CN108727397A - phenanthridine derivatives - Google Patents
phenanthridine derivatives Download PDFInfo
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- CN108727397A CN108727397A CN201810525158.9A CN201810525158A CN108727397A CN 108727397 A CN108727397 A CN 108727397A CN 201810525158 A CN201810525158 A CN 201810525158A CN 108727397 A CN108727397 A CN 108727397A
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- phenanthridines
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- 150000005053 phenanthridines Chemical class 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 50
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 5
- -1 carbon tetrachloride free radical Chemical class 0.000 claims description 26
- 235000010290 biphenyl Nutrition 0.000 claims description 16
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 14
- 239000004305 biphenyl Substances 0.000 claims description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 125000004799 bromophenyl group Chemical class 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N carbon tetrachloride Substances ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 5
- 230000009471 action Effects 0.000 claims description 4
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical class BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 239000004342 Benzoyl peroxide Substances 0.000 claims description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 claims description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 2
- 238000007259 addition reaction Methods 0.000 claims description 2
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 2
- 230000008859 change Effects 0.000 claims description 2
- 230000000977 initiatory effect Effects 0.000 claims description 2
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims 1
- 229940041181 antineoplastic drug Drugs 0.000 claims 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims 1
- 238000002474 experimental method Methods 0.000 abstract description 17
- 102000003915 DNA Topoisomerases Human genes 0.000 abstract description 9
- 108090000323 DNA Topoisomerases Proteins 0.000 abstract description 9
- 230000000259 anti-tumor effect Effects 0.000 abstract description 8
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 238000003556 assay Methods 0.000 abstract description 3
- 238000005259 measurement Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 60
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 56
- 238000005160 1H NMR spectroscopy Methods 0.000 description 34
- 239000007787 solid Substances 0.000 description 33
- INVGWHRKADIJHF-UHFFFAOYSA-N Sanguinarin Chemical compound C1=C2OCOC2=CC2=C3[N+](C)=CC4=C(OCO5)C5=CC=C4C3=CC=C21 INVGWHRKADIJHF-UHFFFAOYSA-N 0.000 description 20
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
- 0 ClC(/C(/c1c2)=C/C*c(cc3OC*c3c3)c3-c1cc1c2OCO1)(Cl)Cl Chemical compound ClC(/C(/c1c2)=C/C*c(cc3OC*c3c3)c3-c1cc1c2OCO1)(Cl)Cl 0.000 description 10
- FCEXWTOTHXCQCQ-UHFFFAOYSA-N Ethoxydihydrosanguinarine Natural products C12=CC=C3OCOC3=C2C(OCC)N(C)C(C2=C3)=C1C=CC2=CC1=C3OCO1 FCEXWTOTHXCQCQ-UHFFFAOYSA-N 0.000 description 9
- 229940084560 sanguinarine Drugs 0.000 description 9
- YZRQUTZNTDAYPJ-UHFFFAOYSA-N sanguinarine pseudobase Natural products C1=C2OCOC2=CC2=C3N(C)C(O)C4=C(OCO5)C5=CC=C4C3=CC=C21 YZRQUTZNTDAYPJ-UHFFFAOYSA-N 0.000 description 9
- 101710183280 Topoisomerase Proteins 0.000 description 8
- 238000001514 detection method Methods 0.000 description 7
- 238000011017 operating method Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000002835 absorbance Methods 0.000 description 6
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
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- 229960005420 etoposide Drugs 0.000 description 3
- 150000007523 nucleic acids Chemical class 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
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- 239000011734 sodium Substances 0.000 description 3
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- 241000196324 Embryophyta Species 0.000 description 2
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-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
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- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
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- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- NLWCWEGVNJVLAX-UHFFFAOYSA-N 1-methoxy-2-phenylbenzene Chemical group COC1=CC=CC=C1C1=CC=CC=C1 NLWCWEGVNJVLAX-UHFFFAOYSA-N 0.000 description 1
- KQMIWCAOEFUBQK-UHFFFAOYSA-N 1-methoxy-3-phenylbenzene Chemical group COC1=CC=CC(C=2C=CC=CC=2)=C1 KQMIWCAOEFUBQK-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 241001614291 Anoplistes Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- OBXRRYDSMFQXEY-UHFFFAOYSA-N COc1cc2c(cccc3)c3c(C(Cl)(Cl)Cl)nc2cc1 Chemical compound COc1cc2c(cccc3)c3c(C(Cl)(Cl)Cl)nc2cc1 OBXRRYDSMFQXEY-UHFFFAOYSA-N 0.000 description 1
- LTUHPCYLNYSSCW-UHFFFAOYSA-N COc1cc2nc(C(Cl)(Cl)Cl)c(cc(cc3OC)OC)c3c2cc1 Chemical compound COc1cc2nc(C(Cl)(Cl)Cl)c(cc(cc3OC)OC)c3c2cc1 LTUHPCYLNYSSCW-UHFFFAOYSA-N 0.000 description 1
- HJKQLEYDZKTVFI-UHFFFAOYSA-N COc1cc2nc(C(Cl)(Cl)Cl)c(cc3[U]COc3c3)c3c2cc1 Chemical compound COc1cc2nc(C(Cl)(Cl)Cl)c(cc3[U]COc3c3)c3c2cc1 HJKQLEYDZKTVFI-UHFFFAOYSA-N 0.000 description 1
- 241001233914 Chelidonium majus Species 0.000 description 1
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 241001269238 Data Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241001247804 Eomecon chionantha Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 240000007849 Macleaya cordata Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- RLOSRCUFYXDHPG-UHFFFAOYSA-N N#[C-].C1=CC=CC=C1C1=CC=CC=C1 Chemical group N#[C-].C1=CC=CC=C1C1=CC=CC=C1 RLOSRCUFYXDHPG-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 240000001090 Papaver somniferum Species 0.000 description 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000008049 TAE buffer Substances 0.000 description 1
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 1
- HGEVZDLYZYVYHD-UHFFFAOYSA-N acetic acid;2-amino-2-(hydroxymethyl)propane-1,3-diol;2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetic acid Chemical compound CC(O)=O.OCC(N)(CO)CO.OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O HGEVZDLYZYVYHD-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
