricetin 4, 4'-dipyridyl ethanol eutectic crystal and preparation method thereof |
| CN107021945A (en) * | 2017-05-02 | 2017-08-08 | 贵州大学 | A kind of analog derivative of myricetin containing piperazine acidamide and preparation method thereof |
| CN109232545A (en) * | 2018-10-22 | 2019-01-18 | 贵州大学 | A kind of myricetin derivative, preparation method and the usage containing quinoxaline |
| CN111961039A (en) * | 2020-08-28 | 2020-11-20 | 贵州大学 | Myricetin derivative containing substituted pyrimidine, preparation method and application thereof |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106518828B (en) * | 2016-11-02 | 2018-10-23 | 贵州大学 | Amides myricetin derivative, preparation method and application |
| CN109053712A (en) * | 2018-09-19 | 2018-12-21 | 南京大学连云港高新技术研究院 | A kind of 2- aminothiophene -3- carboxylate methyl ester derivative C15H22N2O5The synthetic method of S |
| CN109438427B (en) * | 2018-12-04 | 2022-03-29 | 贵州大学 | Thioether-containing triazole Schiff base myricetin derivative, and preparation method and application thereof |
| CN110183429B (en) * | 2019-06-18 | 2020-06-05 | 贵州大学 | 4- (N-methyl) aminopiperidine myricetin derivative containing dithiocarbamate, preparation method and application thereof |
| CN110642825B (en) * | 2019-10-16 | 2021-06-15 | 中国海洋大学 | Flavonoid derivative, preparation method thereof and application thereof in preparation of immunopotentiator |
| CN111285832A (en) * | 2020-03-27 | 2020-06-16 | 长春中医药大学 | Preparation method and novel medical application of myricetin derivative |
| CN112209910B (en) * | 2020-07-03 | 2023-10-17 | 贵州大学 | Myricetin derivative containing sulfonyl piperazine, preparation method and application |
| CN112759581B (en) * | 2020-11-16 | 2022-08-02 | 贵州大学 | Benzoimidazole sulfonamide-containing myricetin derivative, preparation method and application |
| CN112679458B (en) * | 2020-12-15 | 2023-01-17 | 贵州大学 | Sulfonic ester-containing myricetin derivative and preparation method and application thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020147353A1 (en) * | 1999-09-23 | 2002-10-10 | Vereniging Christelijk Wetenschappelijk Anderwijs | Novel flavonoids |
| CN1887881A (en) * | 2006-07-20 | 2007-01-03 | 广西中医学院 | Myricitrin preparing process |
| CN101036675A (en) * | 2006-12-21 | 2007-09-19 | 浙江大学 | Method for extracting flavonoids from the waxberry core |
| CN102698275A (en) * | 2012-06-19 | 2012-10-03 | 中国人民解放军第二军医大学 | Application of myricetin similar flavonol compound to preparation of antitumor medicament |
| CN103214445A (en) * | 2013-05-08 | 2013-07-24 | 郑州大学 | Preparation method and use of quercetin amide derivative |
| CN103271901A (en) * | 2013-04-03 | 2013-09-04 | 广东医学院附属医院 | Application of dihydromyricetin (DHM) in preparation of anti-hepatoma medicines |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2544734B2 (en) * | 1987-03-24 | 1996-10-16 | コスモ開発株式会社 | Immunosuppressant |
| US5407947A (en) * | 1993-11-05 | 1995-04-18 | Eli Lilly And Company | Methods for inhibiting bone loss using pyrolidine and piperidine substituted benzopyrans |
| KR101103728B1 (en) * | 2009-05-12 | 2012-01-11 | 건국대학교 산학협력단 | Quercetin prodrug and the preparation method |
| CN102875620B (en) * | 2012-10-16 | 2015-02-04 | 昆明龙津药业股份有限公司 | New derivatives of myricetin and application of derivatives to medicine preparation |
-
2014
- 2014-01-22 CN CN201410028019.7A patent/CN103804335B/en not_active Expired - Fee Related
- 2014-01-22 CN CN201510621302.5A patent/CN105237504B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020147353A1 (en) * | 1999-09-23 | 2002-10-10 | Vereniging Christelijk Wetenschappelijk Anderwijs | Novel flavonoids |
| CN1887881A (en) * | 2006-07-20 | 2007-01-03 | 广西中医学院 | Myricitrin preparing process |
| CN101036675A (en) * | 2006-12-21 | 2007-09-19 | 浙江大学 | Method for extracting flavonoids from the waxberry core |
| CN102698275A (en) * | 2012-06-19 | 2012-10-03 | 中国人民解放军第二军医大学 | Application of myricetin similar flavonol compound to preparation of antitumor medicament |
| CN103271901A (en) * | 2013-04-03 | 2013-09-04 | 广东医学院附属医院 | Application of dihydromyricetin (DHM) in preparation of anti-hepatoma medicines |
| CN103214445A (en) * | 2013-05-08 | 2013-07-24 | 郑州大学 | Preparation method and use of quercetin amide derivative |
Non-Patent Citations (2)
| Title |
|---|
| 林国钡等: "杨梅素的研究进展", 《国际药学研究杂志》 * |
