CN111499608A - Benzo [ c ] benzopyrone derivatives and application thereof - Google Patents
Benzo [ c ] benzopyrone derivatives and application thereof Download PDFInfo
- Publication number
- CN111499608A CN111499608A CN202010311104.XA CN202010311104A CN111499608A CN 111499608 A CN111499608 A CN 111499608A CN 202010311104 A CN202010311104 A CN 202010311104A CN 111499608 A CN111499608 A CN 111499608A
- Authority
- CN
- China
- Prior art keywords
- benzo
- pharmaceutically acceptable
- benzopyrone
- general formula
- propyl
- 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
- ASIPLGLDOUQLOQ-UHFFFAOYSA-N benzo[c]chromen-1-one Chemical class C1=CC=CC2=C3C(=O)C=CC=C3OC=C21 ASIPLGLDOUQLOQ-UHFFFAOYSA-N 0.000 title claims description 22
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims abstract description 14
- 206010005003 Bladder cancer Diseases 0.000 claims abstract description 12
- 201000005112 urinary bladder cancer Diseases 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 13
- 206010028980 Neoplasm Diseases 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 201000011510 cancer Diseases 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- -1 pyrrolidinyl-1-yl Chemical group 0.000 claims description 5
- TZWPLCNJPJFPDI-UHFFFAOYSA-N CC1CCN(CCCC2=CC=C(C(C=CC=C3)=C3C(O3)=O)C3=C2)CC1 Chemical compound CC1CCN(CCCC2=CC=C(C(C=CC=C3)=C3C(O3)=O)C3=C2)CC1 TZWPLCNJPJFPDI-UHFFFAOYSA-N 0.000 claims description 4
- VWMXXLTWAXLMBO-UHFFFAOYSA-N CN1CCN(CCCC2=CC=C(C(C=CC=C3)=C3C(O3)=O)C3=C2)CC1 Chemical compound CN1CCN(CCCC2=CC=C(C(C=CC=C3)=C3C(O3)=O)C3=C2)CC1 VWMXXLTWAXLMBO-UHFFFAOYSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 claims description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 2
- 229940077388 benzenesulfonate Drugs 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229940050410 gluconate Drugs 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- 229930186301 urolithin Natural products 0.000 abstract description 13
- 239000000126 substance Substances 0.000 abstract description 3
- 239000002246 antineoplastic agent Substances 0.000 abstract description 2
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 2
- 125000005605 benzo group Chemical group 0.000 abstract 2
- 150000008375 benzopyrones Chemical class 0.000 abstract 1
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical compound C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 239000001963 growth medium Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 229920001968 ellagitannin Polymers 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- WXUQMTRHPNOXBV-UHFFFAOYSA-N Urolithin B Chemical compound C1=CC=C2C3=CC=C(O)C=C3OC(=O)C2=C1 WXUQMTRHPNOXBV-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 230000005526 G1 to G0 transition Effects 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- PMBKPVKKUIBVBK-UHFFFAOYSA-N O=C1OC2=CC(CCCN3CCCC3)=CC=C2C2=C1C=CC=C2 Chemical compound O=C1OC2=CC(CCCN3CCCC3)=CC=C2C2=C1C=CC=C2 PMBKPVKKUIBVBK-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical class O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound 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 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- RIUPLDUFZCXCHM-UHFFFAOYSA-N urolithin-A Natural products OC1=CC=C2C3=CC=C(O)C=C3OC(=O)C2=C1 RIUPLDUFZCXCHM-UHFFFAOYSA-N 0.000 description 2
- ATWLRNODAYAMQS-UHFFFAOYSA-N 1,1-dibromopropane Chemical compound CCC(Br)Br ATWLRNODAYAMQS-UHFFFAOYSA-N 0.000 description 1
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 1
- HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical compound C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- UZOFELREXGAFOI-UHFFFAOYSA-N 4-methylpiperidine Chemical compound CC1CCNCC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 229940122041 Cholinesterase inhibitor Drugs 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 229920002079 Ellagic acid Polymers 0.000 description 1
- AFSDNFLWKVMVRB-UHFFFAOYSA-N Ellagic acid Chemical compound OC1=C(O)C(OC2=O)=C3C4=C2C=C(O)C(O)=C4OC(=O)C3=C1 AFSDNFLWKVMVRB-UHFFFAOYSA-N 0.000 description 1
- ATJXMQHAMYVHRX-CPCISQLKSA-N Ellagic acid Natural products OC1=C(O)[C@H]2OC(=O)c3cc(O)c(O)c4OC(=O)C(=C1)[C@H]2c34 ATJXMQHAMYVHRX-CPCISQLKSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 238000004115 adherent culture Methods 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000004791 biological behavior Effects 0.000 description 1
- 230000009702 cancer cell proliferation Effects 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- PMOWTIHVNWZYFI-WAYWQWQTSA-N cis-2-coumaric acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1O PMOWTIHVNWZYFI-WAYWQWQTSA-N 0.000 description 1
