CN111943948A - Beta-carboline indolium salt and preparation method and application thereof - Google Patents
Beta-carboline indolium salt and preparation method and application thereof Download PDFInfo
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- CN111943948A CN111943948A CN202010765769.8A CN202010765769A CN111943948A CN 111943948 A CN111943948 A CN 111943948A CN 202010765769 A CN202010765769 A CN 202010765769A CN 111943948 A CN111943948 A CN 111943948A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 48
- HGQIRDQCVJKSEI-UHFFFAOYSA-N C1=CC=C2NC=CC2=C1.N1=CC=C2C3=CC=CC=C3NC2=C1 Chemical compound C1=CC=C2NC=CC2=C1.N1=CC=C2C3=CC=CC=C3NC2=C1 HGQIRDQCVJKSEI-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 17
- 230000002438 mitochondrial effect Effects 0.000 claims abstract description 13
- 230000008685 targeting Effects 0.000 claims abstract description 13
- 238000000799 fluorescence microscopy Methods 0.000 claims abstract description 12
- 230000002378 acidificating effect Effects 0.000 claims abstract description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims abstract description 5
- OLNJUISKUQQNIM-UHFFFAOYSA-N indole-3-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CNC2=C1 OLNJUISKUQQNIM-UHFFFAOYSA-N 0.000 claims description 43
- -1 methoxy-substituted phenyl Chemical group 0.000 claims description 35
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 23
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 21
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 19
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 18
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 claims description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000006412 propinylene group Chemical group [H]C#CC([H])([H])* 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
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- 238000010438 heat treatment Methods 0.000 abstract description 2
- FAQVDANXTSFXGA-UHFFFAOYSA-N 2,3-dihydro-1h-benzo[g]indole Chemical class C1=CC=CC2=C(NCC3)C3=CC=C21 FAQVDANXTSFXGA-UHFFFAOYSA-N 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 152
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 122
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 106
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 106
- 229920002554 vinyl polymer Polymers 0.000 description 78
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 37
- 238000005160 1H NMR spectroscopy Methods 0.000 description 36
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 36
- 239000007787 solid Substances 0.000 description 36
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 28
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- 229910052740 iodine Inorganic materials 0.000 description 14
- 239000011630 iodine Substances 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 238000001308 synthesis method Methods 0.000 description 14
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 13
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 12
- 238000006467 substitution reaction Methods 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 238000002189 fluorescence spectrum Methods 0.000 description 8
- 238000012360 testing method Methods 0.000 description 7
- RUVJFMSQTCEAAB-UHFFFAOYSA-M 2-[3-[5,6-dichloro-1,3-bis[[4-(chloromethyl)phenyl]methyl]benzimidazol-2-ylidene]prop-1-enyl]-3-methyl-1,3-benzoxazol-3-ium;chloride Chemical compound [Cl-].O1C2=CC=CC=C2[N+](C)=C1C=CC=C(N(C1=CC(Cl)=C(Cl)C=C11)CC=2C=CC(CCl)=CC=2)N1CC1=CC=C(CCl)C=C1 RUVJFMSQTCEAAB-UHFFFAOYSA-M 0.000 description 5
- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical class N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 description 5
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- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 2
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- 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
- 238000012795 verification Methods 0.000 description 2
- CRUILBNAQILVHZ-UHFFFAOYSA-N 1,2,3-trimethoxybenzene Chemical compound COC1=CC=CC(OC)=C1OC CRUILBNAQILVHZ-UHFFFAOYSA-N 0.000 description 1
- SPKSAZPYFRKZLM-UHFFFAOYSA-N 1,9-dimethyl-6-nitropyrido[3,4-b]indole-3-carbaldehyde Chemical group CC1=NC(=CC2=C1N(C3=C2C=C(C=C3)[N+](=O)[O-])C)C=O SPKSAZPYFRKZLM-UHFFFAOYSA-N 0.000 description 1
- XFZZDIHCNHYESF-UHFFFAOYSA-N 7-amino-1-bromo-4-phenyl-5,7,8,9-tetrahydrobenzo[7]annulen-6-one Chemical compound C=12CC(=O)C(N)CCC2=C(Br)C=CC=1C1=CC=CC=C1 XFZZDIHCNHYESF-UHFFFAOYSA-N 0.000 description 1
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- RERZNCLIYCABFS-UHFFFAOYSA-N harmaline Chemical compound C1CN=C(C)C2=C1C1=CC=C(OC)C=C1N2 RERZNCLIYCABFS-UHFFFAOYSA-N 0.000 description 1
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- 125000006203 morpholinoethyl group Chemical group [H]C([H])(*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
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Abstract
The invention belongs to the field of biomedicine, and discloses a beta-carboline indolium salt and a preparation method and application thereof. The beta-carboline indolium salt provided by the invention has the characteristics of mitochondrion targeting and pH sensitive fluorescence imaging, and has the structures shown in general formulas I and II:
the beta-carboline indolium salt provided by the invention is prepared from 9-R1‑6‑R4‑1‑R2-9H-pyrido [3,4-b]Indole-3-formaldehyde and indolium salt or benzindolinium salt are subjected to aldol condensation reaction under the heating condition, and the beta-carboline indolium salt can be promoted under the tumor acidic microenvironmentThe fluorescence of the salt is released in tumor tissues, which is beneficial to the in vitro and in vivo fluorescence imaging of tumors through pH response and/or mitochondrial targeting, and further has important significance for the diagnosis and treatment of cancer cells.
Description
Technical Field
The invention relates to the field of biomedicine, in particular to beta-carboline indolium salts, a preparation method and application thereof, and specifically relates to beta-carboline indolium salts with mitochondrion targeting and pH sensitive fluorescence imaging, a preparation method thereof, and medical application of in vivo and in vitro fluorescence imaging through pH response and/or mitochondrion targeting, especially application in preparation of tumor diagnostic agents.
Background
Mitochondria, an organelle of a double-layered membrane structure present in most cells, is generally considered as the energy factory of the cell, and is the main site for aerobic respiration of the cell, producing most of the cellular energy in the form of Adenosine Triphosphate (ATP). In current studies, mitochondrial dysfunction and metabolic disorders are associated with many diseases. Studies have shown that mitochondrial defects or dysfunction are associated with cancer, inflammatory injury, or cardiovascular disease and are therefore considered to be one of the most important targets in the novel drug design for cancer, inflammation, and cardiovascular disease.
Mitochondrial targeting of lipophilic cations is based primarily on the difference in transmembrane potentials on both the inner and outer membranes of the mitochondria. Tumor cells have higher mitochondrial membrane potential than normal cells due to mitochondrial dysfunction, so that lipophilic cations are more selective for tumor cells, and positively charged compounds can accumulate in the mitochondrial matrix according to a concentration gradient. The most effective method of delivering drugs specifically to the mitochondria is therefore by covalently attaching lipophilic cations (e.g., triphenylphosphine) to the pharmacophore of interest. Mitochondrial targeting has been developed for studying mitochondrial physiology and dysfunction and the interaction between mitochondria and other subcellular organelles, and for treating various malignant diseases.
The development of stimulus-responsive small-molecule fluorescent compounds, particularly the development of pH-responsive small-molecule fluorescent compounds, has prompted the development of the field of tumor imaging. The research shows that the extracellular pH of normal tissue is between 7.2 and 7.4 under the physiological state, while the extracellular pH of malignant tissue is between 5.0 and 6.5, which indicates that the microenvironment of tumor cells is generally acidified. In mitochondria, when oxidation and antioxidation are imbalanced, hypoxia is severe, which results in anaerobic glycolysis producing large amounts of lactic acid, thereby inducing intracellular acidic microenvironment.
The small molecular fluorescent probe is a powerful tool in a detection and imaging biological system due to the characteristics of higher sensitivity, nondestructive rapid analysis and real-time detection. According to the acidic microenvironment of cancer cells, a theoretical basis is provided for developing new and more selective anticancer drugs. Therefore, the research and development of the small molecular fluorescent probe of the beta-carboline indole onium salt can carry out in-vivo fluorescence and photoacoustic imaging on tumor tissues through pH stimulation response, and has important medical application prospect.
Disclosure of Invention
In view of the above, the invention provides a beta-carboline indolium salt, a preparation method and an application thereof, wherein the beta-carboline indolium salt has the functions of pH sensitive fluorescence imaging, mitochondrial targeting and the like, and can be applied to mitochondrial targeting and/or pH sensitive fluorescence imaging.
The specific technical scheme of the invention is as follows:
beta-carboline indolium salts of the general structures shown in formula I and formula II:
wherein R is1Represents one of H, C1-C6 alkyl, alkynyl-substituted C1-C6 alkyl, halogenated C1-C6 alkyl, methoxy-substituted C1-C6 alkyl and morpholine-substituted C1-C6 alkyl; r2Represents one of H, C1-C6 alkyl and methoxy-substituted phenyl; r3Represents one of C1-C6 alkyl, alkynyl-substituted C1-C6 alkyl and halogenated C1-C6 alkyl; y is-Represents one of a halogen anion, a hexafluorophosphate anion, a sulfonic acid anion and a methanesulfonic acid anion; r4Represents one of H, amino and nitro.
