CN116768955A - Cucurbitacin B derivative and preparation method and application thereof - Google Patents
Cucurbitacin B derivative and preparation method and application thereof Download PDFInfo
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- CN116768955A CN116768955A CN202210226288.9A CN202210226288A CN116768955A CN 116768955 A CN116768955 A CN 116768955A CN 202210226288 A CN202210226288 A CN 202210226288A CN 116768955 A CN116768955 A CN 116768955A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 150000001901 cucurbitacin B derivatives Chemical class 0.000 title abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- -1 biotin amine Chemical class 0.000 claims description 32
- 238000006467 substitution reaction Methods 0.000 claims description 20
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 125000002947 alkylene group Chemical group 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 9
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 230000003287 optical effect Effects 0.000 claims description 8
- 206010061218 Inflammation Diseases 0.000 claims description 7
- 229960002685 biotin Drugs 0.000 claims description 7
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N biotin Natural products N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 7
- 235000020958 biotin Nutrition 0.000 claims description 7
- 239000011616 biotin Substances 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 230000004054 inflammatory process Effects 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 6
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 230000019491 signal transduction Effects 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 4
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 4
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 4
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 4
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 4
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 4
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 4
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 3
- 201000010881 cervical cancer Diseases 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 201000011549 stomach cancer Diseases 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 125000006568 (C4-C7) heterocycloalkyl group Chemical group 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 230000004913 activation Effects 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 claims description 2
- 230000003834 intracellular effect Effects 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims description 2
- 230000000259 anti-tumor effect Effects 0.000 abstract description 8
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 5
- 229940124599 anti-inflammatory drug Drugs 0.000 abstract 1
- 229940041181 antineoplastic drug Drugs 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- CVKKIVYBGGDJCR-SXDZHWHFSA-N Cucurbitacin B Natural products CC(=O)OC(C)(C)C=CC(=O)[C@@](C)(O)[C@@H]1[C@@H](O)C[C@]2(C)C3=CC[C@@H]4C(C)(C)C(=O)[C@H](O)C[C@@]4(C)[C@@H]3CC(=O)[C@@]12C CVKKIVYBGGDJCR-SXDZHWHFSA-N 0.000 description 10
- IXQKXEUSCPEQRD-NRNCYQGDSA-N (2S,4R,23E)-2,16beta,20-trihydroxy-9beta,10,14-trimethyl-1,11,22-trioxo-4,9-cyclo-9,10-secocholesta-5,23-dien-25-yl acetate Chemical compound C([C@H]1[C@]2(C)C[C@@H](O)[C@@H]([C@]2(CC(=O)[C@]11C)C)[C@@](C)(O)C(=O)C=CC(C)(C)OC(=O)C)C=C2[C@H]1C[C@H](O)C(=O)C2(C)C IXQKXEUSCPEQRD-NRNCYQGDSA-N 0.000 description 9
- IHTCCHVMPGDDSL-ZJNDIJRCSA-N Cucurbitacin A Natural products O=C([C@@](O)(C)[C@H]1[C@@H](O)C[C@]2(C)[C@]1(C)CC(=O)[C@]1(CO)[C@H]2CC=C2C(C)(C)C(=O)[C@H](O)C[C@@H]12)/C=C/C(OC(=O)C)(C)C IHTCCHVMPGDDSL-ZJNDIJRCSA-N 0.000 description 9
- QZJJDOYZVRUEDY-UHFFFAOYSA-N Dihydrocucurbitacin B Natural products CC12C(=O)CC3(C)C(C(C)(O)C(=O)CCC(C)(C)OC(=O)C)C(O)CC3(C)C1CC=C1C2CC(O)C(=O)C1(C)C QZJJDOYZVRUEDY-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- LNSXRXFBSDRILE-UHFFFAOYSA-N Cucurbitacin Natural products CC(=O)OC(C)(C)C=CC(=O)C(C)(O)C1C(O)CC2(C)C3CC=C4C(C)(C)C(O)C(O)CC4(C)C3(C)C(=O)CC12C LNSXRXFBSDRILE-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 230000001028 anti-proliverative effect Effects 0.000 description 6
- 150000001904 cucurbitacins Chemical class 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 125000001183 hydrocarbyl group Chemical group 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 4
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 150000008052 alkyl sulfonates Chemical class 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical class OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 2
- 229960001467 bortezomib Drugs 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000011698 potassium fluoride Substances 0.000 description 2
- 235000003270 potassium fluoride Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000002103 transcriptional effect Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
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- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- BMQDAIUNAGXSKR-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid Chemical class CC(C)(O)C(C)(C)OB(O)O BMQDAIUNAGXSKR-UHFFFAOYSA-N 0.000 description 1
- HBZBAMXERPYTFS-SECBINFHSA-N (4S)-2-(6,7-dihydro-5H-pyrrolo[3,2-f][1,3]benzothiazol-2-yl)-4,5-dihydro-1,3-thiazole-4-carboxylic acid Chemical compound OC(=O)[C@H]1CSC(=N1)c1nc2cc3CCNc3cc2s1 HBZBAMXERPYTFS-SECBINFHSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- YWARNRIBWGHMIS-UHFFFAOYSA-N 2-[3-[2-(4,5-dimethyl-1,3-thiazol-2-yl)-3-(4-sulfophenyl)-1h-tetrazol-5-yl]phenoxy]acetic acid Chemical compound S1C(C)=C(C)N=C1N1N(C=2C=CC(=CC=2)S(O)(=O)=O)N=C(C=2C=C(OCC(O)=O)C=CC=2)N1 YWARNRIBWGHMIS-UHFFFAOYSA-N 0.000 description 1
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- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
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- C—CHEMISTRY; METALLURGY
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Abstract
The application discloses a cucurbitacin B derivative, a preparation method and application thereof, wherein the structure of the cucurbitacin B derivative is shown as a formula I, and the cucurbitacin B derivative is prepared fromThe definition of the substituent is as described in the specification and the claims. The compound of the application has simple synthesis, better anti-tumor and anti-inflammatory activity and can be used for preparing anti-tumor and anti-inflammatory drugs.