- 125000000332 coumarinyl group Chemical group O1C(=O)C(=CC2=CC=CC=C12)* 0.000 description 1
- 230000007547 defect Effects 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
- 230000009982 effect on human Effects 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 229960002852 ellagic acid Drugs 0.000 description 1
- 235000004132 ellagic acid Nutrition 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical class Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 235000012055 fruits and vegetables Nutrition 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- FAARLWTXUUQFSN-UHFFFAOYSA-N methylellagic acid Natural products O1C(=O)C2=CC(O)=C(O)C3=C2C2=C1C(OC)=C(O)C=C2C(=O)O3 FAARLWTXUUQFSN-UHFFFAOYSA-N 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- PMOWTIHVNWZYFI-UHFFFAOYSA-N o-Coumaric acid Natural products OC(=O)C=CC1=CC=CC=C1O PMOWTIHVNWZYFI-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 239000004017 serum-free culture medium Substances 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000019635 sulfation Effects 0.000 description 1
- 238000005670 sulfation reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000011521 systemic chemotherapy Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
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
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a benzo [ c ]]Benzopyrone derivatives and their use. Different N-terminal end groups are introduced into the urolithin derivative through a 1, 3-dibromopropane bridge chain, and a series of benzo [ c ] containing Uro B skeleton (shown as formula (I)) is designed and synthesized]Benzopyrone) chemical derivatives. Can be used for preparing various antitumor drugs, especially bladder cancer.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a benzo [ c ] benzopyrone derivative and application thereof in treating cancer diseases.
Background
Bladder cancer is the most common malignancy of the urinary system. The biological behavior of bladder tumor is complex and changeable, and the bladder tumor is easy to recur, invade and transfer. Apart from surgery, systemic chemotherapy has become the standard treatment for metastatic bladder cancer. The chemotherapy drugs commonly used for treating bladder cancer include adriamycin, hydroxycamptothecin, mitomycin and the like, however, because of the wide occurrence of drug resistance, bladder cancer cells are less sensitive to the drugs at present, and the clinical application effect of the existing drugs is poor. Therefore, the development of new anti-bladder cancer drugs is more and more urgent, and the search for low-toxicity and high-efficiency anticancer lead compounds from natural drugs is one of the hot spots of medical research.
Phenolic compounds such as ellagitannins are secondary metabolites of fruits and vegetables, are beneficial to human health, and have been shown to be involved in antioxidant, anti-inflammatory, and potential tumor prevention. In recent years, a great deal of research is carried out on Chinese medicinal materials rich in ellagitannins by a plurality of researchers, and the result shows that the content of the ellagitannins in organisms is low, the ellagitannins cannot reach the concentration of the ellagitannins which can exert the biological activity, and the ellagitannins are mostly further metabolized into ellagic acid and Urolithins (Uro) which are easier to absorb under the action of intestinal flora in the bodies, so the uroritins can be true substances of the ellagitannins which can exert the biological activity in the bodies.
Chemically, Urolithins are benzo [ c ] benzopyrone derivatives with different hydroxyl substitutions. Urolithins is found in plasma mostly in the form of a micromolar concentration of dextran glycoside. The Urolithins skeleton can be regarded as that benzene rings are combined with cis-o-hydroxy cinnamic acid lactone, and the hydroxy groups of Uro B, Uro A, Uro C and Uro D are increased in sequence according to the number of phenolic hydroxy groups. At present, research on the urolithin derivatives is less, and the research mainly focuses on the activity research of the urolithin glucuronic acid derivatives and the modification of coumarin structures similar to the urolithin glucuronic acid derivatives. The glucuronic acid acidification and sulfation forms of the compound are proved to have protective effect on myocardial cells, and the introduction of meta-N-benzyl can be used as a cholinesterase inhibitor, and in addition, the compound has potential application prospect in the treatment of Alzheimer's disease. However, no research on the urolithin skeleton derivatives has been found in the field of anticancer.