| 胡国强等: "氟喹诺酮C3羧基等排体的合成及抗肿瘤抗菌活性I.诺氟沙星酰腙衍生物", 《中国药科大学学报》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106674216A (en) * | 2016-12-21 | 2017-05-17 | 贵州大学 | Myricetin derivative containing thiadiazole thioether structure and preparation method thereof |
| CN106674216B (en) * | 2016-12-21 | 2019-06-11 | 贵州大学 | A kind of myricetin derivative of the sulfide based structural containing thiadiazoles and preparation method thereof |
| CN106699718A (en) * | 2016-12-28 | 2017-05-24 | 佳木斯大学 | Myricetin 4, 4'-dipyridyl ethanol eutectic crystal and preparation method thereof |
| CN107021945A (en) * | 2017-05-02 | 2017-08-08 | 贵州大学 | A kind of analog derivative of myricetin containing piperazine acidamide and preparation method thereof |
| CN109232545A (en) * | 2018-10-22 | 2019-01-18 | 贵州大学 | A kind of myricetin derivative, preparation method and the usage containing quinoxaline |
| CN109232545B (en) * | 2018-10-22 | 2021-09-24 | 贵州大学 | Quinoxalin-containing myricetin derivative, preparation method and application thereof |
| CN111961039A (en) * | 2020-08-28 | 2020-11-20 | 贵州大学 | Myricetin derivative containing substituted pyrimidine, preparation method and application thereof |
| CN111961039B (en) * | 2020-08-28 | 2022-11-08 | 贵州大学 | Myricetin derivative containing substituted pyrimidine, preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103804335A (en) | 2014-05-21 |
| CN105237504B (en) | 2018-07-06 |
| CN103804335B (en) | 2016-05-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105237504A (en) | Myricetin nitrogen-containing derivative, preparation method and uses thereof | |
| CN101045046B (en) | Use of Brazil hemoatoxy type compound for preparing antineoplastic | |
| CN102309655B (en) | Traditional Chinese medicine composition with effect of preventing and treating cancers and application of Chinese medicinal composition | |
| CN103222970B (en) | Asymmetric list carbonyl curcumin analog application in preparation of anti-tumor drugs | |
| CN102260260B (en) | 8-phenyl xanthine compound, preparation method, medicine composition including the compound and purpose thereof | |
| CN101804096B (en) | Method for extracting purified total alkaloid of strychnos nux-vomica and application thereof in pharmacy | |
| KR101629077B1 (en) | Stilbenoid compound as inhibitor for squamous carcinoma and heptoma and uses thereof | |
| CN104004037B (en) | 8-position methylamine like derivative of baicalin and ester thereof and preparation method thereof | |
| CN106883244B (en) | Scutellarin derivative and its preparation method and application | |
| CN110922415B (en) | Synthesis and application of novel anti-tumor active compound | |
| CN104478897A (en) | Oxazino-scutellarin aglycone derivative as well as preparation method and application thereof | |
| CN102000073A (en) | Application of coptisine in preventing and curing myocardial ischemic diseases | |
| CN103709140A (en) | Pantoprazole sodium crystal and preparation method thereof | |
| CN102309656A (en) | Chinese medicinal composition with effect of preventing and treating cancers and medicinal application of Chinese medicinal composition | |
| CN104876902B (en) | 7 cyclohexyl methyl 5 (2 ' amino) phenyl Chrysins and its preparation method and application | |
| CN107468684B (en) | It ellagic acid and is cooperateed with Celastrol and is preparing the application in anti-lung-cancer medicament | |
| CN102731459A (en) | Scutellarin aglycone Mannich derivatives, and preparation method and application thereof | |
| CN113549046B (en) | Bisbecklonin S derivative and preparation method and application thereof | |
| CN116554105B (en) | Benzamide compound, preparation method, use method and application | |
| CN109336801A (en) | A kind of doxercalciferol derivative and preparation method thereof | |
| CN101648883B (en) | Isoliquiritigenin derivant with antineoplastic activity and synthetic method thereof | |
| CN101786952B (en) | Anthraquinone compound and preparation method and medical application of lysine salt thereof | |
| SA et al. | DESIGN, SYNTHESIS AND IN-VIVO ANTI-TUMOUR ACTIVITIES OF SOME NOVEL 2-((1H-INDOL-4-YL) OXY)-1-(4, 5-DIPHENYL-1H-PYRAZOL-1-YL) ETHANONE DERIVATIVES | |
| CN101306076A (en) | Use of Erythrina bark extract in preparing antineoplastic medicine | |
| CN106866694B (en) | Oridonin Schiff base derivatives and its preparation method and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180706 |