Description
Technical Field
The application relates to cucurbitacin B derivatives, a preparation method thereof and application of the cucurbitacin B derivatives or pharmaceutically acceptable salts thereof or pharmaceutical compositions containing any one of the cucurbitacin B derivatives in anti-tumor, anti-inflammatory and other aspects.
Background
Cucurbitacins (Cucurbitacins) are a class of bitter and toxic cucurbitane-type tetracyclic triterpenes that are found mainly in cucurbitaceae plants, such as snakegourd fruit, pumpkin, cucumber, watermelon, and others, such as figwort, cruciferae, primula, madder, and others. Cucurbitacins are classified into 12 major classes including cucurbitacins a-T, etc., and derivatives thereof are up to 200 or more, with cucurbitacins B and E being the major classes, according to structural characteristics.
Among the various cucurbitacin subtypes, cucurbitacin B has been widely studied for its abundant sources and various powerful physiological activities, and has been demonstrated to have therapeutic effects on various cancers, aids, and inflammation. Current research on cucurbitacin B and its derivatives mainly focuses on antitumor activity, and it has been found that cucurbitacin B has an antiproliferative effect on breast cancer, lung cancer, skin cancer, brain cancer, liver cancer, leukemia, gastric cancer, prostate cancer, cervical cancer cells and the like, and a large number of related mechanisms and molecular targets have been found. There is still a need in the art to conduct intensive research.
Disclosure of Invention
The application aims to provide various derivatives of cucurbitacin B, salts thereof, a preparation method and application of the derivatives.
In a first aspect of the present application, there is provided a compound of formula (I), or an enantiomer, diastereomer, racemate, tautomer, optical isomer, stereoisomer or pharmaceutically acceptable salt thereof:
wherein each ofIndependently a single bond or a double bond;
R 1 selected from the group consisting of: unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C2-C8 alkenyl, unsubstituted or substituted C2-C8 alkynyl, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted C3-C8 cycloalkyl, unsubstituted or substituted 3-8 membered heterocycloalkyl, unsubstituted or substituted 5-8 membered heteroaryl; the substitution is with one or more substituents selected from the group consisting of: C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, cyano, -COOR d 、-CONHR d 、-OCOR d 、-OCOOR d 、-NR c R d 、-NHCOR d 、-NHCOOR d 、-NHCONHR d ,
Wherein R is c 、R d Each independently selected from: hydrogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted- (C1-C6 alkylene) C3-C8 heterocycloalkyl, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted C3-C8 cycloalkyl, unsubstituted or substituted 3-8 membered heterocycloalkyl, unsubstituted or substituted 5-8 membered heteroaryl; the substitution is with one or more substituents selected from the group consisting of: C1-C8 alkyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, 5-8 membered heteroaryl (C1-C8 alkylene) biotin amine.
In another preferred embodiment, R 1 Selected from the group consisting of: unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substitutedSubstituted C2-C6 alkynyl, unsubstituted or substituted C6 aryl, unsubstituted or substituted C4-C7 cycloalkyl, unsubstituted or substituted 4-7 membered heterocycloalkyl, unsubstituted or substituted 4-7 membered heteroaryl; the substitution is with one or more substituents selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, cyano, -COOR d 、-CONHR d 、-OCOR d 、-OCOOR d 、-NR c R d 、-NHCOR d 、-NHCOOR d 、-NHCONHR d ,
Wherein R is c 、R d Each independently selected from: hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted- (C1-C6 alkylene) C4-C7 heterocycloalkyl, unsubstituted or substituted C6 aryl, unsubstituted or substituted C3-C8 cycloalkyl, unsubstituted or substituted 3-8 membered heterocycloalkyl, unsubstituted or substituted 5-8 membered heteroaryl; the substitution is with one or more substituents selected from the group consisting of: C1-C6 alkyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, 5-8 membered heteroaryl (C1-C4 alkylene) biotin amine.
In another preferred embodiment, R 1 Selected from the group consisting of: unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C2-C4 alkenyl, unsubstituted or substituted C2-C4 alkynyl, unsubstituted or substituted C6 aryl, unsubstituted or substituted C4-C6 cycloalkyl, unsubstituted or substituted 4-6 heterocycloalkyl, unsubstituted or substituted 4-6 heteroaryl; the substitution is with one or more substituents selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano, -COOR d 、-CONHR d 、-OCOR d 、-OCOOR d 、-NR c R d 、-NHCOR d 、-NHCOOR d 、-NHCONHR d ,
Wherein R is c 、R d Each independently selected from: hydrogen, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted- (C1-C4 alkylene) C4-C6 heterocycloalkylUnsubstituted or substituted C6 aryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted 5-6 membered heteroaryl; the substitution is with one or more substituents selected from the group consisting of: C1-C4 alkyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, 5-6 membered heteroaryl (C1-C4 alkylene) biotin amine.