Disclosure of Invention
In order to solve the defects in the prior art, the invention provides a benzo [ c ] benzopyrone derivative with a structure shown in a general formula (I) or a pharmaceutically acceptable salt thereof. Different N-terminal end groups are introduced into the Urolithin derivatives through a 1, 3-dibromopropane bridge chain, a series of chemical derivatives containing Uro B skeleton (benzo [ c ] benzopyrone) are designed and synthesized, the core of the design is to improve the water solubility of Urolithin, enhance the bioavailability of Urolithin and obtain stronger biological activity for inhibiting the proliferation of tumor cells.
The invention also aims to provide application of the benzo [ c ] benzopyrone derivative in preparing medicaments for treating cancer diseases.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, a benzo [ c ] benzopyrone derivative with a structure of general formula (I) or a derivative thereof is provided
wherein,
z is substituted or unsubstituted-O (CH2) n-, n is an integer of 2-6, the substituent is hydroxyl or halogen, or a carbon chain in Z contains double bonds or oxygen atoms;
m is 0, 1 or 2;
x is O, N or one of CH;
r is one or more of hydrogen, substituted or unsubstituted C1-5 alkyl, hydroxyl, tert-butyloxycarbonyl and carbonyl.
Preferably, the benzo [ C ] benzopyrone derivative or pharmaceutically acceptable salt with the structure of the general formula (I), wherein the substituted C1-5 alkyl is selected from halogen substituted C1-5 alkyl, the halogen is fluorine, chlorine, bromine and iodine, and the unsubstituted C1-5 alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl.
Preferably, the benzo [ c ] benzopyrone derivative or pharmaceutically acceptable salt with the structure of the general formula (I) is selected from any one of the following compounds or pharmaceutically acceptable salts thereof:
3- (3- (4-methylpiperazin-1-yl) -propyl) -6H-benzo [ c ] chromen-6-one (BH 1901);
3- (3-morpholin-1-yl) -propyl) -6H-benzo [ c ] chromen-6-one (BH 1902);
3- (3- (4-methylpiperidin-1-yl) -propyl) -6H-benzo [ c ] chromen-6-one (BH 1903);
3- (3- (pyrrolidinyl-1-yl) -propyl) -6H-benzo [ c ] chromen-6-one (BH 1905).
Preferably, the benzo [ c ] benzopyrone derivative or pharmaceutically acceptable salt with the structure of the general formula (I) is a salt containing a pharmaceutically acceptable anion: any one of hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate, tartrate, maleate, fumarate, methanesulfonate, gluconate, saccharate, benzoate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate.
The general synthetic method of the benzo [ c ] benzopyrone derivative with the structure of the general formula (I) is formed by connecting a benzo [ c ] benzopyrone parent body with a nitrogen-containing structure through a carbon-containing chain,
in a second aspect, there is provided a pharmaceutical composition comprising an amount of a benzo [ c ] benzopyrone derivative or a pharmaceutically acceptable salt thereof having a structure of formula (I) sufficient to exert anticancer activity and a pharmaceutically acceptable excipient.
Preferably, the pharmaceutical composition comprises pharmaceutically acceptable excipients which are inert solid fillers or diluents and sterile aqueous solution or organic solvents.
Benzo [ c ] benzopyrone derivatives having the structure of formula (I) may contain a chiral center and thus may exist in different enantiomeric and diastereomeric forms. The present invention relates to all optical isomers and all stereoisomers of the compounds of general formula (I), as racemic mixtures and in the form of individual enantiomers and diastereomers of such compounds, and to methods of treatment of all pharmaceutical compositions containing or using them, as defined above.
In a third aspect, an application of the benzo [ c ] benzopyrone derivative with the structure of the general formula (I) or the pharmaceutically acceptable salt or the pharmaceutical composition in preparing a medicament for treating cancer diseases is provided.
Preferably, the cancer-like disease is bladder cancer.