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- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000001099 anti-trypanosomal effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
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- 229940125782 compound 2 Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
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- 230000029087 digestion Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 239000000686 essence Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 208000007565 gingivitis Diseases 0.000 description 1
- 229940068560 greater celandine Drugs 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229930013397 isoquinoline alkaloid Natural products 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 208000026037 malignant tumor of neck Diseases 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 235000006502 papoula Nutrition 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000000547 structure data Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940034610 toothpaste Drugs 0.000 description 1
- 239000000606 toothpaste Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- JFJZZMVDLULRGK-URLMMPGGSA-O tubocurarine Chemical compound C([C@H]1[N+](C)(C)CCC=2C=C(C(=C(OC3=CC=C(C=C3)C[C@H]3C=4C=C(C(=CC=4CCN3C)OC)O3)C=21)O)OC)C1=CC=C(O)C3=C1 JFJZZMVDLULRGK-URLMMPGGSA-O 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
- C07D491/153—Ortho-condensed systems the condensed system containing two rings with oxygen as ring hetero atom and one ring with nitrogen as ring hetero atom
-
- 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
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/10—Aza-phenanthrenes
- C07D221/12—Phenanthridines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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 mainly relates to chemosynthesis technical fields, and in particular to phenanthridine derivatives, the i.e. compound of general formula I,Wherein R1、R2It is 1 or 2-OCH2O- ,-OCH3, H, by mtt assay measurement antitumor activity of compound, the DNA uncoiling experiment that topoisomerase I, II mediate, the compound of the present invention shows excellent antitumor activity, certain inhibiting effect is all had to topoisomerase I, II.
Description
Technical field
The invention mainly relates to chemosynthesis technical fields, and in particular to phenanthridine derivatives.
Background technology
Sanguinarine (sanguinarine) is a kind of important isoquinoline alkaloid, is widely present in natural plant
In, it can extract obtain from the plants such as snowpoppy, the wooden opium poppy, greater celandine, macleaya cordata at present.Because its parent nucleus-phenanthridines ring has
Larger aromatic conjugated system can interact with DNA, to make phenanthridines class compound have extraordinary bioactivity
And pharmaceutical activity.Sanguinarine is most added into toothpaste initially as a kind of antibacterial anti-inflammatory substance, can effectively reduce plaque and
The generation of gingivitis, in terms of being applied to animal health later, such as long-term anti-trypanosomiasis medicine-Samorin, it can pass through suppression
The DNA and RNA polymerase of trypanosome processed, and effectively hinder the synthesis of nucleic acid.In recent years mainly for the antitumor work of sanguinarine
Property conduct in-depth research, it is found that sanguinarine can influence when cellular replication topoisomerase in core with arresting cell cycle
Content, blocks tumor cells proliferation, inducing apoptosis of tumour cell.Therefore, it is intended that by the structure of modification to sanguinarine, hair
The strong compound of existing high-efficiency low-toxicity, druggability.
Invention content
The technical problem to be solved by the present invention is to：By to sanguinarine structure of modification with modification, synthesize high-efficiency low-toxicity,
The strong compound of druggability.
A series of phenanthridine derivatives of transformation provided by the present invention by sanguinarine structure and modification synthesis, such as formula
I compound,
Wherein, R1、R2It is 1 or 2-OCH2O- ,-OCH3, H.
The compound is selected from：
The preparation method of above compound, synthetic route are as follows：
Wherein R, R1、R2It is 1 or 2-OCH2O- ,-OCH3, H；
Include the following steps：
(1) it is reacted first with N- bromo-succinimides by aminated compounds and generates a series of bromophenyl amine chemical combination
Object；
(2) after, bromophenyl aminated compounds is with phenyl boric acid at 80 DEG C with PdCl2(PPh3)2As catalyst, pass through
Suzuki coupling reactions generate 2- diphenyl amine compounds, and 2- diphenyl amines compound is under the action of formic acid by primary amine methyl
Change, is then dehydrated under the action of phosphorus oxychloride and triethylamine, ultimately generates a series of 2- isonitrile base biphenyl compounds；
(3) then, 2- isonitrile base biphenyl compound can occur certainly under benzoyl peroxide initiation with carbon tetrachloride
By base addition reaction and intramolecular cyclization reaction, phenanthridines class compound is successfully obtained.
The bromophenyl aminated compounds is selected from A1~A5 compounds represented：
The 2- isonitrile base biphenyl compound is selected from B1~B20 compounds represented：
Compound shown in above-mentioned C1~C14 is expected to become the antitumoral compounds with Development volue.
As antitumoral compounds, the present invention provides the screening active ingredients of compound antitumor effect shown in C1~C14.
The present invention uses mtt assay first, is carried out with 5 μm of compounds of concentration pair 14 of ol/L and 1 μm of ol/L two antitumor
Screening active ingredients find that compound C1, C2, C5, C13 are equal to MCF-7, PC3, Hela tumour cell in 5 μm of ol/L and 1 μm of ol/L
With higher inhibiting rate, therefore the present invention chooses compound tetra- preferable compounds of activity of C1, C2, C5, C13 and continues
IC50Value measures, and finds IC of this 4 compounds of C1, C2, C5, C13 to MCF-7, PC3, Hela, A549, HepG2 cell50Value
Respectively less than sanguinarine is less than Etoposide.
Then, the present invention is whether verification phenanthridines class compound acts on topoisomerase, and spiral shell is solved using pBR 322DNA
Inhibiting effect of measuring phenanthridines class compound C1, C2, C5, the C13 to topoisomerase I/II is revolved, discovery C1 is topoisomerase
I/II double inhibitors of enzyme, C2, C5, C13 are topoisomerase II inhibitor.
Description of the drawings
Fig. 1 is bromophenyl amine compound synthesis route map；
Fig. 2 is the synthetic route chart of 2- isonitrile base biphenyl compounds；
Fig. 3 is the synthetic route chart of phenanthridines class compound；
Fig. 4 is that C1, C2, C5, C13 inhibit topoisomerase I activity figure in vitro；
Fig. 5 is that C1, C2, C5, C13 inhibit type Ⅱ topoisomerase activity figure in vitro.
Specific implementation mode
In order to make the purpose , technical scheme and advantage of the present invention be clearer, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not used to
Limit the present invention.
Embodiment 1：Prepare bromophenyl aminated compounds
It is prepared according to attached synthetic route chart shown in FIG. 1.
Operating procedure is as follows：Under condition of ice bath, aminated compounds is dissolved with isopropanol, di-tert-butyl dicarbonate is added dropwise,
After dripping off, 2h is reacted at room temperature, thin-layer chromatography detection stops reaction, filtered, filter cake is put in air dry oven after the reaction was complete
40 DEG C are dried overnight, and above-mentioned dried product is dissolved with acetonitrile, N- bromo-succinimides are slowly added dropwise, is continued after dripping off
To thin-layer chromatography detection, the reaction was complete for heat preservation, is filtered again after stopping reaction, filter cake is dissolved with dichloromethane, ice bath (0-5
DEG C) trifluoroacetic acid is added dropwise, subsequent continuation of insurance temperature is dripped off to the reaction was complete, finally adjusts pH to 8-9, dichloromethane with saturated sodium bicarbonate
Alkane layer is washed with saturated common salt, anhydrous Na2SO4Dry, rotation can be obtained product after being evaporated.
Embodiment 2：Prepare 2- isonitrile base biphenyl compounds
It is prepared according to attached synthetic route chart shown in Fig. 2.
Operating procedure is as follows：Under nitrogen protection, by adjacent amino benzenes compounds 1 (8mmol, 1.0eq), phenylboronic acid compound
2 (9.6mmol, 1.25eq), Anhydrous potassium carbonate (2eq), Isosorbide-5-Nitrae-dioxane：Water (V：V=20:1), catalyst PdCl2
(PPh3)2(0.1eq) is put into the 100mL single-necked flasks of drying, is warming up to 80 DEG C of back flow reaction 5h.It is anti-through thin-layer chromatography detection
Should be completely rear cool but to room temperature, ethyl acetate extraction concentration, column chromatography for separation (eluant, eluent n-hexane is added：Ethyl acetate=5:
1) 2- diphenyl amines compound 3, is obtained.Compound 3 is put into and is evaporated in flask, solvents tetrahydrofurane (50ml), formic acid is added
(16eq) is warming up to 85 DEG C, back flow reaction 5h, after the reaction was complete through TLC detections, is cooled to room temperature, rotates away solvent, be added
Anhydrous Na is added after being washed with saturation NaCl solution in ethyl acetate extraction concentration, organic phase2SO4Dry, silica gel post separation obtains chemical combination
Object 4.Compound 4 is added in two mouth flask, solvents tetrahydrofurane (5ml) is added, NEt is added after dissolving3(1.62ml), it is cold
But to POCl is slowly added dropwise after 0 DEG C3(0.28mL,11mmol).After reaction through thin-layer chromatography detection, with saturation Na2CO3It is molten
Liquid is quenched, and stirs 1h.Ethyl acetate extraction concentration, organic phase anhydrous Na is added2SO4Solvent, silica gel post separation are spin-dried for after drying
Obtain 2- isonitrile base biphenyl compounds.
2- isonitrile base biphenyl compound structured datas are characterized as below：
2- isonitrile -4,5,3 ', 4 '-two sub- methoxyl biphenyls (B1).White-yellowish solid；Yield：78%；Fusing point：154.4-
156.1℃。1H NMR (400MHz, CDCl3) δ 6.90 (d, J=8.9Hz, 4H), 6.78 (s, 1H), 6.05 (s, 2H), 6.01 (s,
2H)。
2- isonitrile -4,5- Asia methoxyl biphenyls (B2).Brown solid；Yield：80%；Fusing point：90.1-90.3℃.1H
NMR (400MHz, CDCl3) δ 7.54-7.30 (m, 5H), 6.91 (s, 1H), 6.82 (s, 1H), 6.05 (s, 2H).
2- isonitrile -4- methoxyl group -4,5- Asia methoxyl biphenyls (B3).White solid；Yield：81%；Fusing point：132-
133.1℃。1H NMR (400MHz, CDCl3) δ 7.39 (d, J=8.7Hz, 2H), 6.98 (d, J=8.7Hz, 2H), 6.90 (s,
1H), 6.80 (s, 1H), 6.05 (s, 2H), 3.85 (s, 3H).
2- isonitrile-the 2 '-Asias methoxyl group -4,5- methoxyl biphenyl (B4).White-yellowish solid；Yield：82%；Fusing point：
139.4-140.7℃。1H NMR (400MHz, CDCl3) δ 7.43-7.34 (m, 1H), 7.20 (dd, J=7.5,1.8Hz, 1H),
7.07-6.96 (m, 2H), 6.90 (s, 1H), 6.79 (s, 1H), 6.05 (s, 2H), 3.83 (s, 3H).
2- isonitrile -2 ', 4 '-dimethoxy-4 's, the Asias 5- methoxyl biphenyl (B5).Brown solid；Yield：79%；Fusing point：
161.4-161.9℃。1H NMR (400MHz, CDCl3) δ 7.10 (s, 1H), 6.88 (s, 1H), 6.77 (s, 1H), 6.56 (dt, J
=5.2,2.5Hz, 2H), 6.04 (s, 2H), 3.85 (s, 3H), 3.81 (s, 3H).
2- isonitrile-the 5- 4 '-methylene of methoxyl group -3 ' oxygroups (B6).White-yellowish solid；Yield：81%；Fusing point：119.6-
120.1℃。1H NMR (400MHz, DMSO) δ 7.58 (d, J=8.6Hz, 1H), 7.12 (d, J=1.7Hz, 1H), 7.09-6.95
(m, 4H), 6.10 (s, 2H), 3.84 (s, 3H).
2- isonitrile -5- methoxyl biphenyls (B7).Dark oil object；Yield：83%.1H NMR (400MHz, DMSO) δ 7.62
(d, J=8.7Hz, 1H), 7.58-7.42 (m, 5H), 7.08-6.99 (m, 2H), 3.85 (s, 3H).
2- isonitrile -3 ', 4 '-methylene oxygroups (B8).Green solid；Yield：85%；Fusing point：71.6-73.9℃.1H NMR
(400MHz, CDCl3) δ 6.02 (s, 2H), 7.02-6.94 (m, 2H), 6.94-6.87 (m, 1H), 7.46 (d, J=9.3Hz,
1H), 7.43-7.30 (m, 3H).
4 '-dimethoxy-biphenyl of 2- isonitrile -2 ' (B9).White-yellowish solid；Yield：79%；Fusing point：90.1-90.5℃.1H
NMR (400MHz, CDCl3) δ 7.41 (ddd, J=8.9,7.4,1.8Hz, 2H), 7.38-7.29 (m, 2H), 7.18-7.10 (m,
1H), 6.58 (dd, J=5.7,2.2Hz, 2H), 3.86 (s, 3H), 3.81 (s, 3H).
The 2- 4 '-trimethoxy of isonitrile -5,2 ' biphenyl (B10).Yellow solid；Yield：80%；Fusing point：104.6-104.9
℃。1H NMR (400MHz, CDCl3) δ 7.35 (d, J=8.4Hz, 1H), 7.14 (d, J=8.9Hz, 1H), 6.88-6.79 (m,
2H), 6.58 (dd, J=5.4,2.3Hz, 2H), 3.86 (s, 3H), 3.82 (s, 6H).
2- isonitrile -4- methoxyl groups -3 ' 4 '-Asia methoxyl biphenyl (B11).White-yellowish solid；Yield：75%；Fusing point：
120.6-120.9℃。1H NMR (400MHz, CDCl3) δ 7.28 (d, J=8.4Hz, 1H), 7.02-6.86 (m, 5H), 6.02 (s,
2H), 3.85 (s, 3H).
2- isonitrile -4- methoxyl biphenyls (B12).Yellow solid；Yield：78%；Fusing point：117.3-117.6℃.1H NMR
(400MHz, CDCl3) δ 7.53-7.43 (m, 4H), 7.43-7.36 (m, 1H), 7.33 (d, J=9.0Hz, 1H), 7.05-6.97
(m, 2H), 3.86 (s, 3H).
2- isonitrile -4,4 '-dimethoxy-biphenyl (B13).Tan solid；Yield：83%；Fusing point：102.4-102.8
℃。1H NMR (400MHz, CDCl3) δ 7.44-7.37 (m, 2H), 7.30 (d, J=9.0Hz, 1H), 6.99 (d, J=9.0Hz,
4H), 3.85 (d, J=4.0Hz, 6H).
2- isonitrile -4,2 '-methoxyl biphenyl (B14).White solid；Yield：82%；Fusing point：125.5-126℃.1H
NMR (400MHz, CDCl3) δ 7.48-7.34 (m, 1H), 7.33-7.17 (m, 2H), 7.08-6.94 (m, 4H), 3.84 (d, J=
5.4Hz,6H)。
2- isonitrile -4,2 ', 4 '-trimethoxy biphenyl (B15).White-yellowish solid；Yield：80%；Fusing point：105.9-
107.3℃。1H NMR (400MHz, CDCl3) δ 7.26 (d, J=1.7Hz, 1H), 7.12 (d, J=8.9Hz, 1H), 7.01-6.93
(m, 2H), 6.61-6.53 (m, 2H), 3.90-3.79 (m, 9H).
2- isonitrile -4,5- dimethoxys -3 ', 4 '-sub- methoxyl biphenyls (B16).Brown solid；Yield：84%；Fusing point：
171.7-172.3℃。1H NMR (400MHz, CDCl3) δ 6.99-6.86 (m, 4H), 6.80 (s, 1H), 6.02 (s, 2H), 3.91
(d, J=2.5Hz, 6H).
2- isonitrile -4,5- dimethoxy-biphenyls (B17).White-yellowish solid；Yield：82%；Fusing point：139.4-139.9℃
。1H NMR (400MHz, DMSO) δ 7.27 (s, 1H), 7.01 (s, 1H), 3.85 (d, J=3.7Hz, 5H), 7.58-7.47 (m,
3H), 7.47-7.39 (m, 1H).
2- isonitrile -4,5,4 '-trimethoxy biphenyl (B18).Tan solid；Yield：84%；Fusing point：102.7-103.7
℃。1H NMR (400MHz, CDCl3) δ 7.43 (d, J=8.7Hz, 2H), 7.00 (d, J=8.7Hz, 2H), 6.93 (s, 1H),
6.82 (s, 1H), 3.92 (d, J=1.5Hz, 6H), 3.86 (s, 3H).
2- isonitrile -4,4,2 '-trimethoxy biphenyl (B19).Yellow solid；Yield：83%；Fusing point：103-103.6℃.1H NMR (400MHz, CDCl3) δ 7.44-7.35 (m, 1H), 7.28-7.20 (m, 1H), 7.09-6.98 (m, 2H), 6.94 (s,
1H), 6.82 (s, 1H), 3.94-3.82 (m, 9H).
2- isonitrile -4,5,2 ', 4 '-tetramethoxy biphenyl (B20).White-yellowish solid；Yield：82%；Fusing point：123.4-
123.9℃。1H NMR (400MHz, CDCl3) δ 7.15 (d, J=8.9Hz, 1H), 6.92 (s, 1H), 6.79 (s, 1H), 6.57
(dq, J=4.2,2.4Hz, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 3.86 (s, 3H), 3.82 (s, 3H).
From the foregoing, it will be observed that 2- isonitrile base biphenyl compound structures are correct.
Embodiment 3：Prepare phenanthridines class compound
It is prepared according to attached synthetic route chart shown in Fig. 3.
Operating procedure is as follows：2- isonitrile biphenyl compound (0.50mol) is added in single-necked flask, peroxidating is added
Benzoyl (1.2eq), AcONa (2eq) and CCl4, nitrogen replace 3 times after be warming up to 80 DEG C, back flow reaction 12h.Thin-layer chromatography
Detection stops reaction and ethyl acetate extraction, saturated sodium bicarbonate washing, ethyl acetate layer anhydrous slufuric acid is added after the reaction was complete
Revolving mixes sample after sodium drying, and column chromatography for separation obtains product.
Phenanthridines class compound structure data characterization is as follows：
Bis- methylene oxygroup -6- trichloromethyls phenanthridines (C1) of 2,3,8,9-.Yellow solid；Yield：40%；Fusing point：198.7-
199.6℃。1H NMR (400MHz, CDCl3) δ 8.23 (s, 1H), 7.77 (s, 1H), 7.67 (s, 1H), 7.53 (s, 1H), 6.18
(d, J=8.5Hz, 4H)13C NMR (101MHz, DMSO) δ 151.43,150.27,149.97,149.09,148.77,
147.57,133.32,129.68,128.98,115.89,107.21,104.01,103.18,102.90,101.57,
100.33.HRMS (ESI) calculated value C16H9Cl3NO4 +([M+H]+) 383.9597, experiment value 383.9592.
Bis- methylene oxygroup -6- trichloromethyls phenanthridines (C2) of 2,3-.Faint yellow solid；Yield：39%；Fusing point：175.4-
176.5℃。1H NMR (400MHz, CDCl3) δ 8.92 (d, J=8.4Hz, 1H), 8.49 (d, J=8.2Hz, 1H), 7.91-7.78
(m, 2H), 7.68 (t, J=7.6Hz, 1H), 7.60 (s, 1H), 6.19 (s, 2H)13C NMR (101MHz, DMSO) δ 150.59,
150.37,150.29,137.46,134.81,131.31,127.60,127.04,124.18,121.88,119.36,107.77,
103.08,100.50.HRMS (ESI) calculated value C15H9Cl3NO2 +([M+H]+) 339.9699, experiment value 339.9696.
8- methoxyl group -2,3- methylene oxygroup -6- trichloromethyls phenanthridines (C3).Brown solid；Yield：41%；Fusing point：
93.8-95.0℃。1H NMR (400MHz, CDCl3) δ 8.12-8.05 (m, 8H), 7.80 (s, 1H), 7.67 (t, J=7.5Hz,
4H), 6.17 (s, 2H), 4.01 (s, 3H)13C NMR (101MHz, DMSO) δ 167.67,163.08,162.77,135.60,
134.08,133.34,131.07,130.82,129.93,129.87,129.78,129.70,129.31,129.01,128.45,
124.97.HRMS (ESI) calculated value C16H11Cl3NO3 +([M+H]+) 369.9805, experiment value 369.9804.
10- methoxyl group -2,3- methylene oxygroup -6- trichloromethyls phenanthridines (C4).Yellow solid；Yield：38%；Fusing point：
219.7-222.3℃。1H NMR (400MHz, DMSO) δ 7.95 (d, J=6.3Hz, 1H), 7.81 (t, J=8.3Hz, 1H),
7.59 (d, J=3.6Hz, 2H), 7.31 (t, J=7.8Hz, 1H), 6.32 (s, 2H), 3.69 (s, 3H) .HRMS (ESI) calculated values
C16H11Cl3NO3 +([M+H]+) 369.9805, experiment value 369.9804.
2- methoxyl group -6- trichloromethyls phenanthridines (C5).White-yellowish solid；Yield：37%；Fusing point：119-120.9℃.1H
NMR (400MHz, CDCl3) δ 8.96 (d, J=8.2Hz, 1H), 8.65 (d, J=8.4Hz, 1H), 8.19 (d, J=9.0Hz,
1H), 7.94-7.83 (m, 2H), 7.80-7.71 (m, 1H), 7.42 (dd, J=9.0,2.7Hz, 1H), 4.05 (s, 3H)；13C
NMR (101MHz, DMSO) δ 160.62,149.93,135.31,134.27,132.51,131.38,128.05,127.82,
126.70,124.59,120.53,120.27,104.00,98.71,56.46.HRMS (ESI) calculated value C15H11Cl3NO+([M+
H]+) 325.9906, experiment value 325.9901.
3- methoxyl group -8,9- methylene oxygroup -6- trichloromethyls phenanthridines (C6).Brown solid；Yield：32%；Fusing point：
197.5-197.8℃。1H NMR (400MHz, CDCl3) δ 8.36-8.19 (m, 2H), 7.91 (s, 1H), 7.59 (d, J=2.7Hz,
1H), 7.35 (dd, J=9.1,2.7Hz, 1H), 6.20 (s, 2H), 4.00 (s, 3H)13C NMR (101MHz, DMSO) δ
160.32,151.87,141.76,133.80,124.77,120.86,119.65,115.39,109.96,108.77,104.45,
103.88,103.25,101.29,100.64,56.08.HRMS (ESI) calculated value C16H11Cl3NO3 +([M+H]+) 369.9805,
Experiment value 369.9798.
3- methoxyl group -6- trichloromethyls phenanthridines (C7).Yellow solid；Yield：26%；Fusing point：175.1-175.3℃.1H
NMR (400MHz, CDCl3) δ 8.93 (d, J=8.7Hz, 1H), 8.62 (d, J=8.4Hz, 1H), 8.48 (d, J=9.1Hz,
1H), 7.90-7.81 (m, 1H), 7.72-7.63 (m, 2H), 7.44-7.36 (m, 1H), 4.02 (s, 3H)13C NMR (101MHz,
DMSO) 160.81 δ, 152.92,142.01,135.11,131.94,127.91,126.82,124.58,123.65,120.95,
119.09,119.06,110.67,98.60,56.13.HRMS (ESI) calculated value C15H11Cl3NO+([M+H]+) 325.9906, it is real
Test value 325.9899.
3,8- dimethoxy -6- trichloromethyls phenanthridines (C8).Yellow solid；Yield：40%；Fusing point：146.7-147.2
℃.1H NMR (400MHz, CDCl3) δ 8.52 (d, J=9.2Hz, 1H), 8.39 (d, J=9.1Hz, 1H), 8.28 (d, J=
2.6Hz, 1H), 7.63 (d, J=2.7Hz, 1H), 7.50 (dd, J=9.2,2.6Hz, 1H), 7.38 (dd, J=9.1,2.7Hz,
1H), 4.01 (d, J=2.4Hz, 6H)13C NMR (101MHz, DMSO) δ 160.06,157.07,151.84,141.12,
129.60,125.46,124.08,122.20,121.18,120.32,119.35,110.40,108.81,56.07,
55.91.HRMS (ESI) calculated value C16H13Cl3NO2 +([M+H]+) 356.0012, experiment value 356.0009.
3,10- dimethoxy -6- trichloromethyls phenanthridines (C9).Yellow solid；Yield：37%；Fusing point：149.9-150.9
℃。1H NMR (400MHz, CDCl3) δ 9.46 (d, J=9.5Hz, 1H), 8.60 (d, J=8.5Hz, 1H), 7.72-7.56 (m,
2H), 7.41-7.29 (m, 2H), 4.16 (s, 3H), 4.02 (s, 3H)13C NMR (101MHz, DMSO) δ 159.78,157.90,
152.59,142.64,129.33,127.12,125.28,120.88,120.27,120.03,118.54,113.19,110.92,
56.63,55.97.HRMS (ESI) calculated value C16H13Cl3NO2 +([M+H]+) 356.0012, experiment value 356.0009.
3,8,10- trimethoxy -6- trichloromethyls phenanthridines (C10).Yellow solid；Yield：35%；Fusing point：97-97.3
℃。1H NMR (400MHz, CDCl3) δ 7.98 (d, J=2.3Hz, 1H), 7.70-7.60 (m, 3H), 7.35 (dd, J=9.5,
2.9Hz, 1H), 4.12 (s, 3H), 4.01 (d, J=2.9Hz, 6H)13C NMR (101MHz, DMSO) δ 162.77,159.25,
159.09,157.44,135.58,130.82,129.78,129.00,128.38,120.61,120.42,110.71,103.67,
101.47,56.84,55.95,55.92.HRMS (ESI) calculated value C17H15Cl3NO3 +([M+H]+) 386.0118, experiment value
386.0112。
2- methoxyl group -6- trichloromethyls phenanthridines (C11).Faint yellow solid；Yield：32%；Fusing point：164.4-165℃.1H
NMR (400MHz, CDCl3) δ 8.43-8.36 (m, 1H), 8.30 (s, 1H), 8.27-8.20 (m, 1H), 8.02 (s, 1H), 7.73
(tt, J=7.1,5.3Hz, 2H), 6.24 (d, J=16.4Hz, 2H)13C NMR (101MHz, DMSO) δ 151.82,151.22,
148.15,140.03,133.36,130.68,129.57,125.30,123.39,118.56,116.49,114.73,104.69,
103.41,101.84.HRMS (ESI) calculated value C15H9Cl3NO2 +([M+H]+) 339.9699, experiment value 339.9697.
2,3- dimethoxy -6- trichloromethyls phenanthridines (C12).Yellow solid；Yield：43%；Fusing point：174.5-176.1
℃。1H NMR (400MHz, CDCl3) δ 8.95 (d, J=8.6Hz, 1H), 8.58 (d, J=8.4Hz, 1H), 8.16-8.08 (m,
4H), 7.86 (s, 2H), 7.74-7.58 (m, 4H), 7.49 (t, J=7.8Hz, 4H), 4.16 (s, 3H), 4.11 (s, 3H)13C
NMR (101MHz, DMSO) δ 167.75,151.93,151.86,133.29,131.16,129.69,128.99,127.70,
126.77,124.17,119.98,119.33,110.56,102.99,56.68,56.30.HRMS (ESI) calculated values
C16H13Cl3NO2 +([M+H]+) 356.0012, experiment value 356.0010.
2,3,8- trimethoxy -6- trichloromethyls phenanthridines (C13).Yellow solid；Yield：39%；Fusing point：125.5-
126.9℃。1H NMR (400MHz, CDCl3) δ 8.48 (d, J=9.1Hz, 1H), 8.29 (d, J=2.5Hz, 1H), 7.77 (s,
1H), 7.62 (s, 1H), 7.50 (dd, J=9.2,2.6Hz, 1H), 4.14 (s, 3H), 4.09 (s, 3H), 4.02 (s, 3H)13C
NMR (101MHz, DMSO) δ 157.06,152.00,151.26,149.05,135.36,129.09,128.95,126.01,
121.63,120.63,120.29,110.36,108.35,102.47,56.64,56.23,55.89.HRMS (ESI) calculated values
C17H15Cl3NO3 +([M+H]+) 386.0118, experiment value 386.0115.
8,10- dimethoxy -6- trichloromethyls phenanthridines (C14).Yellow solid；Yield：39%；Fusing point：161.3-162
℃。1H NMR (400MHz, CDCl3) δ 9.45-9.38 (m, 1H), 8.28-8.21 (m, 1H), 8.01 (d, J=2.3Hz, 1H),
7.71 (dd, J=6.5,3.5Hz, 2H), 7.00 (d, J=2.4Hz, 1H), 4.13 (s, 3H), 4.02 (s, 3H)13C NMR
(101MHz, DMSO) δ 160.02,158.37,151.25,139.93,130.95,130.05,128.51,127.15,124.74,
122.76,119.71,103.62,101.98,99.01,56.93,56.04.HRMS (ESI) calculated value C16H13Cl3NO2 +([M+
H]+) 356.0012, experiment value 356.0007.
From the foregoing, it will be observed that phenanthridines class compound structure is correct.
Embodiment 4：Mtt assay measures antitumor activity of compound
Operating procedure is as follows：
Using sanguinarine hydrate, Etoposide as positive control, using PC3 (prostate gland cancer cell), Hela (uterine neck
Cancer cell), three kinds of tumour cells of MCF-7 (breast cancer), 5 μm of ol/L and 1 μm of ol/L, two concentration carry out screening active ingredients.
(1) after superclean bench ultraviolet irradiation 30min, ultraviolet lamp is closed, opens headlamp and wind turbine.
(2) old culture medium is abandoned, phosphate buffered saline solution is added and cleans 2-3 times, pancreatin is added, under attached cell is digested
Come, add the culture medium containing 10% fetal calf serum and terminate digestion, collects cell, 900rmp/min centrifuges 5min, before abandoning
Culture medium is added new culture medium and is resuspended.
(3) cell count adjusts cell to 5000/hole.
(4) cell is reached in 96 orifice plates, per 100 μ l of hole, is then placed in CO2In constant incubator.
(5) compound of 100 μ l various concentrations, 3 multiple holes of each concentration are added after cell is adherent, and 100 μ are added in apertured
L culture mediums are as blank control.
(6) after cultivating 48h, 20 μ l MTT are added per hole.
(7) after cultivating 4h, plate is directly thrown, 200 μ l dimethyl sulfoxide (DMSO)s are added per hole and are surveyed using microplate reader fully after dissolving
Determine absorbance at 490nm, 630nm, which is used as, refers to wavelength.
Compound absorbance value=compound 490nm absorbance value -630nm absorbance values
Inhibiting rate (%)=(1- compounds absorbance value average value/blank group absorbance value average value) × 100%
The results are shown in table below, and phenanthridines class compound C1, C2, C5, C13 is to tri- kinds of tumour cells of PC3, Hela, MCF-7
Cell proliferation inhibition rate is preferable.
Note：Data result deviation is less than 20%.
Embodiment 5：Phenanthridines IC50Value detection
The present invention filters out active preferable compound and carries out IC50It measures.It sets the concentration gradient of phenanthridines to
20,5,1.25,0.31,0.078 μm of ol/L (4 times of dilutions) are now with the current.Experiment uses PC3, Hela, MCF-7, HepG2 (liver
Cancer cell), five kinds of tumour cells of A549 (lung carcinoma cell), operating procedure is as described in Example 4.
As a result shown in following table, this 4 compounds of C1, C2, C5, C13 are to MCF-7, PC3, Hela, A549, HepG2 cell
IC50Value is respectively less than sanguinarine, is less than Etoposide.
Note：IC50Unit be μm ol/L.
Embodiment 6：The DNA uncoiling experiment that topoisomerase I mediates
Operating procedure is as follows：
(1) electrophoresis tank is installed, a large amount of buffer solutions (1 × TAE) are prepared.
(2) the accurate agarose dry powder 0.24g that weighs is put into the conical flask for containing 30mL buffer solutions, and boiling water bath is heated to agar
Sugar melts, and the Ago-Gel solution for pouring warm enters mold, is configured to 0.8% Ago-Gel.
(3) 10 μ l water, 2 μ l 10 × DNA topoisomerase I buffer solutions, 2 μ l are added into the centrifuge tube of 1.5mL successively
0.1%BSA, topoisomerase I 1U, DNA 0.25 μ g, different 1 μ l of drug, constant volume to 20 μ l.
(4) centrifuge tube is put into 37 DEG C of hatching 30min in water-bath.
(5) it is added in 3.5 μ l 6 × sample-loading buffers to centrifuge tube.
(5) 85V electrophoresis 40-50min, with Genecolour I type TM nucleic acid staining dye 20-40min, gel imaging system
Overall view examines electrophoresis result.
Experimental result is as shown in Fig. 4, the results showed that C1 has certain inhibiting effect to topoisomerase I.
Embodiment 7：The DNA uncoiling experiment that type Ⅱ topoisomerase mediates
Operating procedure is as follows：
(1) 10 × type Ⅱ topoisomerase buffer solution A, in 0 DEG C of mixed in equal amounts, is made with 10 × type Ⅱ topoisomerase buffer solution B
5 × cocktail buffer.
(2) Ago-Gel of 1 × TAE buffer solutions configuration 0.8% is used.
(3) it is added 5 μ l water into the centrifuge tube of 1.5mL successively, 2 μ 5 × cocktail buffers of l, type Ⅱ topoisomerase 2U,
DNA 0.125 μ g, different 0.5 μ l of drug, constant volume to 10 μ l.
(3) centrifuge tube is put into 37 DEG C of hatching 30min in water-bath.
(4) it is added in 2 μ l 6 × sample-loading buffers to centrifuge tube.
(5) 85V electrophoresis 40-50min, with Genecolour I type TM nucleic acid staining dye 20-40min, gel imaging system
Overall view examines electrophoresis result.
Experimental result is as shown in Fig. 5, the results showed that C1, C2, C5, C13 all have type Ⅱ topoisomerase certain suppression
It makes and uses.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all essences in the present invention
All any modification, equivalent and improvement etc., should all be included in the protection scope of the present invention made by within refreshing and principle.
Claims (10)
1. the compound of formula I,
Wherein, R1、R2It is 1 or 2-OCH2O- ,-OCH3, H.
2. the compound of formula I according to claim 1, the compound are selected from：
3. type I compound as claimed in claim 1 or 2, which is characterized in that the compound is C1：Bis- methylene oxygen of 2,3,8,9-
Base -6- trichloromethyl phenanthridines.
4. type I compound as claimed in claim 1 or 2, which is characterized in that the compound is C2：Bis- methylene oxygroup -6- of 2,3-
Trichloromethyl phenanthridines.
5. type I compound as claimed in claim 1 or 2, which is characterized in that the compound is C5：Three chloromethanes of 2- methoxyl groups -6-
Base phenanthridines.
6. type I compound as claimed in claim 1 or 2, which is characterized in that the compound is C13：2,3,8- trimethoxies-
6- trichloromethyl phenanthridines.
7. purposes of the type I compound as claimed in claim 1 or 2 in antitumor drug.
8. the preparation method of the compound of formula I as claimed in claim 1 or 2, which is characterized in that synthetic route is as follows：
Wherein R, R1、R2It is 1 or 2-OCH2O- ,-OCH3, H；
Include the following steps：
(1) it is reacted first with N- bromo-succinimides by aminated compounds and generates a series of bromophenyl aminated compounds；
(2) after, bromophenyl aminated compounds is with phenyl boric acid at 80 DEG C with PdCl2(PPh3)2As catalyst, pass through
Suzuki coupling reactions generate 2- diphenyl amine compounds, and 2- diphenyl amines compound is under the action of formic acid by primary amine methyl
Change, is then dehydrated under the action of phosphorus oxychloride and triethylamine, ultimately generates a series of 2- isonitrile base biphenyl compounds；
(3) then, under benzoyl peroxide initiation with carbon tetrachloride free radical can occur for 2- isonitrile base biphenyl compound
Addition reaction and intramolecular cyclization reaction successfully obtain phenanthridines class compound.
9. the preparation method of the compound of formula I according to any one of claims 8, which is characterized in that the bromophenyl aminated compounds choosing
From A1~A5 compounds represented：
10. the preparation method of the compound of formula I according to any one of claims 8, which is characterized in that the different cyanobiphenyls class chemical combination of 2-
Object is selected from B1~B20 compounds represented：
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111620818A (en) * | 2019-02-28 | 2020-09-04 | 暨南大学 | 8, 9-dimethoxyphenanthridine compound and application thereof |
| CN111732541A (en) * | 2020-07-07 | 2020-10-02 | 四川大学 | Novel method for efficiently synthesizing 6-alkenyl phenanthridine derivative through ruthenium-catalyzed C-H activation/cyclization reaction |
| CN115260097A (en) * | 2022-08-09 | 2022-11-01 | 兰州大学 | 5-methylphenanthridine compound and application thereof in preparing drug or probe for reducing or detecting thioredoxin reductase level |
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| CN104592290A (en) * | 2015-01-23 | 2015-05-06 | 上海大学 | Phenanthridine derivatives and synthetic methods thereof |
| CN105859620A (en) * | 2016-05-05 | 2016-08-17 | 大连理工大学 | 6-trichloromethyl phenanthridine compound and preparation method and application thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111620818A (en) * | 2019-02-28 | 2020-09-04 | 暨南大学 | 8, 9-dimethoxyphenanthridine compound and application thereof |
| CN111620818B (en) * | 2019-02-28 | 2023-09-29 | 暨南大学 | 8, 9-dimethoxy-kephaline compound and application thereof |
| CN111732541A (en) * | 2020-07-07 | 2020-10-02 | 四川大学 | Novel method for efficiently synthesizing 6-alkenyl phenanthridine derivative through ruthenium-catalyzed C-H activation/cyclization reaction |
| CN111732541B (en) * | 2020-07-07 | 2022-11-01 | 四川大学 | Method for efficiently synthesizing 6-alkenyl phenanthridine derivative through ruthenium-catalyzed C-H activation/cyclization reaction |
| CN115260097A (en) * | 2022-08-09 | 2022-11-01 | 兰州大学 | 5-methylphenanthridine compound and application thereof in preparing drug or probe for reducing or detecting thioredoxin reductase level |
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