In another preferred embodiment, the compound has the following structure:
R 1 the definition is the same as before.
In another preferred embodiment, the compound has the following structure:
R 1 the definition is the same as before.
In another preferred embodiment, the compound is selected from: C1-C37.
In a second aspect of the application, there is provided a pharmaceutical composition comprising:
a compound of formula (I) according to the first aspect, or an enantiomer, diastereomer, racemate, tautomer, optical isomer, stereoisomer or a pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable carrier.
"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatibility" means that the components of the composition are capable of being admixed with the active ingredient of the application (compound of the formula (I), or an enantiomer, diastereomer, racemate, tautomer, optical isomer, stereoisomer or pharmaceutically acceptable salt thereof)And, without significantly reducing the efficacy of the active ingredient. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, and the like), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g. ) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
The mode of administration of the active ingredient or pharmaceutical composition of the present application is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and the like.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like. In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active ingredient, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the application may be administered alone or in combination with other therapeutic agents, such as antineoplastic agents.
When a pharmaceutical composition is used, a safe and effective amount of the compound of the present application is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 20 to 500mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
In a third aspect of the present application, there is provided the use of a compound of formula (I) as described in the first aspect, or an enantiomer, diastereomer, racemate, tautomer, optical isomer, stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in the second aspect, for the preparation of a medicament for the prophylaxis and/or treatment of a tumor or inflammation.
In another preferred embodiment, the tumor is selected from the group consisting of: lung cancer, liver cancer, breast cancer, ovarian cancer, cervical cancer, colon cancer, melanoma, prostate cancer, gastric cancer, hematological tumor.
In another preferred embodiment, the inflammation is inflammation caused by activation of an intracellular NF- κB signaling pathway.
The novel cucurbitacin B derivative is simple and convenient to synthesize, has better anti-tumor and anti-inflammatory activities, and part of the derivative has stronger anti-tumor and anti-inflammatory activities than cucurbitacin B.
It is understood that within the scope of the present application, the above-described technical features of the present application and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. Each feature disclosed in the description may be replaced by alternative features serving the same, equivalent or similar purpose. And are limited to a space, and are not described in detail herein.
Detailed Description
The inventor of the application is widely and deeply researched, and by a palladium catalytic coupling method, under the condition of not introducing a protecting group, the C25 acetoxy of cucurbitacin B is structurally modified to obtain a series of cucurbitacin B derivatives which have good anti-tumor and anti-inflammatory activities, have anti-proliferation effects on various tumor cell lines and have activity superior to that of cucurbitacin B. On this basis, the present application has been completed.
Terminology
In the present application, the halogen is F, cl, br or I.
In the present application, the term "C1-C6" means having 1, 2, 3, 4,5 or 6 carbon atoms, "C1-C8" means having 1, 2, 3, 4,5, 6, 7 or 8 carbon atoms, and so on. "3-8 membered" means having 3, 4,5, 6, 7 or 8 ring atoms, and so on.
In the present application, the term "alkyl" means a saturated linear or branched hydrocarbon moiety, e.g., the term "C1-C8 alkyl" refers to a straight or branched alkyl group having 1, 2, 3, 4,5, 6, 7, or 8 carbon atoms, including without limitation methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like; ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl are preferred.
In the present application, the term "alkoxy" means-O-alkyl. For example, the term "C1-C6 alkoxy" refers to straight or branched chain alkoxy groups having 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, n-propoxy, isopropoxy, butoxy and the like.
In the present application, the term "alkylene" refers to a straight or branched saturated aliphatic group having the indicated number of carbon atoms and linking at least two other groups, i.e. a divalent hydrocarbon group. The two groups attached to the alkylene group may be attached to the same or different atoms on the alkylene group. For example, the linear alkylene group may be a divalent group of- (CH 2) n-where n is 1, 2, 3, 4,5 or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene.
In the present application, the term "alkenyl" means a straight or branched hydrocarbon moiety containing at least one double bond, for example, the term "C2-C6 alkenyl" refers to a straight or branched alkenyl group containing one double bond having 2 to 6 carbon atoms, including without limitation ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, and the like.
In the present application, the term "alkynyl" refers to a straight or branched chain alkynyl group containing one triple bond, including, without limitation, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, and the like.
In the present application, the term "cyclic hydrocarbyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbyl moiety, for example the term "C3-C8 cyclic hydrocarbyl" refers to cyclic hydrocarbyl groups having 3 to 8 carbon atoms in the ring, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclodecyl and the like. The term "C3-C6 cyclic hydrocarbon" has similar meaning. Polycyclic cyclic hydrocarbon groups include spiro, fused and bridged cyclic hydrocarbon groups.
In the present application, the term "heterocyclyl" or "heterocycloalkyl" means a saturated or partially unsaturated cyclic group containing at least one ring heteroatom (e.g., N, O or S). For example, the term "3-8 membered heterocyclic group" means a saturated or unsaturated 3-8 membered cyclic group containing 1 to 3 hetero atoms selected from oxygen, sulfur and nitrogen in the ring, such as a dioxolyl group, a tetrahydropyridinyl group, a dihydropyridinyl group, a dihydrofuryl group, a dihydrothienyl group, an oxahexenyl group, a,Etc. The term "3-6 membered heterocyclyl" has similar meaning.
In the present application, the term "3-7 membered nitrogen-containing heterocycle" refers to a cycloalkyl ring having 3-7 ring atoms and containing 1, 2 or 3N atoms, including, without limitation, a cyclopropane ring, a cyclobutane ring, a cycloheptane ring, and the like.