Compared with the prior art, the technical scheme of the invention has the following beneficial effects:
CCK-8 experiment results for detecting cancer cell proliferation activity show that the compound hydrochloride has obvious proliferation inhibition effect on human bladder cancer cell T24, and particularly the derivative BH1905 shows the inhibition activity which is optimal to a positive control medicament. Therefore, the compound can be applied to preparing various antitumor drugs, and is particularly suitable for bladder cancer.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a compound BH 1901;
FIG. 2 is a NMR spectrum of Compound BH 1902;
FIG. 3 is a hydrogen nuclear magnetic resonance spectrum of compound BH 1903;
FIG. 4 is a hydrogen nuclear magnetic resonance spectrum of compound BH 1905;
Detailed Description
The features and advantages of the present invention will be further understood from the following detailed description taken in conjunction with the accompanying drawings. The examples provided are merely illustrative of the method of the present invention and do not limit the remainder of the disclosure in any way. Example 1 preparation of 3- (3- (4-methylpiperazin-1-yl) -propyl) -6H-benzo [ c ] chromen-6-one (BH1901)
Reaction scheme 1
1) And (3) sequentially weighing urolithin B (20.2g), 1, 3-dibromopropane (40.4g) and potassium carbonate (27.6g) in a 500m L round-bottom flask, heating and reacting for 2h at 50 ℃ by using acetone (200m L) as a solvent, monitoring by thin-layer chromatography (T L C), stopping the reaction until a light blue raw material fluorescence spot disappears, carrying out spin-drying on a system, dissolving the solid powder in petroleum ether, carrying out secondary spin-drying, eluting by using silica gel as a stationary phase sequentially using petroleum ether and ethyl acetate as a ratio of 1:0, 20:1, 10:1 and 8:1, and concentrating to obtain 14.4g of white powdery solid, and verifying by nuclear magnetic resonance to obtain the target compound, namely, the dibromopropane urolithin B intermediate.
2) The target compound is synthesized by sequentially taking 2.2g of an intermediate, 1.1g of 4-methylpiperazine, 1.1g of potassium carbonate and 20m of L acetonitrile, adding the intermediate into a 100m L round-bottom flask, refluxing at 60 ℃ for 2h, feeding materials according to a molar ratio of 1:1:2, during the reaction, the system exists in a suspension form, the proportion of large and small polarity fluorescent spots is not changed, stopping the reaction after the reaction is detected by T L C, repeatedly adding acetonitrile to spin-dry the system, adding 5.4g of silica gel, sequentially frying with methanol and dichloromethane as solvents, taking the silica gel as a stationary phase, carrying out forward elution with dichloromethane and methanol of 1:0, 20:1, 10:1 and 0:1, concentrating to obtain 0.6g of a yellow white viscous solid, redissolving with 5ml of methanol, taking a thick silica gel plate as a stationary phase and methanol as a rotary normal phase, separating the thin layer plate, scraping all silica gel on which the upper blue fluorescent stripe is located on the bottom of a deep blue fluorescent stripe, dissolving the methanol under heating at 60 ℃, stirring, carrying out dry filtration, and obtaining a yellow solid with a yellow nuclear magnetic resonance structure shown in a drawing, and obtaining a picture of.
3) Preparation of hydrochloride salt: saturated ethyl acetate hydrochloride solution is prepared firstly, and the principle is that high boiling point acid is used for preparing low boiling point acid. Reacting excessive concentrated sulfuric acid with sodium chloride to generate hydrogen chloride gas and sodium bisulfate, and introducing the hydrogen chloride gas into an ethyl acetate solution to obtain the catalyst. And introducing a compound dissolved by ethyl acetate, oscillating, observing that snowflake-shaped particles are separated out, gradually forming milky floccule precipitates along with the reaction, standing, performing suction filtration to obtain white needle-shaped crystals, and drying to constant weight.
White needle-shaped crystals are obtained. 1H NMR (400MHz, DMSO-d6)8.30(d, J ═ 8.1Hz,1H, Ar-H),8.26 to 8.17(m,2H, Ar-H),7.90(t, J ═ 7.1Hz,1H, Ar-H),7.59(t, J ═ 7.6Hz,1H, Ar-H),7.04 to 6.88(m,2H, Ar-H),4.10(t, J ═ 6.3Hz,2H, -CH2 "), 2.48 to 2.17(m,10H, -CH 2"), 2.14(s,3H, N-CH3),1.93 to 1.83(m,2H, -CH2-), anal.calcd for C21H24O3N2, ESI-MS: 352.43[ M + H ] +
Example 2 preparation of 3- (3-morpholin-1-yl) -propyl) -6H-benzo [ c ] chromen-6-one (BH1902)
The title compound was prepared as in example 1, substituting morpholine for 4-methylpiperazine. White crystals are obtained. As shown in fig. 2. 1H NMR (400MHz, DMSO-d6)8.29(d, J ═ 8.1Hz,1H, Ar-H),8.25 to 8.15(m,2H, Ar-H),7.89(t, J ═ 7.6Hz,1H, Ar-H),7.58(t, J ═ 7.5Hz,1H, Ar-H),6.97(dd, J ═ 4.5,2.2Hz,2H, Ar-H),4.10(t, J ═ 6.3Hz,2H, O-CH2),3.57(t, J ═ 4.4Hz,4H, -CH2-O-CH2),2.41(dd, J ═ 18.6,11.4Hz,6H, N-CH2),1.90(p, J ═ 6.6, CH 2H, -2H, cd 20 Hz, C — 5920 Hz, C: 339.38[ M + H ] +.