Further, in the general structures shown in formula I and formula II, R1Representation H, CH3、CH2CH3And N-ethylmorpholine; r2Representation H, CH3、C(CH3)3、CH2CH(CH3)3One of 4-methoxyphenyl and 3,4, 5-trimethoxyphenyl; r3Represents CH3、CH2CH3One of propargyl and propargyl.
Further, the preferred structure of the beta-carboline indolium salt is shown in table 1:
table 1 partial compound symbols of formulae i and ii and their corresponding structures
I1: (E) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-indol-1-iodo salt;
I2: (E) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -3, 3-dimethyl-1- (prop-2-yn-1-yl) -3H-indol-1-bromo salt
I3: (E) -2- (2- (9-ethyl-1-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-indole-1-hexafluorophosphate;
I4: (E) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -3, 3-dimethyl-1- (but-3-yn-1-yl) -3H-indole-1-methanesulfonate
I5: (E) -2- (2- (1- (1- (tert-butyl) -9-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -1,3, 3-trimethyl-3H-indol-1-iodo salt
I6: (E) -2- (2- (1- (1- (isobutyl) -9-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -1,3, 3-trimethyl-3H-indol-1-iodo salt
I7: (E) -1,3, 3-trimethyl-2- (2- (9-methyl-1- (3,4, 5-trimethoxyphenyl) -9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -3H-indol-1-iodonium salts
I8: (E) -1,3, 3-trimethyl-2- (2- (1-methyl-9- (2-morpholinoethyl) -9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -3H-indol-1-iodonium salts;
I9: (E) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-benzo [ g]Indole-1-iodonium salts;
I10: (E) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -3, 3-dimethyl-1- (prop-2-yn-1-yl) -3H-benzo [ g]Indole-1-bromo salts
I11: (E) -2- (2- (9-ethyl-1-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-benzo [ g]Indole-1-hexafluorophosphate;
I12: (E) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -3, 3-dimethyl-1- (but-3-yn-1-yl) -3H-benzo [ g]Indole-1-methanesulfonate
I13: (E) -2- (2- (1- (1- (tert-butyl) -9-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-benzo [ g]Indole-1-iodonium salts
I14: (E) -2- (2- (1- (1- (isobutyl) -9-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-benzo [ g]Indole-1-iodonium salts
I15: (E) -1,3, 3-trimethyl-2- (2- (9-methyl-1- (3,4, 5-trimethoxyphenyl) -9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -3H-benzo [ g]Indole-1-iodonium salts
I16: (E) -1,1, 3-trimethyl-2- (2- (1-methyl-9- (2-)Morpholinoethyl) -9H-pyrido [3,4-b]Indol-3-yl) ethenyl) -1H-benzo [ g]Indole-3-iodonium salts;
I17: (E) -2- (2- (1, 9-dimethyl-6-nitro-9H-pyridine [3, 4-b)]Indol-3-yl) vinyl) -1,1, 3-trimethyl-1H-benzo [ g]Indole-3-iodonium salts
I18: (E) -2- (2- (1, 9-dimethyl-6-amino-9H-pyridine [3, 4-b)]Indol-3-yl) vinyl) -1,1, 3-trimethyl-1H-benzo [ g]Indole-3-iodonium salts
II1: (Z) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-indol-1-iodo salt;
II2: (Z) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -3, 3-dimethyl-1- (prop-2-yn-1-yl) -3H-indol-1-bromo salt
II3: (Z) -2- (2- (9-ethyl-1-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-indole-1-hexafluorophosphate;
II4: (E) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -3, 3-dimethyl-1- (but-3-yn-1-yl) -3H-indol-1-methanesulfonate
II5: (Z) -2- (2- (1- (1- (tert-butyl) -9-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -1,3, 3-trimethyl-3H-indol-1-iodo salt
II6: (Z) -2- (2- (1- (1- (isobutyl) -9-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -1,3, 3-trimethyl-3H-indol-1-iodo salt
II7: (Z) -1,3, 3-trimethyl-2- (2- (9-methyl-1- (3,4, 5-trimethoxyphenyl) -9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -3H-indol-1-iodonium salts
II8: (E) -1,3, 3-trimethyl-2- (2- (1-methyl-9- (2-morpholinoethyl) -9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -3H-indol-1-iodonium salts;
II9: (Z) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-benzo [ g]Indole-1-iodonium salts;
II10: (Z) -2- (2- (1, 9-dimethyl-9H-pyrido [3,4-b]indol-3-yl) vinyl) -3, 3-dimethyl-1- (prop-2-yn-1-yl) -3H-benzo [ g]Indole-1-bromo salts
II11: (Z) -2- (2- (9-ethyl-1-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-benzo [ g]Indole-1-hexafluorophosphate;
II12: (Z) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -3, 3-dimethyl-1- (but-3-yn-1-yl) -3H-benzo [ g]Indole-1-methanesulfonate
II13: (Z) -2- (2- (1- (1- (tert-butyl) -9-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-benzo [ g]Indole-1-iodonium salts
II14: (Z) -2- (2- (1- (1- (isobutyl) -9-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-benzo [ g]Indole-1-iodonium salts
II15: (Z) -1,3, 3-trimethyl-2- (2- (9-methyl-1- (3,4, 5-trimethoxyphenyl) -9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -3H-benzo [ g]Indole-1-iodonium salts
II16: (Z) -1,1, 3-trimethyl-2- (2- (1-methyl-9- (2-morpholinoethyl) -9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -1H-benzo [ g]Indole-3-iodonium salts;
II17: (Z) -2- (2- (1, 9-dimethyl-6-nitro-9H-pyridine [3, 4-b)]Indol-3-yl) vinyl) -1,1, 3-trimethyl-1H-benzo [ g]Indole-3-iodonium salts
II18: (Z) -2- (2- (1, 9-dimethyl-6-amino-9H-pyridine [3, 4-b)]Indol-3-yl) vinyl) -1,1, 3-trimethyl-1H-benzo [ g]Indole-3-iodonium salts
Another object of the present invention is to provide a process for preparing the beta-carboline indolium salts of the general formulae I and II of the present invention as follows:
9-R1-6-R4-1-R2-9H-pyrido [3,4-b]Indole-3-formaldehyde (1) and indolium salt (2) or benzindolium salt (2) are subjected to aldol condensation under the heating condition to obtain the compound.
Furthermore, the preparation method specifically comprises the following steps: reacting 9-R1-6-R4-1-R2-9H-pyrido [3,4-b]Indole-3-carbaldehyde(1) Dissolving the beta-carboline indolium salt compound I and the beta-carboline indolium salt compound II with an indolium salt (2) or a benzindoline indolium salt (2) in absolute ethyl alcohol, dropwise adding a catalytic amount of piperidine, carrying out reflux reaction, and carrying out recrystallization or column separation and purification to obtain the beta-carboline indolium salt compound I and the beta-carboline indolium salt compound II.
The synthetic route is as follows:
the invention also provides an application of the beta-carboline indolium salt in preparing a pH-responsive fluorescent probe, wherein the beta-carboline indolium salt has acidic pH-sensitive fluorescent change.
The invention also provides application of the beta-carboline indolium salt in pH-sensitive tumor fluorescence imaging in tumor cell and tissue acid microenvironments.
The invention also provides an application of the beta-carboline indolium salt in preparation of a mitochondrion targeted fluorescent probe.
The invention also provides application of the beta-carboline indolium salt in mitochondrion targeting and/or pH sensitive fluorescence imaging of tumor cells or tissues.
The invention also provides an application of the beta-carboline indolium salt in preparing a tumor diagnostic agent.
Compared with the prior art, the invention has the following beneficial effects: the beta-carboline alkaloid has a plane tricyclic framework of pyridine [3,4-b ] indole, lipophilic cations are introduced into the 3-position of a beta-carboline mother ring through Knoevenagel condensation, so that a D-pi-A structure is formed, a beta-carboline mother ring conjugated system is further prolonged, and the beta-carboline indolium salt with mitochondrial targeting and pH sensitive fluorescence imaging characteristics is obtained. Experiments prove that the tumor acidic microenvironment can promote the release of the fluorescence of the beta-carboline indolium salt in tumor tissues, is beneficial to in vivo and in vitro fluorescence imaging of tumors through pH response and/or mitochondrion targeting, and further has important significance for diagnosis and treatment of tumor cells.
Drawings
FIG. 1 is a graph of the UV absorption spectra of compounds I9 and I16 obtained in the examples of the present invention in 1% DMSO aqueous solution, with the abscissa being the wavelength and the ordinate being the absorbance value;
FIG. 2 is a fluorescence emission spectrum of compounds I1, II1, II9, I16 and I17 obtained in the example of the present invention in a 1% DMSO aqueous solution, with the abscissa as wavelength and the ordinate as fluorescence intensity;
FIG. 3 shows fluorescence emission spectra of compounds I16, I17 and I18 obtained in the example of the present invention in 1% DMSO aqueous solution at different pH values, with the abscissa as wavelength and the ordinate as fluorescence intensity;
FIG. 4 is a confocal fluorescence imaging diagram of the location verification of mitochondria of Hela cells co-stained with compounds I1, I9, I16 and MitoTracker green obtained in the example of the present invention;
FIG. 5 is a diagram of confocal fluorescence imaging for location verification of mitochondria of HT29 cells co-stained with compounds II1, II9, I18 and MitoTracker green obtained in the example of the present invention.
Detailed Description
The beta-carboline indolium salts of the present invention and the methods of preparation and use thereof are described in further detail below with reference to specific examples, which are purely illustrative and are not to be construed as limiting the invention.
The embodiment of the invention provides a beta-carboline indolium salt with general structures shown as a formula I and a formula II:
wherein R is1Represents one of H, C1-C6 alkyl, alkynyl-substituted C1-C6 alkyl, halogenated C1-C6 alkyl, methoxy-substituted C1-C6 alkyl and morpholine-substituted C1-C6 alkyl; r2Represents one of H, C1-C6 alkyl and methoxy-substituted phenyl; r3Represents one of C1-C6 alkyl, alkynyl-substituted C1-C6 alkyl and halogenated C1-C6 alkyl; y is-Represents one of a halogen anion, a hexafluorophosphate anion, a sulfonic acid anion and a methanesulfonic acid anion; r4Represents one of H, amino and nitro.
In one embodiment, R1 represents one of H, CH3, CH2CH3 and N-ethylmorpholine; r2 represents one of H, CH3, C (CH3)3, CH2CH (CH3)3, 4-methoxyphenyl and 3,4, 5-trimethoxyphenyl; r3 represents one of CH3, CH2CH3, propargyl and propargyl; r4Represents one of H, amino and nitro.
In one embodiment, in the structures of formula I and formula II, R1、R2、R3、R4And
selected from the following combinations:
R1＝CH3，R2＝CH3，R3＝CH3，R4＝H，
or R1＝CH3，R2＝CH3，R3＝CH2C≡CH，R4＝H，
Or R1＝CH2CH3，R2＝CH3，R3＝CH3，R4＝H，
Or R1＝CH3，R2＝CH3，R3＝CH2CH2C≡CH，R4＝H，
Or R1＝CH3，R2＝C(CH3)3，R3＝CH3，R4＝H，
Or R1＝CH3，R2＝CH2C(CH3)3，R3＝CH3，R4＝H，
Or R1＝H，R2＝3,4,5-trimethoxyphenyl，R3＝CH3，R4＝H，
Or
R2＝CH3，R3＝CH3，R4＝H，
R1＝CH3，R2＝CH3，R3＝CH3，R4＝H，
Or R1＝CH3，R2＝CH3，R3＝CH2C≡CH，R4＝H，
Or R1＝CH2CH3，R2＝CH3，R3＝CH3，R4＝H，
Or R1＝CH3，R2＝CH3，R3＝CH2CH2C≡CH，R4＝H，
Or R1＝CH3，R2＝C(CH3)3，R3＝CH3，R4＝H，
Or R1＝CH3，R2＝CH2C(CH3)3，R3＝CH3，R4＝H，
Or R1＝H，R2＝3,4,5-trimethoxyphenyl，R3＝CH3，R4＝H，
Or
R2＝CH3，R3＝CH3，R4＝H，
The names of the compounds corresponding to each combination are respectively:
compound I1: (E) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-indol-1-iodo;
compound I2: (E) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -3, 3-dimethyl-1- (prop-2-yn-1-yl) -3H-indole-1-bromo;
compound I3: (E) -2- (2- (9-ethyl-1-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-indole-1-hexafluorophosphate;
compound I4: (E) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -3, 3-dimethyl-1- (but-3-yn-1-yl) -3H-indole-1-methanesulfonic acid;
compound I5: (E) -2- (2- (1- (1- (tert-butyl) -9-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-indol-1-iodo;
compound I6: (E) -2- (2- (1- (1- (isobutyl) -9-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-indol-1-iodo;
compound I7: (E) -1,3, 3-trimethyl-2- (2- (9-methyl-1- (3,4, 5-trimethoxyphenyl) -9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -3H-indol-1-iodo;
compound I8: (E) -1,3, 3-trimethyl-2- (2- (1-methyl-9- (2-morpholinoethyl) -9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -3H-indol-1-iodo;
compound I9: (E) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-benzo [ g]Indole-1-iodine;
compound I10: (E) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -3, 3-dimethyl-1- (prop-2-yn-1-yl) -3H-benzo [ g]Indole-1-bromo;
compound I11: (E) -2- (2- (9-ethyl-1-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-benzo [ g]Indole-1-hexafluorophosphoric acid;
compound I12: (E) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -3, 3-dimethyl-1- (but-3-yn-1-yl) -3H-benzo [ g]Indole-1-methanesulfonic acid;
compound I13: (E) -2- (2- (1- (1- (tert-butyl) -9-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-benzo [ g]Indole-1-iodine;
compound I14: (E) -2- (2- (1- (1- (isobutyl) -9-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-benzo [ g]Indole-1-iodine;
compound I15: (E) -1,3, 3-trimethyl-2- (2- (9-methyl-1- (3,4, 5-trimethoxyphenyl) -9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -3H-benzo [ g]Indole-1-iodine;
compound I16: (E) -1,1, 3-trimethyl-2- (2- (1-methyl-9- (2-morpholinoethyl) -9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -1H-benzo [ g]Indole-3-iodine;
compound I17: (E) -2- (2- (1, 9-dimethyl-6-nitro-9H-pyridine [3, 4-b)]Indol-3-yl) vinyl) -1,1, 3-trimethyl-1H-benzo [ g]Indole-3-iodine;
compound I18: (E) -2- (2- (1, 9-dimethyl-6-amino-9H-pyridine [3, 4-b)]Indol-3-yl) vinyl) -1,1, 3-trimethyl-1H-benzo [ g]Indole-3-iodine;
compound II1: (Z) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-indol-1-iodo;
compound II2: (Z) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -3, 3-dimethyl-1- (prop-2-yn-1-yl) -3H-indol-1-bromo;
compound II3: (Z) -2- (2- (9-ethyl-1-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-indole-1-hexafluorophosphate;
compound II4: (E) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -3, 3-dimethyl-1- (but-3-yn-1-yl) -3H-indole-1-methanesulfonic acid;
compound II5: (Z) -2- (2- (1- (1- (tert-butyl) -9-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-indol-1-iodo;
compound II6: (Z) -2- (2- (1- (1- (isobutyl) -9-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-indol-1-iodo;
compound II7: (Z) -1,3, 3-trimethyl-2- (2- (9-methyl)-1- (3,4, 5-trimethoxyphenyl) -9H-pyrido [3,4-b]Indol-3-yl) vinyl) -3H-indol-1-iodo;
compound II8: (E) -1,3, 3-trimethyl-2- (2- (1-methyl-9- (2-morpholinoethyl) -9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -3H-indol-1-iodo;
compound II9: (Z) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-benzo [ g]Indole-1-iodine;
compound II10: (Z) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -3, 3-dimethyl-1- (prop-2-yn-1-yl) -3H-benzo [ g]Indole-1-bromo;
compound II11: (Z) -2- (2- (9-ethyl-1-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-benzo [ g]Indole-1-hexafluorophosphoric acid;
compound II12: (Z) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -3, 3-dimethyl-1- (but-3-yn-1-yl) -3H-benzo [ g]Indole-1-methanesulfonic acid;
compound II13: (Z) -2- (2- (1- (1- (tert-butyl) -9-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-benzo [ g]Indole-1-iodine;
compound II14: (Z) -2- (2- (1- (1- (isobutyl) -9-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-benzo [ g]Indole-1-iodine;
compound II15: (Z) -1,3, 3-trimethyl-2- (2- (9-methyl-1- (3,4, 5-trimethoxyphenyl) -9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -3H-benzo [ g]Indole-1-iodine;
compound II16: (Z) -1,1, 3-trimethyl-2- (2- (1-methyl-9- (2-morpholinoethyl) -9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -1H-benzo [ g]Indole-3-iodine;
compound II17: (Z) -2- (2- (1, 9-dimethyl-6-nitro-9H-pyridine [3, 4-b)]Indol-3-yl) vinyl) -1,1, 3-trimethyl-1H-benzo [ g]Indole-3-iodine;
compound II18: (Z) -2- (2- (1, 9-dimethyl-6-amino)-9H-pyridine [3,4-b ]]Indol-3-yl) vinyl) -1,1, 3-trimethyl-1H-benzo [ g]Indole-3-iodine;
example 1: (E) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-indol-1-ium iodide salt (Compound I)1) Preparation of (A) and (Z) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-indol-1-ium iodide salt (Compound II)1) Preparation of
1, 9-dimethyl-9H-pyrido [3,4-b ]]Adding indole-3-formaldehyde (2.24g,10mmol) and 1,2,3, 3-tetramethyl-3H-indole-1-iodonium salt (2.35g,10mmol) into a single-neck flask, adding 5ml of absolute ethanol, then adding 1 drop of piperidine, refluxing overnight, monitoring by TLC to complete reaction, cooling the reaction solution, concentrating under reduced pressure, and separating and purifying by a column to obtain a beta-carboline indolium salt compound red solid (compound I)1)2.4g, 61.1% yield and orange solid (Compound II)1)1.3g, yield 32.3%.
Compound I1The spectrogram data is as follows: ESI-MS (M/z):381[ M + H]+；1H NMR(d6-DMSO,400MHz):8.92(m,1H,Ar-H),8.17(m,1H,Ar-H),8.02(m,1H,Ar-H),7.59(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.37(m,2H,2Ar-H),7.33(s,1H,Ar-H),7.11(d,J＝15.7Hz,1H,CH＝C),6.28(d,J＝15.7Hz,1H,CH＝C),3.28(s,3H,CH3),2.89(s,3H,CH3),1.49(s,6H,2CH3),0.9(s,3H,CH3).
Compound II1The spectrogram data is as follows: ESI-MS (M/z):381[ M + H]+；1H NMR(d6-DMSO,400MHz):8.92(m,1H,Ar-H),8.17(m,1H,Ar-H),8.02(m,1H,Ar-H),7.59(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.37(m,2H,2Ar-H),7.33(s,1H,Ar-H),7.11(d,J＝8.5Hz,1H,CH＝C),5.51(d,J＝8.5Hz,1H,CH＝C),3.28(s,3H,CH3),2.89(s,3H,CH3),1.49(s,6H,2CH3),0.9(s,3H,CH3).
Example 2: (E) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -3, 3-dimethyl-1- (prop-2-yn-1-yl) -3H-indol-1-bromo salt (Compound I)2) And (Z) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -3, 3-dimethyl-1- (prop-2-yn-1-yl) -3H-indol-1-Bromide salt (Compound II)2)
Reference example 1 Compound I1The synthesis method of (1) is replaced by 2,3, 3-trimethyl-1- (prop-2-yne-1-yl) -3H-indole-1-bromine salt, and finally red solid (compound I) is obtained2)2.3g, 52.9% yield and orange solid (Compound II)2)1.8g, yield 34.3%.
Compound I2The spectrogram data is as follows: ESI-MS (M/z):405[ M + H]+；1H NMR(d6-DMSO,400MHz):8.92(m,1H,Ar-H),8.17(m,1H,Ar-H),8.02(m,1H,Ar-H),7.59(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.37(m,2H,2Ar-H),7.33(s,1H,Ar-H),7.11(d,J＝15.7Hz,1H,CH＝C),6.28(d,J＝15.7Hz,1H,CH＝C),3.28(s,3H,CH3),2.89(s,3H,CH3),2.83(s,1H,CH),2.1(m,2H,CH2),1.49(s,6H,2CH3).
Compound II2The spectrogram data is as follows: ESI-MS (M/z):405[ M + H]+；1H NMR(d6-DMSO,400MHz):8.92(m,1H,Ar-H),8.17(m,1H,Ar-H),8.02(m,1H,Ar-H),7.59(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.37(m,2H,2Ar-H),7.33(s,1H,Ar-H),7.11(d,J＝8.5Hz,1H,CH＝C),5.51(d,J＝8.5Hz,1H,CH＝C),3.28(s,3H,CH3),2.89(s,3H,CH3),2.83(s,1H,CH),2.1(m,2H,CH2),1.49(s,6H,2CH3).
Example 3: (E) -2- (2- (9-ethyl-1-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-indol-1-hexafluorophosphate (Compound I)3) Preparation of (A) and (Z) -2- (2- (9-ethyl-1-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-indol-1-hexafluorophosphate (compound II)3) Preparation of
Reference example 1 Compound I1The synthesis method of (1) is that 9-ethyl-1-methyl-9H-pyrido [3, 4-b)]Indole-3-carbaldehyde substitution method for 1, 9-dimethyl-9H-pyrido [3,4-b ]]Indole-3-carbaldehyde, 1,2,3, 3-tetramethyl-3H-indole-1-hexafluorophosphate instead of the 1,2,3, 3-tetramethyl-3H-indole-1-iodide salt in the procedure, to give a red solid (Compound I)3)2.9g, 45.1% yield and orange solid (Compound II)3)1.5g, yield 23.3%.
Compound I3The spectrogram data is as follows: ESI-MS (M/z):395[ M + H]+；1H NMR(d6-DMSO,400MHz):8.92(m,1H,Ar-H),8.17(m,1H,Ar-H),8.02(m,1H,Ar-H),7.59(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.37(m,2H,2Ar-H),7.33(s,1H,Ar-H),7.11(d,J＝15.7Hz,1H,CH＝C),6.28(d,J＝15.7Hz,1H,CH＝C),4.53(m,2H,CH2),2.89(s,3H,CH3),1.49(s,6H,2CH3),1.29(s,3H,CH3),0.9(s,3H,CH3).
Compound II3The spectrogram data is as follows: ESI-MS (M/z):395[ M + H]+；1H NMR(d6-DMSO,400MHz):8.92(m,1H,Ar-H),8.17(m,1H,Ar-H),8.02(m,1H,Ar-H),7.59(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.37(m,2H,2Ar-H),7.33(s,1H,Ar-H),7.11(d,J＝8.5Hz,1H,CH＝C),5.51(d,J＝8.5Hz,1H,CH＝C),4.53(m,2H,CH2),2.89(s,3H,CH3),1.49(s,6H,2CH3),1.29(s,3H,CH3),0.9(s,3H,CH3).
Example 4: (E) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -3, 3-dimethyl-1- (but-3-yn-1-yl) -3H-indol-1-methanesulfonate (Compound I)4) Preparation of (A) and (Z) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -3, 3-dimethyl-1- (but-3-yn-1-yl) -3H-indol-1-methanesulfonate (Compound II)4) Preparation of
Reference example 1 Compound I1The synthesis method of (1) is replaced by 2,3, 3-trimethyl-1- (butyl-3-alkyne-1-yl) -3H-indole-1-mesylate to obtain red solid (compound I) finally4)2.6g, 57.8% yield and orange solid (Compound II)4)1.8g, yield 27.8%.
Compound I4The spectrogram data is as follows: ESI-MS (M/z):419[ M + H]+；1H NMR(d6-DMSO,400MHz):8.92(m,1H,Ar-H),8.17(m,1H,Ar-H),8.02(m,1H,Ar-H),7.59(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.37(m,2H,2Ar-H),7.33(s,1H,Ar-H),7.11(d,J＝15.7Hz,1H,CH＝C),6.28(d,J＝15.7Hz,1H,CH＝C),4.20(m,2H,CH2),3.28(s,3H,CH3),2.89(s,3H,CH3),2.83(s,1H,CH),2.1(m,2H,CH2),1.49(s,6H,2CH3).
Compound II4The spectrogram data is as follows: ESI-MS (M/z):419[ M + H]+；1H NMR(d6-DMSO,400MHz):8.92(m,1H,Ar-H),8.17(m,1H,Ar-H),8.02(m,1H,Ar-H),7.59(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.37(m,2H,2Ar-H),7.33(s,1H,Ar-H),7.11(d,J＝8.5Hz,1H,CH＝C),5.51(d,J＝8.5Hz,1H,CH＝C),4.20(m,2H,CH2),3.28(s,3H,CH3),2.89(s,3H,CH3),2.83(s,1H,CH),2.1(m,2H,CH2),1.49(s,6H,2CH3).
Example 5: (E) -2- (2- (1- (1- (tert-butyl) -9-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-indol-1-ium iodide salt (Compound I)5) Preparation of (A) and (Z) -2- (2- (1- (1- (tert-butyl) -9-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-indol-1-ium iodide salt (Compound II)5) Preparation of
Reference example 1 Compound I1The synthesis method of (1-tert-butyl-9-methyl-9H-pyrido [3, 4-b)]Indole-3-carbaldehyde substitution method for 1, 9-dimethyl-9H-pyrido [3,4-b ]]Indole-3-carbaldehyde to give a red solid (Compound I)5)2.4g, 53.6% yield and orange solid (Compound II)5)1.4g, yield 23.3%.
Compound I5The spectrogram data is as follows: ESI-MS (M/z):423[ M + H]+；1H NMR(d6-DMSO,400MHz):8.92(m,1H,Ar-H),8.17(m,1H,Ar-H),8.02(m,1H,Ar-H),7.59(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.37(m,2H,2Ar-H),7.33(s,1H,Ar-H),7.11(d,J＝15.7Hz,1H,CH＝C),6.28(d,J＝15.7Hz,1H,CH＝C),3.82(s,3H,CH3),1.49(s,6H,2CH3),1.29(s,3H,CH3),1.35(s,9H,3CH3),0.9(s,3H,CH3).
Compound II5The spectrogram data is as follows: ESI-MS (M/z):423[ M + H]+；1H NMR(d6-DMSO,400MHz):8.92(m,1H,Ar-H),8.17(m,1H,Ar-H),8.02(m,1H,Ar-H),7.59(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.37(m,2H,2Ar-H),7.33(s,1H,Ar-H),7.11(d,J＝8.5Hz,1H,CH＝C),5.51(d,J＝8.5Hz,1H,CH＝C),3.82(s,3H,CH3),1.49(s,6H,2CH3),1.29(s,3H,CH3),1.35(s,9H,3CH3),0.9(s,3H,CH3).
Example 6: (E) -2- (2- (1- (1- (isobutyl) -9-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-indol-1-ium iodide salt (Compound I)6) Preparation of (A) and (Z) -2- (2- (1- (1- (isobutyl) -9-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-indol-1-ium iodide salt (Compound II)6) Preparation of
Reference example 1 Compound I1The synthesis method of (1-isobutyl-9-methyl-9H-pyrido [3, 4-b)]Indole-3-carbaldehyde substitution method for 1, 9-dimethyl-9H-pyrido [3,4-b ]]Indole-3-carbaldehyde to give a red solid (Compound I)6)2.1g, 56.1% yield and orange solid (Compound II)6)1.1g, yield 23.1%.
Compound I6The spectrogram data is as follows: ESI-MS (M/z):423[ M + H]+；1H NMR(d6-DMSO,400MHz):8.92(m,1H,Ar-H),8.17(m,1H,Ar-H),8.02(m,1H,Ar-H),7.59(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.37(m,2H,2Ar-H),7.33(s,1H,Ar-H),7.11(d,J＝15.7Hz,1H,CH＝C),6.28(d,J＝15.7Hz,1H,CH＝C),3.82(s,3H,CH3),2.84(m,2H,CH2),1.82(m,1H,CH),1.49(s,6H,2CH3),0.91(s,6H,2CH3),0.9(s,3H,CH3).
Compound II6The spectrogram data is as follows: ESI-MS (M/z):423[ M + H]+；1H NMR(d6-DMSO,400MHz):8.92(m,1H,Ar-H),8.17(m,1H,Ar-H),8.02(m,1H,Ar-H),7.59(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.37(m,2H,2Ar-H),7.33(s,1H,Ar-H),7.11(d,J＝8.5Hz,1H,CH＝C),5.51(d,J＝8.5Hz,1H,CH＝C),3.82(s,3H,CH3),2.84(m,2H,CH2),1.82(m,1H,CH),1.49(s,6H,2CH3),0.91(s,6H,2CH3),0.9(s,3H,CH3).
Example 7: (E) -1,3, 3-trimethyl-2- (2- (9-methyl-1- (3,4, 5-trimethoxyphenyl) -9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -3H-indol-1-ium salts (Compound I)7) Preparation of (Z) -1,3, 3-trimethyl-2- (2- (9-methyl-1- (3,4, 5-trimethoxybenzene)Yl) -9H-pyrido [3,4-b]Indol-3-yl) ethenyl) -3H-indol-1-ium salts (Compound II)7) Preparation of
Reference example 1 Compound I1The synthesis method of (1) is carried out by 1- (3,4, 5-trimethoxyphenyl) -9H-pyrido [3,4-b]Indole-3-carbaldehyde substitution method for 1, 9-dimethyl-9H-pyrido [3,4-b ]]Indole-3-carbaldehyde to give a red solid (Compound I)7)2.1g, 45.6% yield and orange solid (Compound II)7)1.1g, yield 23.2%.
Compound I7The spectrogram data is as follows: ESI-MS (M/z):533[ M + H]+；1H NMR(d6-DMSO,400MHz):8.92(m,1H,Ar-H),8.17(m,1H,Ar-H),8.02(m,1H,Ar-H),7.59(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.37(m,2H,2Ar-H),7.32(s,2H,2Ar-H),7.09(s,1H,Ar-H),7.11(d,J＝15.7Hz,1H,CH＝C),6.28(d,J＝15.7Hz,1H,CH＝C),3.83(s,9H,3OCH3),3.28(s,3H,CH3),1.49(s,6H,2CH3),0.9(s,3H,CH3).
Compound II7The spectrogram data is as follows: ESI-MS (M/z):533[ M + H]+；1H NMR(d6-DMSO,400MHz):8.92(m,1H,Ar-H),8.17(m,1H,Ar-H),8.02(m,1H,Ar-H),7.59(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.37(m,2H,2Ar-H),7.32(s,2H,2Ar-H),7.09(s,1H,Ar-H),7.11(d,J＝8.5Hz,1H,CH＝C),5.51(d,J＝8.5Hz,1H,CH＝C),3.83(s,9H,3OCH3),3.28(s,3H,CH3),1.49(s,6H,2CH3),0.9(s,3H,CH3).
Example 8: (E) -1,3, 3-trimethyl-2- (2- (1-methyl-9- (2-morpholinoethyl) -9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -3H-indol-1-ium salts (Compound I)8) Preparation of (Z) -1,3, 3-trimethyl-2- (2- (1-methyl-9- (2-morpholinoethyl) -9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -3H-indol-1-ium salts (Compound II)8) Preparation of
Reference example 1 Compound I1The synthesis method of (1-methyl-9- (2-morpholinoethyl) -9H-pyrido [3, 4-b)]Indole-3-carbaldehyde substitution method for 1, 9-dimethyl-9H-pyrido [3,4-b ]]Indole-3-carbaldehyde to give a red solid (Compound I)8)2.4g, 50.3% yield and orange solid (combined)Substance II8)1.6g, yield 25.6%.
Compound I8The spectrogram data is as follows: ESI-MS (M/z) 480[ M + H]+：1H NMR(400MHz,CDCl3)9.28(s,1H,ArH),8.59(m,2H,ArH),8.14(d,J＝15.7Hz,1H,CH＝C),7.73(m,1H,ArH),7.70(m,5H,5ArH),7.42(d,J＝15.7Hz,1H,CH＝C),4.79(m,2H,CH2),4.45(s,3H,CH3),3.70(m,4H,2CH2),3.20(m,6H,2CH3),2.90(m,2H,CH2),2.59(m,4H,2CH2),1.29(s,3H,CH3).
Compound II8The spectrogram data is as follows: ESI-MS (M/z) 480[ M + H]+：1H NMR(400MHz,CDCl3)9.28(s,1H,ArH),8.59(m,2H,ArH),8.14(d,J＝8.5Hz,1H,CH＝C),7.73(m,1H,ArH),7.70(m,5H,5ArH),5.51(d,J＝8.5Hz,1H,CH＝C),4.79(m,2H,CH2),4.45(s,3H,CH3),3.70(m,4H,2CH2),3.20(m,6H,2CH3),2.90(m,2H,CH2),2.59(m,4H,2CH2),1.29(s,3H,CH3).
Example 9: (E) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-benzo [ g]Indole-1-iodonium salts (Compound I)9) Preparation of (A) and (Z) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-benzo [ g]Indole-1-iodonium salts (Compound II)9) Preparation of
Reference example 1 Compound I1The synthesis method of (1), 1,2, 3-tetramethyl-3H-benzo [ g ]]Indole-1-iodonium salt instead of the 1,2,3, 3-tetramethyl-3H-indole-1-iodonium salt in the procedure to give a red solid (Compound I)9)2.6g, 52.1% yield and orange solid (Compound II)9)1.3g, yield 22.5%.
Compound I9The spectrogram data is as follows: ESI-MS (M/z):431[ M + H]+；1H NMR(d6-DMSO,400MHz):8.18(m,2H,2Ar-H),8.05(m,1H,Ar-H),7.92(m,1H,Ar-H),7.59(m,1H,Ar-H),7.54(m,2H,2Ar-H),7.47(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.33(s,1H,Ar-H),7.11(d,J＝15.7Hz,1H,CH＝C),6.28(d,J＝15.7Hz,1H,CH＝C),3.28(s,3H,CH3),2.89(s,3H,CH3),1.62(s,6H,2CH3),0.9(s,3H,CH3).
Compound II9The spectrogram data is as follows: ESI-MS (M/z):431[ M + H]+；1H NMR(d6-DMSO,400MHz):8.18(m,2H,2Ar-H),8.05(m,1H,Ar-H),7.92(m,1H,Ar-H),7.59(m,1H,Ar-H),7.54(m,2H,2Ar-H),7.47(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.33(s,1H,Ar-H),7.11(d,J＝8.5Hz,1H,CH＝C),5.51(d,J＝8.5Hz,1H,CH＝C),3.28(s,3H,CH3),2.89(s,3H,CH3),1.62(s,6H,2CH3),0.9(s,3H,CH3).
Example 10: (E) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -3, 3-dimethyl-1- (prop-2-yn-1-yl) -3H-benzo [ g]Indole-1-bromo salts (Compound I)10) Preparation of (A) and (Z) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -3, 3-dimethyl-1- (prop-2-yn-1-yl) -3H-benzo [ g]Indole-1-bromo salt (Compound II)10) Preparation of
Reference example 1 Compound I1The synthesis of (1), 1, 2-trimethyl-1- (prop-2-yn-1-yl) -3H-benzo [ g)]Indole-1-bromo salt instead of the 1,2,3, 3-tetramethyl-3H-indole-1-iodo salt in the procedure, a red solid was finally obtained (Compound I)10)2.1g, 60.0% yield and orange solid (Compound II)10)1.1g, yield 23.1%.
Compound I10The spectrogram data is as follows: ESI-MS (M/z):455[ M + H]+；1H NMR(d6-DMSO,400MHz):8.18(m,2H,2Ar-H),8.05(m,1H,Ar-H),7.92(m,1H,Ar-H),7.59(m,1H,Ar-H),7.54(m,2H,2Ar-H),7.47(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.33(s,1H,Ar-H),7.11(d,J＝15.7Hz,1H,CH＝C),6.28(d,J＝15.7Hz,1H,CH＝C),3.28(s,3H,CH3),2.89(s,3H,CH3),2.83(s,1H,CH),2.1(m,2H,CH2),1.62(s,6H,2CH3).
Compound II10The spectrogram data is as follows: ESI-MS (M/z):455[ M + H]+；1H NMR(d6-DMSO,400MHz):8.18(m,2H,2Ar-H),8.05(m,1H,Ar-H),7.92(m,1H,Ar-H),7.59(m,1H,Ar-H),7.54(m,2H,2Ar-H),7.47(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.33(s,1H,Ar-H),7.11(d,J＝8.5Hz,1H,CH＝C),5.51(d,J＝8.5Hz,1H,CH＝C),3.28(s,3H,CH3),2.89(s,3H,CH3),2.83(s,1H,CH),2.1(m,2H,CH2),1.62(s,6H,2CH3).
Example 11: (E) -2- (2- (9-ethyl-1-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-benzo [ g]Indole-1-hexafluorophosphate salt (Compound I)11) Preparation of (A) and (Z) -2- (2- (9-ethyl-1-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-benzo [ g]Indole-1-hexafluorophosphate salt (Compound II)11) Preparation of
Reference example 1 Compound I1The synthesis method of (1) is that 9-ethyl-1-methyl-9H-pyrido [3, 4-b)]Indole-3-carbaldehyde substitution method for 1, 9-dimethyl-9H-pyrido [3,4-b ]]Indole-3-carbaldehyde, 1,2,3, 3-tetramethyl-3H-benzo [ g]Indole-1-hexafluorophosphate was substituted for the 1,2,3, 3-tetramethyl-3H-indole-1-iodonium salt in the procedure to give a red solid (Compound I)11)2.2g, 60.3% yield and orange solid (Compound II)11)1.2g, yield 24.3%.
Compound I11The spectrogram data is as follows: ESI-MS (M/z):445[ M + H]+；1H NMR(d6-DMSO,400MHz):8.18(m,2H,2Ar-H),8.05(m,1H,Ar-H),7.92(m,1H,Ar-H),7.59(m,1H,Ar-H),7.54(m,2H,2Ar-H),7.47(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.33(s,1H,Ar-H),7.11(d,J＝15.7Hz,1H,CH＝C),6.28(d,J＝15.7Hz,1H,CH＝C),4.53(m,2H,CH2),2.89(s,3H,CH3),1.62(s,6H,2CH3),1.29(s,3H,CH3),0.9(s,3H,CH3).
Compound II11The spectrogram data is as follows: ESI-MS (M/z):445[ M + H]+；1H NMR(d6-DMSO,400MHz):8.18(m,2H,2Ar-H),8.05(m,1H,Ar-H),7.92(m,1H,Ar-H),7.59(m,1H,Ar-H),7.54(m,2H,2Ar-H),7.47(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.33(s,1H,Ar-H),7.11(d,J＝8.5Hz,1H,CH＝C),5.51(d,J＝8.5Hz,1H,CH＝C),4.53(m,2H,CH2),2.89(s,3H,CH3),1.62(s,6H,2CH3),1.29(s,3H,CH3),0.9(s,3H,CH3).
Example 12: (E) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -3, 3-dimethyl-1- (but-3-yn-1-yl) -3H-benzo [ g]Indole-1-methanesulfonate (Compound I)12) Preparation of (A) and (Z) -2- (2- (1, 9-dimethyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -3, 3-dimethyl-1- (but-3-yn-1-yl) -3H-benzo [ g]Indole-1-methanesulfonate (Compound II)12) Preparation of
Reference example 1 Compound I1The synthesis of (1), 1, 2-trimethyl-3- (but-3-yn-1-yl) -3H-benzo [ g)]Indole-1-mesylate salt instead of the 1,2,3, 3-tetramethyl-3H-indole-1-iodide salt in the procedure to give a red solid (Compound I)12)2.2g, 52.1% yield and orange solid (Compound II)12)1.2g, yield 26.1%.
Compound I12The spectrogram data is as follows: ESI-MS (M/z):469[ M + H]+；1H NMR(d6-DMSO,400MHz):8.18(m,2H,2Ar-H),8.05(m,1H,Ar-H),7.92(m,1H,Ar-H),7.59(m,1H,Ar-H),7.54(m,2H,2Ar-H),7.47(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.33(s,1H,Ar-H),7.11(d,J＝15.7Hz,1H,CH＝C),6.28(d,J＝15.7Hz,1H,CH＝C),4.20(m,2H,CH2),3.28(s,3H,CH3),2.89(s,3H,CH3),2.83(s,1H,CH),2.1(m,2H,CH2),1.62(s,6H,2CH3).
Compound II12The spectrogram data is as follows: ESI-MS (M/z):469[ M + H]+；1H NMR(d6-DMSO,400MHz):8.18(m,2H,2Ar-H),8.05(m,1H,Ar-H),7.92(m,1H,Ar-H),7.59(m,1H,Ar-H),7.54(m,2H,2Ar-H),7.47(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.33(s,1H,Ar-H),7.11(d,J＝8.5Hz,1H,CH＝C),5.51(d,J＝8.5Hz,1H,CH＝C),4.20(m,2H,CH2),3.28(s,3H,CH3),2.89(s,3H,CH3),2.83(s,1H,CH),2.1(m,2H,CH2),1.62(s,6H,2CH3).
Example 13: (E) -2- (2- (1- (1- (tert-butyl) -9-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-benzo [ g]Indole-1-iodonium salt (Compound I1)13) Preparation of (A) and (Z) -2- (2- (1- (1- (tert-butyl) -9-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-benzo [ g]Indole-1-iodonium salts (Compound II)13) Preparation of
Reference example 1 Compound I1By 1-tert-butyl-9-methyl-9H-pyrido [3,4-b]Indole-3-carbaldehyde substitution method for 1, 9-dimethyl-9H-pyrido [3,4-b ]]Indole-3-carbaldehyde prepared from 1,1,2, 3-tetramethyl-3H-benzo [ g ]]Indole-1-iodonium salt instead of the 1,2,3, 3-tetramethyl-3H-indole-1-iodonium salt in the procedure to give a red solid (Compound I)13)2.4g, 53.3% yield and orange solid (Compound II)13)1.4g, yield 23.6%.
Compound I13The spectrogram data is as follows: ESI-MS (M/z):473[ M + H]+；1H NMR(d6-DMSO,400MHz):8.18(m,2H,2Ar-H),8.05(m,1H,Ar-H),7.92(m,1H,Ar-H),7.59(m,1H,Ar-H),7.54(m,2H,2Ar-H),7.47(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.33(s,1H,Ar-H),7.11(d,J＝15.7Hz,1H,CH＝C),6.28(d,J＝15.7Hz,1H,CH＝C),3.28(s,3H,CH3),1.62(s,6H,2CH3),1.35(s,9H,3CH3),0.9(s,3H,CH3).
Compound II13The spectrogram data is as follows: ESI-MS (M/z):473[ M + H]+；1H NMR(d6-DMSO,400MHz):8.18(m,2H,2Ar-H),8.05(m,1H,Ar-H),7.92(m,1H,Ar-H),7.59(m,1H,Ar-H),7.54(m,2H,2Ar-H),7.47(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.33(s,1H,Ar-H),7.11(d,J＝8.5Hz,1H,CH＝C),5.51(d,J＝8.5Hz,1H,CH＝C),3.28(s,3H,CH3),1.62(s,6H,2CH3),1.35(s,9H,3CH3),0.9(s,3H,CH3).
Example 14: (E) -2- (2- (1- (1- (isobutyl) -9-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-benzo [ g]Indole-1-iodonium salts (Compound I)14) Preparation of (A) and (Z) -2- (2- (1- (1- (isobutyl) -9-methyl-9H-pyrido [3, 4-b)]Indol-3-yl) vinyl) -1,3, 3-trimethyl-3H-benzo [ g]Indole-1-iodonium salts (Compound II)14) Preparation of
Reference example 1 (I)1) The synthesis method of (1-isobutyl-9-methyl-9H-pyrido [3, 4-b)]Indole-3-carbaldehyde substitution method for 1, 9-dimethyl-9H-pyrido [3,4-b ]]Indole-3-carbaldehyde prepared from 1,1,2, 3-tetramethyl-3H-benzo [ g ]]Indole-1-iodonium salt instead of the 1,2,3, 3-tetramethyl-3H-indole-1-iodonium salt in the procedure to give a red solid (Compound I)14)2.0g, 55.5% yield and orange solid (Compound II)14)1.3g, yield 26.4%.
Compound I14The spectrogram data is as follows: ESI-MS (M/z):473[ M + H]+；1H NMR(d6-DMSO,400MHz):8.18(m,2H,2Ar-H),8.05(m,1H,Ar-H),7.92(m,1H,Ar-H),7.59(m,1H,Ar-H),7.54(m,2H,2Ar-H),7.47(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.33(s,1H,Ar-H),7.11(d,J＝15.7Hz,1H,CH＝C),6.28(d,J＝15.7Hz,1H,CH＝C),3.82(s,3H,CH3),2.84(m,2H,CH2),1.82(s,1H,CH),1.62(m,6H,2CH3),0.91(s,6H,2CH3),0.9(s,3H,CH3).
Compound II14The spectrogram data is as follows: ESI-MS (M/z):473[ M + H]+；1H NMR(d6-DMSO,400MHz):8.18(m,2H,2Ar-H),8.05(m,1H,Ar-H),7.92(m,1H,Ar-H),7.59(m,1H,Ar-H),7.54(m,2H,2Ar-H),7.47(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.33(s,1H,Ar-H),7.11(d,J＝8.5Hz,1H,CH＝C),5.51(d,J＝8.5Hz,1H,CH＝C),3.82(s,3H,CH3),2.84(m,2H,CH2),1.82(s,1H,CH),1.62(m,6H,2CH3),0.91(s,6H,2CH3),0.9(s,3H,CH3).
Example 15: (E) -1,3, 3-trimethyl-2- (2- (9-methyl-1- (3,4, 5-trimethoxyphenyl) -9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -3H-benzo [ g]Indole-1-iodonium salts (Compound I)15) Preparation of (Z) -1,3, 3-trimethyl-2- (2- (9-methyl-1- (3,4, 5-trimethoxyphenyl) -9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -3H-benzo [ g]Indole-1-iodonium salts (Compound II)15) Preparation of
Reference example 1 (I)1) The synthesis method of (1) is carried out by 1- (3,4, 5-trimethoxyphenyl) -9H-pyrido [3,4-b]Indole-3-carbaldehyde substitution method for 1, 9-dimethyl-9H-pyrido [3,4-b ]]Indole-3-carbaldehyde prepared from 1,1,2, 3-tetramethyl-3H-benzo [ g ]]Indole-1-iodonium salt instead of the 1,2,3, 3-tetramethyl-3H-indole-1-iodonium salt in the procedure to give a red solid (Compound I)15)2.8g, 53.6% yield and orange solid (Compound II)15)1.3g, yield 23.4%.
Compound I15The spectrogram data is as follows: ESI-MS (M/z):583[ M + H]+；1H NMR(d6-DMSO,400MHz):8.18(m,2H,2Ar-H),8.05(m,1H,Ar-H),7.92(m,1H,Ar-H),7.59(m,1H,Ar-H),7.54(m,2H,2Ar-H),7.47(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.32(s,2H,2Ar-H),7.09(s,1H,1Ar-H),7.11(d,J＝15.7Hz,1H,CH＝C),6.28(d,J＝15.7Hz,1H,CH＝C),3.83(s,9H,3OCH3),3.82(s,3H,CH3),1.62(m,6H,2CH3),0.9(s,3H,CH3).
Compound II15The spectrogram data is as follows: ESI-MS (M/z):583[ M + H]+；1H NMR(d6-DMSO,400MHz):8.18(m,2H,2Ar-H),8.05(m,1H,Ar-H),7.92(m,1H,Ar-H),7.59(m,1H,Ar-H),7.54(m,2H,2Ar-H),7.47(m,1H,Ar-H),7.42(m,2H,2Ar-H),7.32(s,2H,2Ar-H),7.09(s,1H,1Ar-H),7.11(d,J＝8.5Hz,1H,CH＝C),5.51(d,J＝8.5Hz,1H,CH＝C),3.83(s,9H,3OCH3),3.82(s,3H,CH3),1.62(m,6H,2CH3),0.9(s,3H,CH3).
Example 16: (E) -1,1, 3-trimethyl-2- (2- (1-methyl-9- (2-morpholinoethyl) -9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -1H-benzo [ g]Indole-3-iodonium salts (Compound I)16) Preparation of (Z) -1,1, 3-trimethyl-2- (2- (1-methyl-9- (2-morpholinoethyl) -9H-pyrido [3, 4-b)]Indol-3-yl) ethenyl) -1H-benzo [ g]Indole-3-iodonium salts (Compound II)16) Preparation of
Reference example 1 (I)1) The synthesis method of (1-methyl-9- (2-morpholinoethyl) -9H-pyrido [3, 4-b)]Indole-3-carbaldehyde substitution method for 1, 9-dimethyl-9H-pyrido [3,4-b ]]Indole-3-carbaldehyde to give a red solid (Compound I)16)2.2g, 58.3% yield and orange solid (Compound II)16)1.2g, yield 29.3%.
Compound I16The spectrogram data is as follows: ESI-MS (M/z):530[ M + H]+；1H NMR(400MHz,CDCl3)9.28(s,1H,ArH),8.59(m,2H,ArH),8.14(d,J＝15.7Hz,1H,ArH),8.09(m,2H,2ArH),7.73(d,J＝15.7Hz,1H,CH＝C),7.70(m,5H,5ArH),7.42(d,J＝15.7Hz,1H,CH＝C),4.79(m,2H,CH2),4.45(s,3H,CH3),3.70(m,4H,2CH2),3.20(m,6H,2CH3),2.90(m,2H,CH2),2.59(m,4H,2CH2),1.29(s,3H,CH3).
Compound II16The spectrogram data is as follows: ESI-MS (M/z):530[ M + H]+；1H NMR(400MHz,CDCl3)9.28(s,1H,ArH),8.59(m,2H,ArH),8.14(d,J＝15.7Hz,1H,ArH),8.09(m,2H,2ArH),7.73(m,1H,CH＝C),7.10(d,J＝8.5Hz,1H,CH＝C),5.51(d,J＝8.5Hz,1H,CH＝C),4.79(m,2H,CH2),4.45(s,3H,CH3),3.70(m,4H,2CH2),3.20(m,6H,2CH3),2.90(m,2H,CH2),2.59(m,4H,2CH2),1.29(s,3H,CH3).
Example 17: (E) -2- (2- (1, 9-dimethyl-6-nitro-9H-pyridine [3, 4-b)]Indol-3-yl) vinyl) -1,1, 3-trimethyl-1H-benzo [ g]Indole-3-iodonium salts (Compound I)17) Preparation of (A) and (Z) -2- (2- (1, 9-dimethyl-6-nitro-9H-pyridine [3, 4-b)]Indol-3-yl) vinyl) -1,1, 3-trimethyl-1H-benzo [ g]Indole-3-iodonium salts (Compound II)17) Preparation of
Reference example 1 Compound I1The synthesis method of (1) is carried out by 1, 9-dimethyl-6-nitro-9H-pyrido [3,4-b]Indole-3-carbaldehyde substitution method for 1, 9-dimethyl-9H-pyrido [3,4-b ]]Indole-3-carbaldehyde to give a red solid (Compound I)17)2.1g, 64.3% yield and orange solid (Compound II)17)1.1g, yield 21.1%.
Compound I17The spectrogram data is as follows: ESI-MS (M/z):475[ M + H]+；1H NMR(400MHz,CDCl3)8.99(s,1H,ArH),8.59(m,2H,ArH),8.14(d,J＝15.7Hz,1H,CH＝C),8.09(m,2H,2ArH),7.73(m,1H,ArH),7.70(m,4H,4ArH),7.42(d,J＝15.7Hz,1H,CH＝C),4.79(m,2H,CH2),4.45(s,3H,CH3),3.70(m,4H,2CH2),3.20(m,6H,2CH3),2.90(m,2H,CH2),2.59(m,4H,2CH2),1.29(s,3H,CH3).
Compound II17The spectrogram data is as follows: ESI-MS (M/z):475[ M + H]+；1H NMR(400MHz,CDCl3)8.99(s,1H,ArH),8.59(m,2H,ArH),8.14(d,J＝15.7Hz,1H,ArH),8.09(m,2H,2ArH),7.73(d,J＝8.5Hz,1H,CH＝C),7.70(m,4H,4ArH),5.51(d,J＝8.5Hz,1H,CH＝C),4.79(m,2H,CH2),4.45(s,3H,CH3),3.70(m,4H,2CH2),3.20(m,6H,2CH3),2.90(m,2H,CH2),2.59(m,4H,2CH2),1.29(s,3H,CH3).
Example 18(E) -2- (2- (1, 9-dimethyl-6-amino-9H-pyridine [3, 4-b)]Indol-3-yl) vinyl) -1,1, 3-trimethyl-1H-benzo [ g]Indole-3-iodonium salts (Compound I)18) Preparation of (A) and (Z) -2- (2- (1, 9-dimethyl-6-amino-9H-pyridine [3, 4-b)]Indol-3-yl) vinyl) -1,1, 3-trimethyl-1H-benzo [ g]Indole-3-iodonium salts (Compound II)18) Preparation of
Reference example 1 Compound I1The synthesis method of (1), 9-dimethyl-6-amino-9H-pyrido [3, 4-b)]Indole-3-carbaldehyde substitution method for 1, 9-dimethyl-9H-pyrido [3,4-b ]]Indole-3-carbaldehyde to give a red solid (Compound I)18)2.3g, 53.3% yield and orange solid (Compound II)18)1.1g, yield 23.6%.
Compound I18The spectrogram data is as follows: ESI-MS (M/z):445[ M + H]+；1H NMR(400MHz,CDCl3)8.99(s,1H,ArH),8.59(m,2H,ArH),8.14(m,1H,ArH),8.09(m,2H,2ArH),7.73(d,J＝15.7Hz,1H,CH＝C),7.70(d,4H,4ArH),7.42(d,J＝15.7Hz,1H,CH＝C),6.27(s,2H,NH2),4.79(m,2H,CH2),4.45(s,3H,CH3),3.70(m,4H,2CH2),3.20(m,6H,2CH3),2.90(m,2H,CH2),2.59(m,4H,2CH2),1.29(s,3H,CH3).
Compound II18The spectrogram data is as follows: ESI-MS (M/z):445[ M + H]+；1H NMR(400MHz,CDCl3)8.99(s,1H,ArH),8.59(m,2H,ArH),8.14(d,J＝15.7Hz,1H,ArH),8.09(m,2H,2ArH),7.73(d,J＝8.5Hz,1H,CH＝C),7.70(m,4H,4ArH),5.51(d,J＝8.5Hz,1H,CH＝C),6.27(s,2H,NH2),4.79(m,2H,CH2),4.45(s,3H,CH3),3.70(m,4H,2CH2),3.20(m,6H,2CH3),2.90(m,2H,CH2),2.59(m,4H,2CH2),1.29(s,3H,CH3).
Example 19: ultraviolet absorption Spectroscopy testing of Compounds of the invention
Selecting the compound I of the invention9And I16For ultraviolet absorption spectrum test, preparing into 1-25 μ M detection solution, and using violetThe ultraviolet absorption spectrum data of the compound is tested by an external-visible spectrophotometer, the ultraviolet absorption spectrum is shown in figure 1, and the result shows that the maximum ultraviolet absorption wavelength of the compound is in the range of 420-600 nm. Wherein the compound I9And I16The maximum ultraviolet absorption wavelength is in the range of 580-600nm, and the peak values thereof are respectively associated with the compound I9And I16Increased with increasing concentration (fig. 1);
example 20: fluorescence Spectroscopy testing of partial Compounds of the invention
Selecting the compound I of the invention1、II1、II9、I16And I17For representing the fluorescence spectrum test, the compound is prepared into 1-25 mu M detection liquid, a fluorescence spectrometer is adopted to test the fluorescence emission spectrum data, the fluorescence emission spectrum is shown as 2, and the result shows that the maximum emission wavelength of the compound is in the range of 515-660 nm. Wherein the compound I1、II1、II9、I16And I17The maximum emission wavelengths are around 585-610nm, 540-570nm, 580-610nm, 590-610nm and 590-610nm respectively, and the fluorescence peaks thereof are respectively associated with the compounds I1、II1、II9、I16And I17Increased with increasing concentration (fig. 2);
example 21: fluorescence spectroscopy of pH response of partial Compounds of the invention
Selecting the compound I of the invention16、I17And I18To represent the fluorescence spectrum test for pH response, it was formulated into a test solution of 1-25 μ M at pH 3-8. Fluorescence emission spectrum data of the sample are tested by a fluorescence spectrometer, and fluorescence emission spectra of different pH values are shown in FIG. 3. The results show that the maximum emission wavelength of the fluorescent compound of the invention is in the range of 515-660 nm. Wherein the compound I16(Em＝590-610nm)、I17(Em. 590-18(Em 590-610nm) with the compound I16、I17And I18The pH value of (1) is decreased and increased, and the fluorescence peak values of the fluorescence peaks are decreased along with the increase of the pH value, and the difference of the peak values is 2-15 times (figure 3);
example 22: the compound of the invention adopts a confocal microscope to carry out mitochondrial positioning experiment
Selecting the compound I of the invention1、II1、I9、II9、I16And I18For representation, a confocal microscope is adopted to carry out a mitochondrial localization experiment, a Hela or HT29 cell is cultured in a laser confocal dish for 12-24 h by DEME culture solution, 1-25 mu M of tested compound is added into the cell, and the cell is placed at 37 ℃ and contains 5% CO2Is incubated in the cell culture chamber for half an hour. After 3 washes with phosphate buffer solution with pH 7.4, 1 μ M mitochondrial stain MitoTracker green solution was added and incubation continued for half an hour, 3 washes with phosphate buffer solution with pH 7.4, the incubated cells were placed on the stage of a confocal microscope for confocal fluorescence imaging, setting MitoTracker green: λ ex is 488nm, λ em is 500-550 nm; set test compound excitation wavelength: λ ex is 552nm and λ em is 550-650 nm. The results are shown in fig. 4 and 5, and show that the co-localization images of the compound (red) of the present invention and the mitochondrial stain MitoTracker green (green) fluorescence overlap well, I1(Rr＝0.83)、II1(Rr＝0.82)、I9(Rr＝0.85)、II9(Rr＝0.85)、I16(Rr ═ 0.84) and I18(Rr ═ 0.84) Pearson coefficients all above 0.8 (where I9And II9The best overlapping effect, reaching 0.85), thereby showing that the beta-carboline indolium salt fluorescent compound has a remarkable effect of targeting mitochondria in tumor cells (fig. 4 and 5).
It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (9)
1. Beta-carboline indolium salts of the general structures shown in formula I and formula II:
wherein R is1Represents one of H, C1-C6 alkyl, alkynyl-substituted C1-C6 alkyl, halogenated C1-C6 alkyl, methoxy-substituted C1-C6 alkyl and morpholine-substituted C1-C6 alkyl; r2Represents one of H, C1-C6 alkyl and methoxy-substituted phenyl; r3Represents one of C1-C6 alkyl, alkynyl-substituted C1-C6 alkyl and halogenated C1-C6 alkyl; y is-Represents one of a halogen anion, a hexafluorophosphate anion, a sulfonic acid anion and a methanesulfonic acid anion; r4Represents one of H, amino and nitro.
2. The beta-carboline indolium salt of claim 1, wherein R is1Representation H, CH3、CH2CH3And N-ethylmorpholine; r2Representation H, CH3、C(CH3)3、CH2CH(CH3)3One of 4-methoxyphenyl and 3,4, 5-trimethoxyphenyl; r3Represents CH3、CH2CH3One of propargyl and propargyl.
3. The beta-carboline indolium salt of claim 1, wherein in the structures of formula i and formula ii, R is1、R2、R3、R4And
selected from the following combinations:
R1＝CH3，R2＝CH3，R3＝CH3，R4＝H，
or R1＝CH3，R2＝CH3，R3＝CH2C≡CH，R4＝H，
Or R1＝CH2CH3，R2＝CH3，R3＝CH3，R4＝H，
Or R1＝CH3，R2＝CH3，R3＝CH2CH2C≡CH，R4＝H，
Or R1＝CH3，R2＝C(CH3)3，R3＝CH3，R4＝H，
Or R1＝CH3，R2＝CH2C(CH3)3，R3＝CH3，R4＝H，
Or R1＝H，R2＝3,4,5-trimethoxyphenyl，R3＝CH3，R4＝H，
Or
R2＝CH3，R3＝CH3，R4＝H，
Or R1＝CH3，R2＝CH3，R3＝CH3，R4＝H，
Or R1＝CH3，R2＝CH3，R3＝CH2C≡CH，R4＝H，
Or R1＝CH2CH3，R2＝CH3，R3＝CH3，R4＝H，
Or R1＝CH3，R2＝CH3，R3＝CH2CH2C≡CH，R4＝H，
Or R1＝CH3，R2＝C(CH3)3，R3＝CH3，R4＝H，
Or R1＝CH3，R2＝CH2C(CH3)3，R3＝CH3，R4＝H，
Or R1＝H，R2＝3,4,5-trimethoxyphenyl，R3＝CH3，R4＝H，
Or
R2＝CH3，R3＝CH3，R4＝H，
4. A process for the preparation of a β -carboline indolium salt according to any one of claims 1-3, comprising: reacting 9-R1-6-R4-1-R2-9H-pyrido [3,4-b]Dissolving indole-3-formaldehyde (1) and indolium salt (2) or benzindolium salt (2) in absolute ethyl alcohol, dropwise adding a catalytic amount of piperidine, carrying out reflux reaction, and carrying out recrystallization or column separation and purification to obtain beta-carboline indolium salts I and II;
the synthetic route is as follows:
wherein R is1Representation H, CH3、CH2CH3And N-ethylmorpholine; r2Representation H, CH3、C(CH3)3、CH2CH(CH3)3One of 4-methoxyphenyl and 3,4, 5-trimethoxyphenyl; r3Represents CH3、CH2CH3One of propargyl and propargyl; y is-Represents one of a halogen anion, a hexafluorophosphate anion, a sulfonic acid anion and a methanesulfonic acid anion; r4Representing H, amino and nitroOne kind of the medicine.
5. Use of the β -carboline indolium salt of any one of claims 1-3 in the preparation of a pH-responsive fluorescent probe.
6. Use of the β -carboline indolium salt of any one of claims 1-3 for pH sensitive tumor fluorescence imaging in tumor cell and tissue acidic microenvironments.
7. Use of the β -carboline indolium salt of any one of claims 1-3 in the preparation of a mitochondrial-targeted fluorescent probe.
8. Use of the β -carboline indolium salt of any one of claims 1-3 for mitochondrial targeting and/or pH sensitive fluorescence imaging of tumor cells or tissues.
9. Use of the β -carboline indolium salt of any one of claims 1-3 in the preparation of a tumor diagnostic agent.
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