In the present application unless otherwise indicated,representing the ligation site.
Unless otherwise indicated, alkyl, alkoxy, cycloalkyl, heterocyclyl and aryl groups described herein are substituted and unsubstituted groups. Possible substituents on alkyl, alkoxy, cycloalkyl, heterocyclyl and aryl groups include, but are not limited to: hydroxy, amino, nitro, nitrile, halogen, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C20 cycloalkyl, C3-C20 cycloalkenyl, C1-C20 heterocycloalkyl, C1-C20 heterocycloalkenyl, C1-C6 alkoxy, aryl, heteroaryl, heteroaryloxy, C1-C10 alkylamino, C1-C20 dialkylamino, arylamino, diarylamino, C1-C10 alkylsulfinyl, arylsulfinyl, C1-C10 alkylimino, C1-C10 alkylsulfonimino, arylsulfonyl imino, mercapto, C1-C10 alkylthio, C1-C10 alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, guanidino, ureyl, cyano, acyl, thio acyl, acyloxy, carboxyl and carboxylate groups. On the other hand, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl may also be fused to each other.
In the present application, the substitution is mono-substitution or poly-substitution, and the poly-substitution is di-substitution, tri-substitution, tetra-substitution, or penta-substitution. The disubstitution means having two substituents and so on.
Unless specifically indicated otherwise, the structural formulae described herein are intended to include all tautomeric, optical, and stereoisomers (e.g., enantiomers, diastereomers, geometric isomers, or conformational isomers): for example R, S configuration with asymmetric centers, the (Z), (E) isomers and the conformational isomers of (Z), (E) of double bonds. Thus, individual stereochemical isomers, tautomers or enantiomers, diastereomers or geometric isomers or conformational isomers or mixtures of tautomers of the compounds of the application are all within the scope of the application.
The term "tautomer" means that structural isomers having different energies can exceed the low energy barrier and thus interconvert. For example, proton tautomers (i.e., proton transfer) include interconversions by proton transfer, such as 1H-indazole with 2H-indazole, 1H-benzo [ d ] imidazole with 3H-benzo [ d ] imidazole, valence tautomers include interconversions by recombination of some bonding electrons.
In this context, the pharmaceutically acceptable salts are not particularly limited, and preferably include: inorganic acid salts, organic acid salts, alkyl sulfonates, and aryl sulfonates; the inorganic acid salts include hydrochloride, hydrobromide, nitrate, sulfate, phosphate and the like; the organic acid salts include formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, and the like; the alkyl sulfonate includes methyl sulfonate, ethyl sulfonate, etc.; the arylsulfonate includes benzenesulfonate, p-toluenesulfonate and the like.
Preparation method
The cucurbitacin B derivative of the present application can be prepared by the following route.
Route 1
The reaction is carried out in methylene chloride or tetrahydrofuran; the palladium catalyst used was tris (dibenzylideneacetone) dipalladium (Pd) 2 (dba) 3 ) Or palladium chloride (PdCl) 2 ) The method comprises the steps of carrying out a first treatment on the surface of the The alkali is potassium fluoride or potassium carbonate; the other reactant is a substituted boric acid or a substituted pinacol borate; the reaction temperature is room temperature; the reaction time is about 12 to 24 hours; the solvent was removed by spin-drying, and the concentrate was subjected to column chromatography to give the desired product, which was confirmed by NMR or the like.
Wherein R is as defined above.
Route 2
Route 3
Route 4
Route 5
Route 6
The application will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application. The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions (e.g.those described in Sambrook et al, molecular cloning: A laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989)) or under conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present application. The preferred methods and materials described herein are presented for illustrative purposes only.
In the following preparation examples, MR was measured by means of a AVANCE III M instrument manufactured by Bruker and NMR calibration was carried out: δH27.26 ppm (CDCl 3), 2.50ppm (DMSO-d 6); mass spectra were measured using an Agilent 1200Quadrupole LC/MS simadzu GCMS-QP 5050A; reagents are mainly provided by Shanghai chemical reagent company; the TLC thin layer chromatography silica gel plate is manufactured by Shandong tobacco Confucius silica gel development Co., ltd, model HSGF 254; the normal phase column chromatography silica gel used for purifying the compounds is produced by ocean chemical plants of Qingdao in Shandong, and has the model of zcx-11 and 200-300 meshes.
The chinese abbreviations herein correspond to the following:
DMAP 4-dimethylaminopyridine; DCM: dichloromethane; DMF: n, N-dimethylformamide; THF: tetrahydrofuran.
Example 1
Cucurbitacin B (30 mg,0.054 mmol), phenylboronic acid (13.11 mg,0.11 mmol), potassium fluoride (6.24 mg,0.11 mmol), tris (dibenzylideneacetone) dipalladium (2.46 mg,0.027 mmol) were dissolved in dry DCM (4 mL) and stirred overnight at room temperature, the next day TLC indicated complete reaction. DCM was spun off and the product C1.0 mg (0.028 mmol) was isolated by column chromatography in yield: 51.44%.