Example 3 preparation of 3- (3- (4-methylpiperidin-1-yl) -propyl) -6H-benzo [ c ] chromen-6-one (BH1903)
The title compound was prepared by substituting 4-methylpiperazine for 4-methylpiperidine according to the procedure of example 1. Yellow crystals are obtained. As shown in fig. 3. 1H NMR (400MHz, DMSO-d6)8.17 to 8.27(m,3H, Ar-H),7.87(t, J ═ 7.5Hz,1H, Ar-H),7.56(t, J ═ 7.5Hz,1H, Ar-H),6.93(d, J ═ 6.8Hz,2H, Ar-H),4.06(t, J ═ 5.8Hz,2H, -O-CH2-),2.81(d, J ═ 10.9Hz,2H),2.39(t, J ═ 6.9Hz,2H, -CH2-),1.84(t, J ═ 9.6Hz,4H, -CH2-),1.54(d, J ═ 12.0Hz,2H, -CH2-),1.27(s, 1H-), 1H ═ 11, 1.11 ═ CH 11, 10H, -CH2-),1.54(d, J ═ 12.10H, — 10H, — 11H, — 2H, — 11H, 10H, — 11H, 10H, — 11H, — 2H, — 10H, — 2H, — 11H: 351.44[ M + H ] +.
Example 4 preparation of 3- (3- (pyrrolidin-1-yl) -propyl) -6H-benzo [ c ] chromen-6-one (BH1905)
The title compound was prepared by the method of example 1, substituting 4-methylpiperazine for pyrrolidine. White crystals are obtained. As shown in fig. 4. 1H NMR (400MHz, DMSO-d6)8.29(d, J ═ 8.1Hz,1H, Ar-H),8.25 to 8.14(m,2H, Ar-H),7.89(t, J ═ 8.2Hz,1H, Ar-H),7.58(t, J ═ 7.6Hz,1H, Ar-H),6.97(dd, J ═ 6.5,2.3Hz,2H, Ar-H),4.10(t, J ═ 6.3Hz,2H, -O-CH2-),2.62(t, J ═ 7.3Hz,2H, -CH2-),2.00 to 1.85(m,6H, -CH2-),1.71(s,4H, -CH2-), anal.esi for C20H21O3 MS 3N: 323.44[ M + H ] +.
Table 1: number of Compounds prepared in examples and structural formulas thereof
[ example 5 ] in vitro anti-human bladder cancer cell T24 proliferation Activity study of derivatives
Adopts CCK-8[2- (2-methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2, 4-disulfonic acid benzene) -2H-tetrazole monosodium salt]Method for measuring the Inhibitory Concentration (IC) of a urolithin derivative on T24 cells of human bladder cancer50)。
1) T24 cell culture and passage: the complete culture medium is RPMI-1640 culture medium: fetal bovine serum: qing-streptomycin ═ 90:10: 1; at 37 ℃ with 5% CO2As shown in FIG. 1, the culture was carried out in an incubator saturated with humidity. When the cell growth density is more than 80%, digesting with trypsin digestion solution containing 0.05% EDTA, observing the cells in suspension state under a microscope, stopping digestion with complete culture medium, centrifuging at 1000r/min for 5 minutes, pouring out supernatant, resuspending the cells with fresh culture medium, and carrying out passage at a ratio of 1: 4.
2) Preparing liquid medicine and grouping administration: the hydrochloride of the compound to be tested in the experimental group is dissolved by a basic culture medium and diluted to different concentration gradients, and 5-fluorouracil is used as a positive control drug. And a blank group and a normal control group are additionally arranged, wherein the blank group is only culture medium liquid with the same amount so as to eliminate the influence of the color of the culture medium on the absorbance, and the normal control group is only added with the culture medium and the cells and is not added with a test medicament.
3) And (3) activity determination: taking T24 cells in logarithmic growth phase, adjusting cell density by a cell counter, and then carrying out cell density adjustment at 1x10 per hole5The density of (A) was inoculated in a 96-well plate, 6 multiple wells were set, and 5% CO was performed at 37 ℃2Culturing in an incubator. Adherent culture for 24 hoursAnd then, abandoning cell supernatant, respectively adding 200 mu L6 of each derivative with different concentrations, continuously culturing, taking out the plate after the drugs are respectively stimulated for 24 hours, 36 hours and 48 hours, abandoning the supernatant, adding 100 mu L of serum-free culture medium containing 5 percent of CCK8, incubating in an incubator for 1 to 2 hours, and measuring the absorbance value (A) at 450nm of an enzyme-labeling instrument.
Each set of experiments was repeated 3 times. According to the formula: the cell growth inhibition (%) was (normal control a value-experimental a value)/(normal control a value-blank a value) x 100%), and the T24 cell inhibition (%) was calculated. Median Inhibitory Concentration (IC)50) Defined as the drug concentration when 50% of the tumor cells survived. A standard curve of the cell growth inhibition rate is prepared based on the measured A value, and the corresponding drug concentration is determined on the standard curve.
Measured IC50See table 2.
TABLE 2 Activity of the individual Compounds HCl on human bladder cancer cells T24
Claims (8)
1. A benzo [ c ] benzopyrone derivative with a structure shown as a general formula (I) or a pharmaceutically acceptable salt thereof is characterized in that,
wherein,
z is substituted or unsubstituted-O (CH2) n-, n is an integer of 2-6, the substituent is hydroxyl or halogen, or a carbon chain in Z contains double bonds or oxygen atoms;
m is 0, 1 or 2;
x is O, N or one of CH;
r is one or more of hydrogen, substituted or unsubstituted C1-5 alkyl, hydroxyl, tert-butyloxycarbonyl and carbonyl.
2. The benzo [ C ] benzopyrone derivative or its pharmaceutically acceptable salt with the structure of general formula (I) according to claim 1, wherein the substituted C1-5 alkyl is selected from C1-5 alkyl substituted by halogen, the halogen is fluorine, chlorine, bromine, iodine, and the unsubstituted C1-5 alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl.
3. The benzo [ c ] benzopyrone derivative having the structure of the general formula (I) or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from any one of the following compounds:
3- (3- (4-methylpiperazin-1-yl) -propyl) -6H-benzo [ c ] chromen-6-one (BH 1901);
3- (3-morpholin-1-yl) -propyl) -6H-benzo [ c ] chromen-6-one (BH 1902);
3- (3- (4-methylpiperidin-1-yl) -propyl) -6H-benzo [ c ] chromen-6-one (BH 1903);
3- (3- (pyrrolidinyl-1-yl) -propyl) -6H-benzo [ c ] chromen-6-one (BH 1905).
4. The benzo [ c ] benzopyrone derivative having the structure of the general formula (I) or the pharmaceutically acceptable salt thereof according to claim 1, wherein the salt is a salt containing a pharmaceutically acceptable anion: any one of hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate, tartrate, maleate, fumarate, methanesulfonate, gluconate, saccharate, benzoate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate.
5. A pharmaceutical composition, which comprises a therapeutically effective amount of the benzo [ c ] benzopyrone derivatives or pharmaceutically acceptable salts thereof having the structure of the general formula (I) as claimed in any one of claims 1 to 4, and pharmaceutically acceptable excipients.
6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition comprises inert solid fillers or diluents and sterile aqueous solution or organic solvent as pharmaceutically acceptable excipients.
7. Use of the benzo [ c ] benzopyrone derivatives having the structure of general formula (I) or pharmaceutically acceptable salts thereof according to any one of claims 1 to 4 or the pharmaceutical compositions according to claim 5 or 6 for the preparation of a medicament for the treatment of cancer diseases.