1 H NMR(400MHz,Chloroform-d)δ7.32–7.28(m,4H),7.25–7.19(m,2H),6.41(d,J=15.6Hz,1H),5.80–5.78(m,1H),4.44–4.34(m,4H),3.61(d,J=4.0Hz,1H),3.23(d,J=14.8Hz,1H),2.74(d,J=10.8Hz,1H),2.69(dd,J=14.8,2.4Hz,1H),2.53(d,J=6.8Hz,1H),2.41(ddt,J=19.2,8.0,2.8Hz,1H),2.30(ddd,J=12.4,6.0,3.2Hz,1H),2.04–1.94(m,3H),1.86(dd,J=13.6,8.8Hz,1H),1.74(s,1H),1.66–1.58(m,5H),1.49(s,3H),1.48(s,3H),1.43(s,3H),1.35(s,3H),1.34(s,3H),1.28(s,3H),1.07(s,3H),0.98(s,3H).
In a similar manner as in example 1, cucurbitacin B was reacted with a different substituted boric acid or substituted pinacol ester to give the following compounds:
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example 2
C13 (20 mg,0.036 mmol) was dissolved in methanol (5 mL), after nitrogen exchange, pd/C was added rapidly, after nitrogen exchange, hydrogen was exchanged, and stirring was performed at room temperature. After 2 hours the reaction was complete by TLC. After nitrogen exchange, pd/C was filtered off and the solvent was dried, the product C30.3 mg (0.031 mmol) was isolated by column chromatography, yield: 86.12%.
1 H NMR(400MHz,Chloroform-d)δ5.78(d,J=5.6Hz,1H),4.43–4.38(m,2H),4.31(t,J=8.0Hz,1H),3.60(d,J=4.0Hz,1H),3.26(d,J=14.4Hz,1H),2.75–2.62(m,3H),2.53(d,J=6.8Hz,1H),2.47–2.37(m,2H),2.33–2.28(m,1H),2.00–1.93(m,2H),1.84(dd,J=13.2,8.8Hz,1H),1.63(s,2H),1.55–1.50(m,2H),1.41(s,4H),1.36(s,3H),1.34(s,3H),1.28(s,3H),1.12(d,J=5.6Hz,2H),1.07(s,3H),0.97(s,3H),0.91(s,3H),0.89(s,3H),0.87(s,6H).
Example 3
C19 (15 mg,0.025 mmol), potassium hydroxide (14.22 mg,0.25 mmol) was dissolved in 2mL of methanol: dmf=1: 1 in the mixed solution, stirring for 1h at room temperature, tlc showed complete reaction. Extraction with ethyl acetate (3X 50 mL) and washing of the combined organic layers with deionized water and saturated brine, respectively, drying and concentration over sodium sulfate, column chromatography gave product C31.2 mg (0.014 mmol), yield: 55.59%.
1 H NMR(400MHz,Chloroform-d)δ7.22–7.15(m,2H),6.86(d,J=7.6Hz,1H),6.71(d,J=2.0Hz,1H),6.69(dd,J=8.2,2.0Hz,1H),6.42(d,J=15.6Hz,1H),6.18(s,1H),5.94–5.93(m,2H),5.75(t,J=3.2Hz,1H),4.46(t,J=8.0Hz,1H),4.41(s,1H),3.49(s,1H),3.19(d,J=14.4Hz,1H),2.71(d,J=14.4Hz,1H),2.55(d,J=6.8Hz,1H),2.37(dd,J=20.4,8.8Hz,1H),2.32–2.26(m,1H),2.04–2.01(m,2H),1.98–1.85(m,5H),1.47(s,1H),1.46(s,3H),1.44(s,3H),1.43(s,3H),1.36(s,3H),1.35(s,3H),1.25(s,2H),1.23(s,3H),1.02(s,3H),0.99(s,3H).
Example 4
C18 (47.2 mg,0.080 mmol), DMAP (19.48 mg,0.16 mmol), EDCI (30.57 mg,0.16 mmol), 2- (3-butynyl-aziridin-3-yl) acetic acid (13.34 mg,0.088 mmol) were dissolved in dry DCM (4 mL) and stirred at room temperature in the dark for 3h, TLC showed complete reaction. Extraction with ethyl acetate (3X 50 mL) and washing of the combined organic layers with saturated ammonium chloride solution, deionized water and saturated brine, respectively, drying and concentrating over sodium sulfate, column chromatography to give product C32.5 mg (0.041 mmol), yield: 50.79%.
1 H NMR(400MHz,Methanol-d 4 )δ7.36(t,J=8.0Hz,1H),7.27(dt,J=8.0,1.2Hz,1H),7.10(t,J=2.0Hz,1H),7.05(d,J=15.6Hz,1H),6.98(ddd,J=8.0,2.4,1.2Hz,1H),6.70(d,J=15.6Hz,1H),5.82(dt,J=5.6,2.4Hz,1H),4.57(dd,J=12.8,6.0Hz,1H),4.49(t,J=7.6Hz,1H),3.44(d,J=14.8Hz,1H),2.99(d,J=12.8Hz,1H),2.71(s,1H),2.66(s,1H),2.63–2.59(m,2H),2.45–2.37(m,1H),2.34(t,J=2.4Hz,1H),2.13(td,J=7.2,2.4Hz,2H),2.10–2.05(m,2H),2.02–1.97(m,2H),1.87–1.83(m,1H),1.80(td,J=7.2,2.0Hz,2H),1.50(s,3H),1.49(s,3H),1.45(s,1H),1.41(s,3H),1.37(s,3H),1.30(s,3H),1.29(s,3H),1.05(s,3H),0.91(s,3H).
In a similar manner as in example 4, condensation of C18 with different carboxylic acids gives the following compounds:
1 H NMR(400MHz,Chloroform-d)δ7.31(t,J=8.0Hz,1H),7.21–7.15(m,2H),6.99(t,J=2.0Hz,1H),6.96–6.93(m,1H),6.39(d,J=15.6Hz,1H),5.80(dt,J=6.0,2.0Hz,1H),4.44–4.36(m,3H),3.61(d,J=4.0Hz,1H),3.24(d,J=14.4Hz,1H),2.75–2.67(m,2H),2.50(d,J=6.8Hz,1H),2.41(t,J=7.2Hz,3H),2.30(ddd,J=12.6,6.0,3.6Hz,1H),2.02–1.96(m,2H),1.86–1.82(m,3H),1.67(d,J=5.2Hz,1H),1.62(s,4H),1.49(s,3H),1.46(s,3H),1.42(s,3H),1.35(s,3H),1.33(s,3H),1.29(s,3H),1.09(s,3H),1.07(s,3H),0.97(s,3H).
example 5
C32 (29.5 mg,0.041 mmol), N- (3-azidopropyl) biotin amine (13.26 mg,0.041 mmol), copper sulfate pentahydrate (5.07 mg, 0.020mmol), sodium ascorbate (8.05 mg,0.041 mmol) were dissolved in 4mL methanol: water = 3:1, stirred overnight at room temperature in the dark, TLC showed complete reaction. Extraction with ethyl acetate (3X 50 mL) and washing of the combined organic layers with deionized water and saturated brine, respectively, drying and concentration over sodium sulfate, column chromatography gave product C34.7 mg (0.026 mmol), yield: 64.16%.
1 H NMR(400MHz,Methanol-d 4 )δ7.82(s,1H),7.36(t,J=8.0Hz,1H),7.27(dt,J=8.0,1.2Hz,1H),7.09(t,J=2.0Hz,1H),7.04(d,J=15.6Hz,1H),6.97(ddd,J=8.0,2.4,0.8Hz,1H),6.71(d,J=15.6Hz,1H),5.81(dt,J=6.0,2.4Hz,1H),4.56(dd,J=13.0,6.0Hz,1H),4.51–4.46(m,2H),4.39(t,J=7.2Hz,2H),4.29(dd,J=7.8,4.8Hz,1H),3.43(d,J=14.8Hz,1H),3.21–3.17(m,3H),2.98(d,J=12.8Hz,1H),2.91(dd,J=12.6,5.2Hz,1H),2.71(d,J=2.4Hz,1H),2.67(d,J=6.4Hz,1H),2.62–2.57(m,5H),2.40(dd,J=19.4,8.0Hz,1H),2.20(t,J=7.6Hz,2H),2.08(d,J=6.8Hz,2H),2.05–2.02(m,2H),2.00–1.96(m,2H),1.84(dd,J=13.4,8.8Hz,1H),1.76–1.55(m,5H),1.49(s,3H),1.48(s,3H),1.40(s,3H),1.37(s,3H),1.30(s,3H),1.28(s,3H),1.04(s,3H),0.91(s,3H).
Example 6
C19 (34.8 mg,0.059 mmol), HOBt (11.93 mg,0.088 mmol), EDCI (16.93 mg,0.088 mmol), 2- (3-butynylaziridin-3-yl) acetic acid (7.17 mg,0.047 mmol), DIPEA (15.22 mg,0.12 mmol) were dissolved in dry DCM (4 mL), stirred at room temperature in the absence of light for 3h and TLC showed complete reaction. Extraction with ethyl acetate (3X 50 mL) and washing of the combined organic layers with saturated ammonium chloride solution, deionized water and saturated brine, respectively, drying and concentrating over sodium sulfate, column chromatography to give product C35.6 mg (0.019 mmol), yield: 31.79%.
1 H NMR(400MHz,Chloroform-d)δ7.64(s,1H),7.46(dd,J=8.0,2.0Hz,1H),7.33(t,J=2.0Hz,1H),7.29(t,J=8.0Hz,1H),7.19(d,J=15.2Hz,1H),7.11(dd,J=6.6,2.0Hz,1H),6.48(d,J=16.0Hz,1H),5.81(dt,J=6.0,2.0Hz,1H),4.44–4.38(m,3H),3.61(d,J=4.0Hz,1H),3.25(d,J=14.4Hz,1H),2.75–2.68(m,2H),2.57(d,J=6.8Hz,1H),2.47–2.39(m,2H),2.32–2.26(m,3H),2.13–2.08(m,2H),2.02–1.97(m,2H),1.96–1.90(m,1H),1.88–1.80(m,2H),1.65(s,5H),1.50(s,3H),1.46(s,3H),1.46(s,3H),1.35(s,3H),1.34(s,3H),1.28(s,3H),1.08(s,3H),0.99(s,3H).
In a similar manner as in example 6, condensation of C19 with different carboxylic acids gives the following compounds:
1 H NMR(400MHz,Methanol-d 4 )δ7.51(d,J=2.0Hz,1H),7.43(d,J=8.4Hz,1H),7.24(t,J=8.0Hz,1H),7.08(d,J=4.8Hz,1H),7.05(d,J=12.0Hz,1H),6.73(d,J=15.6Hz,1H),5.81(d,J=5.6Hz,1H),4.59–4.49(m,2H),3.41(d,J=14.8Hz,1H),2.98(d,J=12.8Hz,1H),2.63–2.59(m,2H),2.41(dd,J=19.2,7.6Hz,1H),2.11(s,3H),2.08–1.97(m,3H),1.86(dd,J=13.2,9.2Hz,1H),1.47(s,6H),1.41(s,3H),1.38(s,3H),1.30(s,3H),1.29(s,3H),1.04(s,3H),0.91(s,3H).
example 7
C29 (50 mg,0.074 mmol) was dissolved in DCM (4 mL) and trifluoroacetic acid (0.5 mL) was added and stirred at room temperature for 2h, TLC showed completion of the reaction. The solvent was removed by spin chromatography to give product C37.7 mg (0.040 mmol), yield: 54.71%.
1 H NMR(400MHz,Methanol-d 4 )δ8.01(t,J=2.0Hz,1H),7.88(dt,J=8.0,1.2Hz,1H),7.59(ddd,J=7.8,2.0,1.2Hz,1H),7.42(t,J=8.0Hz,1H),7.06(d,J=15.6Hz,1H),6.77(d,J=15.6Hz,1H),5.81(dt,J=5.6,2.0Hz,1H),4.57(dd,J=13.0,5.6Hz,1H),4.52(t,J=8.0Hz,1H),3.41(d,J=14.8Hz,1H),2.98(d,J=13.2Hz,1H),2.63–2.62(m,1H),2.59(d,J=5.2Hz,1H),2.44–2.38(m,1H),2.10(ddd,J=12.4,5.6,3.6Hz,1H),2.05(d,J=5.6Hz,1H),1.98(d,J=8.4Hz,1H),1.86(dd,J=13.6,8.4Hz,1H),1.52(s,6H),1.42(s,3H),1.38(s,3H),1.30(s,3H),1.28(s,3H),1.04(s,3H),0.91(s,3H).
Example 8 antiproliferative testing of Compounds against A549 (human non-small cell lung carcinoma) and PLC/PRF/5 (human liver carcinoma) cell lines (MTS assay)
Principle of experiment
By CellTiterAQueous One Solution Cell Proliferation Assay (MTS) colorimetric method detects cell proliferation. The analysis method uses tetrazole compound (3- (4, 5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazole, inner salt and MTS]Based on the following. The conversion of yellow MTS to blue-violet water-soluble formazan is catalyzed by dehydrogenases that are present in metabolically active living cells; dead cells are unable to complete the conversion of MTS to formazan. The amount of Formazan (Formazan) determined from absorbance at 490nm is directly proportional to the number of living cells in culture.
Experimental method
Sample treatment: the samples were dissolved in DMSO and stored at low temperature. The concentration of DMSO in the final system is controlled within a range that does not affect the assay activity.
Detecting the cell survival rate by MTS method, namely, growing cells in logarithmic phase, digesting the adherent cells by 0.025% pancreatin, and counting; a549 cells were seeded at a density of 3000/well, PLC/PRF/5 cells at 5000/well (each plated with 10% fbs) into 80ul in 96 well plates and placed in 5% co 2 The incubator grows overnight at 37 ℃. The test compounds were each diluted in a three-fold concentration gradient, tested for eight concentrations, each concentration set with three multiplex wells; adding 20ul of diluted compound into corresponding cell holes, and adhering cells to 5% CO 2 Culturing in a 37 ℃ incubator for 72 hours; 20ul of MTS in 5% CO was added separately 2 Incubate for 2 hours at 37 ℃. The absorbance at 490nm (L1) was measured using Molecular Device VersaMax, the reference wavelength 690nm (L2), the (L1-L2) values plotted against the different concentrations of inhibitor, and the IC50 was obtained by fitting the formula.
Experimental results (examples of compounds in the table, but not limited to these compounds)
The anti-tumor cell proliferation results of the compounds are shown in tables 1 (A549 cells) and 2 (PLC/PRF/5 cells), and the tested compounds have better anti-proliferation activity (IC) on both the A549 and the PLC/PRF/5 cells 50 <100nM)。
Antiproliferative results of compounds of table 1 on a549 cell line
Antiproliferative results of compounds of Table 2 on PLC/PRF/5 cell lines
Compounds of formula (I) | IC 50 |
Cucurbitacin B | *** |
C1 | *** |
C2 | *** |
C3 | *** |
C4 | *** |
C5 | *** |
C6 | *** |
C7 | *** |
C8 | *** |
C9 | *** |
C10 | *** |
C11 | *** |
C12 | *** |
C16 | *** |
C17 | *** |
C18 | *** |
C19 | *** |
C20 | *** |
C21 | *** |
C22 | ** |
C23 | *** |
C24 | *** |
C25 | *** |
C26 | *** |
C27 | *** |
C28 | *** |
C29 | *** |
C31 | *** |
C33 | *** |
C36 | *** |
Note that: IC (integrated circuit) 50 Is half inhibition, i.e. 50% inhibition concentration.
“*”:1-10μM;“**”:0.1-1μM;“***”:100-1nM
Example 9NF- κB Signal pathway inhibitory Activity assay
Principle of experiment
The effect of test compounds on NF- κB signaling pathway was evaluated using TNF α to stimulate NF- κB transcriptional activity, PS-341 (Bortezomib) as a positive control. And (3) co-processing cells by the positive compound or the compound to be tested and TNF alpha, and adding a luciferase substrate containing cell lysate after 6 hours for full lysis. The influence of the compounds on NF- κB transcriptional activity was evaluated by measuring the intensity of the luminencesignal.
Experimental procedure
Sample treatment: the sample is dissolved by DMSO, stored at low temperature, and the concentration of DMSO in the final system is controlled within a range which does not affect the detection activity.
And (3) connecting plates: 293T cells with good growth status were plated into CulterplateTM-96 well plates at a density of 2 ten thousand per well per 50. Mu.L.
Tnfα stimulation: after 24h of cell wall-attached growth, 50. Mu.l of complete medium containing 20ng/ml of TNFα (containing 10% FBS) was added, i.e., the final concentration of TNFα was 10ng/ml.
Compound treatment: 1 μl of compound from the compound master and control compound master was added to a 96-well screen plate.
And (3) detection: after 4h CellTiter-Blue was added and incubated in the dark. After 6 hours total, enVision (TM) detection; immediately after completion, 90. Mu.L of liquid was removed from the 96-well screening plate, and 20. Mu.L of luciferate substrate was added thereto, and the reading of 2101Multilabel Reader was taken to measure the signal intensity of luciferases.
Experimental results (examples of compounds in the table, but not limited to these compounds)
The tested compounds all have inhibitory activity on NF- κB signaling pathway, and most of the compounds have good NF- κB inhibitory activity (IC 50 <1μM)。
TABLE 3NF- κB Signal pathway inhibitory Activity results
/>
Note that: IC (integrated circuit) 50 Is half inhibition, i.e. 50% inhibition concentration.
“*”:10-100μM;“**”:1-10μM;“***”:0.1-1μM
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.
Claims (10)
1. A compound of formula (I), or an enantiomer, diastereomer, racemate, tautomer, optical isomer, stereoisomer, or pharmaceutically acceptable salt thereof:
wherein each ofIndependently a single bond or a double bond;
R 1 selected from the group consisting of: unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C2-C8 alkenyl, unsubstituted or substituted C2-C8 alkynyl, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted C3-C8 cycloalkyl, unsubstituted or substituted 3-8 membered heterocycloalkyl, unsubstituted or substituted 5-8 membered heteroaryl; the substitution is with one or more substituents selected from the group consisting of: C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, cyano, -COOR d 、-CONHR d 、-OCOR d 、-OCOOR d 、-NR c R d 、-NHCOR d 、-NHCOOR d 、-NHCONHR d ,
Wherein R is c 、R d Each independently selected from: hydrogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted- (C1-C6 alkylene) C3-C8 heterocycloalkyl, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted C3-C8 cycloalkyl, unsubstituted or substituted 3-8 membered heterocycloalkyl, unsubstituted or substituted 5-8 membered heteroaryl; the substitution is with one or more substituents selected from the group consisting of: C1-C8 alkyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, 5-8 membered heteroaryl (C1-C8 alkylene) biotin amine.
2. The compound of claim 1, wherein the compound has the structure:
R 1 is defined as in claim 1.
3. The compound of claim 1, wherein the compound has the structure:
R 1 is defined as in claim 1.
4. The compound of claim 1, wherein R 1 Selected from the group consisting of: unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C6 aryl, unsubstituted or substituted C4-C7 cycloalkyl, unsubstituted or substituted 4-7 membered heterocycloalkyl, unsubstituted or substituted 4-7 membered heteroaryl; the substitution is with one or more substituents selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, cyano, -COOR d 、-CONHR d 、-OCOR d 、-OCOOR d 、-NR c R d 、-NHCOR d 、-NHCOOR d 、-NHCONHR d ,
Wherein R is c 、R d Each independently selected from: hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted- (C1-C6 alkylene) C4-C7 heterocycloalkyl, unsubstituted or substituted C6 aryl, unsubstituted or substituted C3-C8 cycloalkyl, unsubstituted or substituted 3-8 membered heterocycloalkyl, unsubstituted or substituted 5-8 membered heteroaryl; the substitution is with one or more substituents selected from the group consisting of: C1-C6 alkyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, 5-8 membered heteroaryl (C1-C4 alkylene) biotin amine.
5. The compound of claim 1, wherein R 1 Selected from the group consisting of: unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C2-C4 alkenyl, unsubstituted or substituted C2-C4 alkynyl, unsubstituted or substituted C6 aryl, unsubstituted or substituted C4-C6 cycloalkyl, unsubstituted or substituted 4-67 membered heterocycloalkyl, unsubstituted or substituted 4-6 membered heteroaryl; the substitution is with one or more substituents selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano, -COOR d 、-CONHR d 、-OCOR d 、-OCOOR d 、-NR c R d 、-NHCOR d 、-NHCOOR d 、-NHCONHR d ,
Wherein R is c 、R d Each independently selected from: hydrogen, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted- (C1-C4 alkylene) C4-C6 heterocycloalkyl, unsubstituted or substituted C6 aryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted 5-6 membered heteroaryl; the substitution is with one or more substituents selected from the group consisting of: C1-C4 alkyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, 5-6 membered heteroaryl (C1-C4 alkylene) biotin amine.
6. The compound of claim 1, wherein the compound is:
7. a pharmaceutical composition comprising:
a compound of formula (I) according to claim 1, or an enantiomer, diastereomer, racemate, tautomer, optical isomer, stereoisomer or a pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable carrier.
8. Use of a compound of general formula (I) according to claim 1, or an enantiomer, diastereomer, racemate, tautomer, optical isomer, stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, for the preparation of a medicament for the prophylaxis and/or treatment of tumors or inflammation.
9. The use of claim 8, wherein the tumor is selected from the group consisting of: lung cancer, liver cancer, breast cancer, ovarian cancer, cervical cancer, colon cancer, melanoma, prostate cancer, gastric cancer, hematological tumor.
10. The use of claim 8, wherein the inflammation is inflammation caused by activation of an intracellular NF- κb signaling pathway.
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