8. The use according to claim 7, wherein the cancer-like disease is bladder cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010311104.XA CN111499608B (en) | 2020-04-20 | 2020-04-20 | Benzo [ c ] benzopyrone derivatives and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010311104.XA CN111499608B (en) | 2020-04-20 | 2020-04-20 | Benzo [ c ] benzopyrone derivatives and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111499608A true CN111499608A (en) | 2020-08-07 |
| CN111499608B CN111499608B (en) | 2022-04-15 |
Family
ID=71867489
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010311104.XA Active CN111499608B (en) | 2020-04-20 | 2020-04-20 | Benzo [ c ] benzopyrone derivatives and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111499608B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113336735A (en) * | 2021-06-08 | 2021-09-03 | 常州大学 | Urolithin compound, preparation method, pharmaceutical composition and application |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109928963A (en) * | 2019-04-02 | 2019-06-25 | 武汉大学 | The synthetic method and application of a kind of three carbochain methyl piperidine urolithin B of antibacterials and its hydrochloride |
-
2020
- 2020-04-20 CN CN202010311104.XA patent/CN111499608B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109928963A (en) * | 2019-04-02 | 2019-06-25 | 武汉大学 | The synthetic method and application of a kind of three carbochain methyl piperidine urolithin B of antibacterials and its hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| ZHENPENG QIU ET AL.: "In vitro antioxidant and antiproliferative effects of ellagic acid and its colonic metabolite, urolithins, on human bladder cancer T24 cells", 《FOOD AND CHEMICAL TOXICOLOGY》 * |
| 周本宏等: "鞣花鞣质肠道代谢产物urolithins 研究进展", 《中国中药杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113336735A (en) * | 2021-06-08 | 2021-09-03 | 常州大学 | Urolithin compound, preparation method, pharmaceutical composition and application |
| CN113336735B (en) * | 2021-06-08 | 2022-09-30 | 常州大学 | Urolithin compound, preparation method, pharmaceutical composition and application |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111499608B (en) | 2022-04-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3111940B1 (en) | Silicon phthalocyanine complex, preparation method and medicinal application thereof | |
| EP2562172A1 (en) | Sphaelactone derivatives, their pharmaceutical compositions, preparation methods and uses | |
| CN109134586B (en) | Tripterine derivative and application thereof | |
| CN105085383B (en) | 5 methyl 2 (1H) Pyridione derivatives and its production and use | |
| CN106749513A (en) | Bifunctional molecule and its preparation and application based on the induction BET degradeds of VHL parts | |
| KR20230153533A (en) | Urolithin derivatives and methods of use thereof | |
| CN111153912B (en) | Curcumol derivative containing triazole structure and application thereof in preparation of medicine for treating human colorectal cancer | |
| CN115197227A (en) | Tryptanthrin 1-position or 3-position substituted aromatic thioether derivative, and preparation method and application thereof | |
| CN111499608B (en) | Benzo [ c ] benzopyrone derivatives and application thereof | |
| EP2776029A1 (en) | Treatment of ovarian cancer with benzylidenebenzohydrazides | |
| WO2018086242A1 (en) | Ph-sensitive axially-substituted silicon phthalocyanine complex, preparation method therefor, and medical application thereof | |
| JP2021509399A (en) | Indoleamine-2,3-dioxygenase inhibitor and its preparation method and use | |
| CN103450165A (en) | 2,3-dehydrosilybin derivative, and preparation method and use thereof | |
| CN103864765B (en) | Benzazepine analog derivative containing five-membered ring, Preparation Method And The Use | |
| CN107892691B (en) | 2,8, 9-trisubstituted-9H-purine compound and salt and application thereof | |
| EP1965790B1 (en) | Metabolites of wortmannin analogs and methods of using the same | |
| CN115124531A (en) | 4-azatryptanthrin aromatic thioether derivatives, and preparation method and application thereof | |
| JP7301222B2 (en) | Substituted tricyclic compounds as PRMT5 inhibitors and their applications | |
| CN108640965B (en) | 2-substituted-18 beta-glycyrrhetinic acid derivative and application thereof | |
| CN111484495A (en) | Preparation method and application of derivative containing dihydropteridine diketone framework | |
| CN105175326B (en) | 5 methyl 2 (1H) Pyridione derivatives and its production and use | |
| CN115677812B (en) | Tripterine derivatives, and preparation method and application thereof | |
| CN116715650A (en) | Urine Dan Sulei derivative and preparation method and application thereof | |
| CN110092759A (en) | The chloro- 2,4- pyrimidine derivatives of 5- as anti-tumor drug | |
| WO2013070998A1 (en) | TREATMENT OF OVARIAN CANCER WITH 2-AMINO-4H-NAPHTHO[1,2-b]PYRAN-3-CARBONITRILES |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |