AU2020356793B2 - PH/glutathione-responsive β-carbolines/cycloketene derivatives and their preparation and application - Google Patents
PH/glutathione-responsive β-carbolines/cycloketene derivatives and their preparation and application Download PDFInfo
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- AU2020356793B2 AU2020356793B2 AU2020356793A AU2020356793A AU2020356793B2 AU 2020356793 B2 AU2020356793 B2 AU 2020356793B2 AU 2020356793 A AU2020356793 A AU 2020356793A AU 2020356793 A AU2020356793 A AU 2020356793A AU 2020356793 B2 AU2020356793 B2 AU 2020356793B2
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- methyl
- pyrido
- carbamate
- indol
- oxocyclohex
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- 238000002360 preparation method Methods 0.000 title claims description 5
- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical class N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 title abstract 5
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 title description 58
- 229960003180 glutathione Drugs 0.000 title description 29
- 108010024636 Glutathione Proteins 0.000 title description 3
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- 239000003814 drug Substances 0.000 claims abstract description 18
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- 238000011282 treatment Methods 0.000 claims abstract description 14
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- 230000004044 response Effects 0.000 claims abstract description 8
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- -1 methoxy, ethoxy, methyl amino group Chemical group 0.000 claims description 101
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 71
- 150000001875 compounds Chemical class 0.000 claims description 59
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 55
- 230000015572 biosynthetic process Effects 0.000 claims description 47
- 238000003786 synthesis reaction Methods 0.000 claims description 47
- 238000000034 method Methods 0.000 claims description 43
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 125000001424 substituent group Chemical group 0.000 claims description 18
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
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- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 6
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 5
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- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 claims description 3
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- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- 238000012512 characterization method Methods 0.000 claims 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
-
- A—HUMAN NECESSITIES
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- 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"
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- 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
- G01N21/645—Specially adapted constructive features of fluorimeters
- G01N21/6456—Spatial resolved fluorescence measurements; Imaging
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1044—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms
Abstract
The invention discloses a class of beta-carboline-cycloenone derivatives with
structures as shown in a general formula which are described in the specification.
According to the invention, an electron-donatinggroup is introduced into a proper part
of beta-carboline, and the 3-site amino group of beta-carboline is connected with
5 cycloenone having anti-tumor activity by utilizing a carbamate bond, so the novel
beta-carboline-cycloenone derivatives are designed and synthesized. The derivatives
realize pH and GSH dual-response fluorescence imaging and diagnosis in a tumor
microenvironment, and can selectively target to GSTpi highly-expressed in tumor
tissue, so tumor cell proliferation can be significantly inhibited. Such a pH/GSH dual
10 response fluorescence and cancer-targeting treatment diagnosis and treatment drug
provides a new choice for accurate diagnosis and targeting treatment of tumors, and
broadens the application of multifunctional molecules in accurate medical treatment.
Description
pH/Glutathione-Responsive p-Carbolines/cycloketene Derivatives and their Preparation and Application Technical field The present invention relates to the field of biomedicine, in particular to pH/glutathione dual-responsive p-carbolines/cycloketene derivatives and their prepatation method, as well as pharmaceutical applications with targeting GSH/GSTxt to inhibit tumor proliferation, especially in the application of diagnostic and therapeutic agents against tumor. Background technology Malignant tumors are a serious threat to human health and life, and the number of deaths from cancer has risen rapidly. It has become the world's first lethal disease and a global challenge. Now, the development of theranostic agents has been one of the hotspots in the field of medicine, which combines diagnosis and treatment into one. When the diagnosis is being performed, the effective treatment (surgery and/or medicines) is given immediately which can improve the theranostic efficiency and the specificity of drug release. Among them, there are mainly small molecule theranostic agents and macromolecular theranostic agents. The former is easier to prepare, usually using the prodrug strategy through covalent bonds linking anti-cancer medicine, imaging agent, and an activation unit. Small-molecule theranostic agents generally have better fluorescence imaging ability, and could be induced by tumor cell-related molecules to synergistically release original drugs so as to increase the selectivity to tumors, and thereby improve the anti-cancer effect. Compared with macromolecular or nano-theranostic agents, these small molecule theranostic agents have better biocompatibility and cell absorption. A tumor microenvironment (TME), the special environment formed by the interactions between tumor cells and cell surroundings during the tumor cell growth process, plays a pivotal role during tumor initiation, progression, and metastasis, and significantly influences therapeutic response and clinical outcome. The differences in the physical and chemical properties of the TME from normal tissue have been widely developed for targeted therapy in order to improve therapeutic efficacy and reduce side effects. Considering that the tumor cells and their microenvironment undergo glycolysis under hypoxic conditions to excrete H+, the tumor tissue shows obvious slightly acidic (pH 6.5-6.8), while the normal tissue pH is 7.2-7.4. Furthermore, there
are organelles with higher acidity in tumor cells, such as lysosomes (pH 4.5-5.0). Therefore, the study of pH-sensitive fluorescent probes allows them to selectively target tumor cells and their microenvironment. However, traditional pH-sensitive fluorescent probes are mainly activated by acid-sensitive hydrazone bonds or acetal fragments, but these groups generally have some problems such as instability in vivo, slower coloration, and easy metabolism. The glutathione-S-transferase (GSTs) is a multifunctional isoenzyme widely found in mammals. Its main function is to catalyze the sulhydryl group of glutathione (GSH) nucleophilic attacks on endogenous or exogenous electrophilic groups (such as carbon, nitrogen, sulfur, etc.) to undergo coupling reactions to form more water soluble metabolites, which are easily excreted from bile or urine. The structure of GSTs is greatly related to the occurrence and progression of human diseases. According to the amino acid sequence, physical structure and immune cross reactivity, human cytoplasmic GSTs can be divided into 7 subtypes, namely: a, t, t,
o, 0, co and (. And the human glutathione transferase a isozyme (GST) is a key member of the family of glutathione transferase (GST) proteins that catalyze the nucleophilic attack and conjugation of GSH with reactive electrophiles. GSTh is overexpressed in many cancer cells, such as breast and colon cancer, and in medicine resistant tumors and is associated with cell carcinogenesis, tumor formation, and medicine resistance of human tissues. This feature of GSTx makes it an important target in the design of anti-tumor medicine promedicines. In view of this, the use of high expressed GSTI in tumor tissues to develop and design chemotherapy medicines and probes has great application value.
Summary of the invention The present invention is based on the structural modification of the natural indole alkaloid p-carboline with anti-tumor activity. The P-carboline is connected to the cycloketene through the carbamate bond, and the electron donor group is introduced to p-carboline to produce pH-sensitive fluorescence and emit fluorescence at 492 nm after being covalently bound to GSH. At the same time, it can target GST[, which significantly enhances the anti-tumor proliferation and metastasis activity of the compound, and achieves the diagnosis and precise treatment effects of cancer.
The specific technical scheme of the present invention is as follows: A class of p-carboline/cycloalkenone derivatives has the general structure shown in the following general formula:
R4 oO N R/ \N0 ./N N R3
Ri Ri or R2 are same or different, representing one or more substituents on the corresponding substituted ring, selected from one or more of H, amino, halogen, hydroxyl, nitro, alkoxy, alkyl, and alkylamino. When Ri or R2 represents multiple substituents, each substituent is same or different; R3 is selected from H, benzyl, allyl, alkyl, methoxyalkyl; 0
oa' R4 is selected from H, alkyl, methoxyalkyl or n , n=l, 2 or 3; Preferably, R 1 or R2 is selected from one or more of H, amino, halogen, hydroxy, nitro, Cl-C6 alkoxy, Cl-C6 alkyl, Cl-C6 alkylamino, and more preferably one or more of H, F, Cl, Br,I, hydroxyl, amino, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, methylethylamino, N,N-dimethylamino; R3 is selected from H, benzyl, allyl, C-C6 alkyl, C-C6 methoxyalkyl, more preferably H, benzyl, allyl, methyl, ethyl, propyl, isopropyl Group, methoxymethyl, methoxyethyl, methoxypropyl or methoxyisopropyl; 0
R4 is selected from H, Cl-C6 alkyl, Cl-C6 methoxyalkyl or n , and more preferably H, methyl, ethyl, propyl, isopropyl, methoxymethyl, methoxyethyl, 0
0
methoxypropyl, methoxyisopropyl or n ,n=1, 2 or 3.
A specific class of p-carboline/cycloketene derivatives of the present invention, where in Ri represents: 3,4,5-Tri-OCH 3 , 4-CH 3 , 3-OCH 3 , 4-OCH 3 , 4-N,N-Di-CH 3 , 2,4 -Di-OCH3, 2,5-Di-OCH 3 , 3,4-Di-OCH 3 or 3,5-Di-OCH 3 ; R2 or R3 represent H; 0
R4 represents H or n , n=1, 2 or 3. The p-carboline/cycloketene derivatives involved in the specific embodiments of the present invention have the following structure: 0
H O N n 0 h
Compd. R n Compd. R n I1 3,4,5-Tri-OCH 3 n=2 III 3,4,5-Tri-OCH 3 n=2
12 4-CH 3 n=2 112 4-CH 3 n=2
13 3-OCH 3 n=2 113 3-OCH 3 n=2
14 4-OCH 3 n=2 114 4-OCH 3 n=2
15 4-N,N-Di-CH 3 n=2 115 4-N,N-Di-CH 3 n=2
I6 2,4- Di-OCH 3 n=2 116 2,4- Di-OCH 3 n=2
17 2,5- Di-OCH 3 n=2 117 2,5- Di-OCH 3 n=2
18 3,4-Di-OCH 3 n=2 118 3,4-Di-OCH 3 n=2
19 3,5-Di-OCH 3 n=2 119 3,5-Di-OCH 3 n=2
Iio 3,4,5-Tri-OCH 3 n= IIio 3,4,5-Tri-OCH 3 n=1
Iii 4-N,N-Di-CH 3 n=1 IiiI 4-N,N-Di-CH 3 n=1
112 3,4,5-Tri-OCH 3 n=3 1112 3,4,5-Tri-OCH3 n=3 113 4-N,N-Di-CH 3 n=3 1113 4-N,N-Di-CH 3 n=3
Ii: (6-oxocyclohex-1-en-I-yl)methyl (1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; IIi: Di(6-oxocyclohex-1-en-1-yl)methy (1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; 12: (6-oxocyclohex-1-en-I-yl)methyl (1-(p-tolyl)-9H-pyrido[3,4-b]indol-3 yl)carbamate; 112: Di(6-oxocyclohex-1-en-I-yl)methyl (1-(p-tolyl)-9H-pyrido[3,4-b]indol-3 yl)carbamate; 13:(6-oxocyclohex-i-en-1-yl)methyl(1-(3-methoxyphenyl)-9H-pyrido[3,4-b]indol-3 yl)carbamate; 113: Di(6-oxocyclohex-I-en-I-yl)methyl (1-(3-methoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; 14:(6-oxocyclohex-i-en-1-yl)methyl(1-(4-methoxyphenyl)-9H-pyrido[3,4-b]indol-3 yl)carbamate; 114: Di(6-oxocyclohex-I-en-I-yl)methyl (1-(4-methoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; 15: (6-oxocyclohex-i-en-1-yl)methyl (1-(4-(dimethylamino)phenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; II: Di(6-oxocyclohex-I-en-I-yl)methyl (1-(4-(dimethylamino)phenyl)-9H pyrido[3,4-b]indol-3-yl)carbamate; 16: (6-oxocyclohex-I-en-I-yl)methyl (1-(2,4-dimethoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; 116: Di(6-oxocyclohex-i-en-1-yl)methyl (1-(2,4-dimethoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; 17: (6-oxocyclohex-I-en-I-yl)methyl (1-(2,5-dimethoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; 117: Di(6-oxocyclohex-i-en-1-yl)methyl (1-(2,5-dimethoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; 18: (6-oxocyclohex-I-en-I-yl)methyl (1-(3,4-dimethoxyphenyl)-9H-pyrido[3,4
b]indol-3-yl)carbamate; 118: Di(6-oxocyclohex-1-en-1-yl)methyl (1-(3,4-dimethoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; 19: (6-oxocyclohex-1-en-I-yl)methyl (1-(3,5-dimethoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; 119: Di(6-oxocyclohex-1-en-1-yl)methyl (1-(3,5-dimethoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; Iio: (5-oxocyclopent-1-en-1-yl)methyl (1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; IIio: Di(5-oxocyclopent-i-en-1-yl)methyl (1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; Il: (5-oxocyclopent--en-1-yl)methyl (1-(4-(dimethylamino)phenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; lIIn: Di(5-oxocyclopent-I-en-I-yl)methyl (1-(4-(dimethylamino)phenyl)-9H pyrido[3,4-b]indol-3-yl)carbamate; 112: (7-oxocyclohept-i-en-1-yl)methyl (1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; 1112: Di(7-oxocyclohept--en-1-yl)methyl (1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; 113: (7-oxocyclohept-i-en-1-yl)methyl (1-(4-(dimethylamino)phenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; 1113: Di(7-oxocyclohept-I-en-I-yl)methyl (1-(4-(dimethylamino)phenyl)-9H pyrido[3,4-b]indol-3-yl)carbamate.
Another object of the present invention is to provide a method of preparing the compounds of formula the present invention, comprising the following steps: (1) Compound 1 is reacted with hydrazine hydrate to obtain compound 2, preferably reacted with 85% hydrazine hydrate in methanol, 0 0 NNH 2 R R- H \, N; NH2NH2 H20 - \N N N R3 \ R3 \
1 R1 2 R .
(2) Compound 2 is reacted with NaNO2 under acidic conditions, preferably dilute hydrochloric acid to obtain compound 3,
0NH 2 N N3 \/N NaNO 2 N o N R3 R3
2 R1 3 R
. (3) Compound 3 is reacted under acidic conditions, preferably aqueous acetic acid, to obtain compound 4, 0 NH 2 N3
3 R, 4 Ri
(4) Compound 5 is reacted with p-nitrophenyl chloroformate under alkaline conditions, preferably DIPEA, to obtain compound 6, 0 NO2 NO 2 0 O OHC A 0 0
5 n 6
(5) Compound 4 and compound 6 are reacted under alkaline conditions, preferably DIPEA, to obtain compound 7 and/or compound 8, 0
0 0 NH2 H o0 N 6 R R2 N \ + \N R, /\ N N R, 4 R, R, R,
7 8
Alternatively, the above synthesis step also includes step (6) that compound 7 reacts with benzyl bromide, allyl bromide or alkyl bromide under the condition of sodium hydrogen to obtain compound 9.
H 0OO
N N R3 R3
Ri
7 9
Ri or R2 are same or different, representing one or more substituents on the corresponding substituted ring, selected from one or more of H, amino, halogen, hydroxyl, nitro, alkoxy, alkyl, and alkylamino; When R1 or R2 represents multiple substituents, each substituent is same or different; R3 is selected from H, benzyl, allyl, alkyl, methoxyalkyl; R4 is selected from H, alkyl or methoxyalkyl; n=1, 2 or 3. Another object of the present invention is to provide the application of thep carboline/cycloketene derivatives in the preparation of GST-targeting medicines or probes. On the one hand, when catalyzed by the highly expressed GSTh in tumor tissue, GSH can specifically conjugate with the cycloketene fragment of p carboline/cycloketene derivative and undergo Michael addition to emit GSH responsive fluorescence. The compounds of the present invention also exhibit remarkable pH-responsive fluorescence. When the pH drops from 8 to 4, the fluorescence intensity can significantly increase. On the other hand, after targeting GST, the p-carboline/cycloketene derivatives of the present invention can be selectively activated by GSH/GSTn in tumor cells to release the active fragment 2 exomethylene-3-glutathionyl-cyclohexanone and p-carboline fragments, therefore generating significant anti-proliferation, anti-metastasis activities, and other pharmacological activities. The GSTi-targeting drug is for treating and/or preventing cancer. Preferably, the cancer is selected from liver cancer, colon cancer, cervical cancer, or gastric cancer. The compounds of the present invention possess excellent fluorescence imaging,
high selectivity to solid tumors, and can achieve the dual purpose of diagnosis
+ treatment. The compound of the present invention can be used alone or in combination with one or more pharmaceutically acceptable carriers to prepare preparations for supplying medicine. For example, solvents, diluents, etc., can also be used in oral dosage forms such as capsules, dispersibles, powders, tablets, granules, etc. The various dosage forms of the pharmaceutical composition of the present invention can be prepared according to methods well known in the pharmaceutical field. These pharmaceutical preparations may contain, for example, 0.05% to 90% by weight of active ingredients in combination with a carrier, more commonly about 15% to 60% of the weight of the active ingredient. The dose of the compound of the present invention can be 0.005 to 5000 mg/kg/day, and the dosage can also exceed this dosage range according to the severity of the disease or the different dosage forms. The compounds of the present invention can self-assemble into nanoparticles to improve activity alone, or be combined with other anti-tumor drugs such as alkylating agents (such as cyclophosphamide or chlorambucil), antimetabolites (such as 5 fluorouracil or hydroxyurea), topological Isomerase inhibitors (such as camptothecin), mitotic inhibitors (such as paclitaxel or vinblastine), DNA intercalators (such as doxorubicin) to improve activity, and can also be combined with radiotherapy. Other anti-tumor drugs or radiotherapy can be administered with the compounds of this invention at the same time or at different times. These combined treatments can produce a synergistic effect to help improve the therapeutic effect. The invention combines the structural features, structure-activity relationship and pharmacophore model of the anti-tumor drug 2-crotonyloxymethyl-2-cyclohexene (COMC-6) and the natural alkaloid p-carboline with moderate anti-tumor activity. The compounds of the present invention can selectively produce fluorescence in tumor cells through pH or GSH/GST, adopt the prodrug strategy to release active fragments, and realized tumor selective fluorescence imaging and therapy. The research results of the present invention in malignant tumor cells show that these type of compounds not only perform the pre-diagnosis of cancer cells through fluorescent signals, but also strongly inhibit the proliferation of various tumor cells such as liver cancer, colon cancer, and cervical cancer. The compounds of the present invention have many advantages such as ingenious design, excellent selectivity to GSH, high
anti-tumor activity and low toxicity. It may be utilized as a sensor for intracellular GSH/GSTi fluorescence imaging with high selectivity, and can be directly observed easily. Real-time monitoring also plays an important role in the detection, imaging, and treatment of cancer cells. Description of Fictures Figure 1. The pH response ultraviolet spectrum and fluorescence spectrum of Ii. (A) Absorption spectra of compound Ii at pH 3-8. (B) Fluorescence emission spectrum of compound Ii at pH 3-8 (Ex = 445 nm). (C) Absorbance-pH titration profiles of Ii at an absorption wavelength of 445 nm. (D) Fluorescence intensity-pH titration profiles of Ii at an emission wavelength of 490 nm. Figure 2. The GSH response ultraviolet spectrum and fluorescence spectrum of Ii. (A) Absorption spectra of Ii in the presence of varying amounts of GSH (0-10 equiv) with cat. GST. The spectra were recorded after incubation at 37 °C for 0.5 h. (B) Fluorescence emission spectrum of Ii at 492 nm as a function of varying concentrations of GSH with cat. GSTR (Xex = 445 nm). (C) Fluorescence intensity-concentration (GSH) titration profiles of HJTA at an emission wavelength of 492 nm. (D) GSH concentration (0, 5, 15, 25, and 50 M)-dependent fluorescence activation rates of Ii. Figure 3. Fluorescence response of Ii with cat. GSTR after treatment with various biological analytes. Bars represent comparative fluorescence changes at 492 nm, Xex = 440 nm.
Figure 4. Confocal microscopy images of HT29 cells treated with compounds. Figure 5. Ex vivo fluorescence imaging of Ii. Figure 6. Antitumor effect of Ii on HT29 xenograft in nude mice Detailed description To further clarify the present invention, the following series of examples are given. These embodiments are purely illustrative and only used detailed description of the present invention, which should not be construed as limiting the present invention. Example 1 Synthesis of (6-oxocyclohex-1-en-1-yl)methyl (1-(3,4,5 trimethoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)carbamate(Ii)ordi(6-oxocyclohex-1 en-I-yl)methyl (1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)carbamate (II1)
0 0 o 0 O S C1 NO2 O DIPEA, DCM 6
0 NH2 N3 NH 2
- \ N NH 2NH 2 H 2O \ \,N NaNO 2 , HCI \ \,N HAc, H 2 0 \ / \,N N N N N H H H H
I R 2 R 3 R 4 R 0 n O
H 0 70 0 6 N__ DIPEA, DCM /N
NN +
(1) 1-(3,4,5-Trimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-carbohydrazide (2a) The compound 1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4-b]indole-3 carboxylate (la) (19.6 g, 50 mmol) was dissolved in 80 mL of methanol, and than 176.4 mL of 85% hydrazine hydrate (75 g, 1.50 mol) was added, refluxing for 4-5 h. After TLC monitored the total consumption of starting material, the reaction mixture was cooled to 0 °C. A light brown solid was obtained by vacuum pump suction filtration. Adding a lot of cold water to in the filtrate, the solid continued to separate out, and vacuum-dried after suction filtration to obtain 16.5 g of a light brown solid, with a yield of 84.2%. (2) 1-(3,4,5-Trimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-carbonyl azide (3a) After dissolving compound (2a) (19.6 g, 50 mmol) with 2mol/L HCl solution (80 mL) and stirring in an ice bath, NaNO2 (10.4 g, 150 mmol) in 60 mL of H 20was added dropwise into the compound (2a) solution. After stirring for 1-4 h, TLC monitored the completion of the reaction. The pH of the reaction mixture was adjusted to 7-8 with 1 mol/L NaOH solution, and a light yellow solid precipitated. After suction filtration, the solid product was dried in vacuum to 17.8 g, with a yield of 88.4%. (3) 1-(3,4,5-Trimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-amine (4a) After dissolving compound (3a) (20.1 g, 50 mmol) in a mixture of 100 mL of water and glacial acetic acid (1:1), the reaction was stirred at 90 °C for 4-5 h. After
TLC monitored the total consumption of starting material, the reaction mixture was concentrated in vacuo, and finally purified by flash column chromatography to obtain a light yellow solid (8.4 g), with a yield of 48.2%. ESI-MS (m/z): 350 [M + H]*. (4) 4-Nitrophenyl ((6-oxocyclohex-1-en-I-yl)methyl) carbonate (6b) Compound (5b) (1.3 g, 10 mmol) and 4-nitrophenyl carbonochloridate (3.1 g, 15 mmol) were dissolved in 15 mL dry CH 2 Cl2 cooled to 0 °C. DIPEA (3.9 g, 30 mmol) was added and the mixture was stirred for 2 h at 0 °C, at which point reaction was completed. The mixture was diluted with CH 2 Cl2 (40 mL), washed with saturated aqueous NaHCO3 (15 mL), and brine. Then organic layer was dried with Na2SO 4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using Petroleum ether/EtOAc (8:1, v/v) as eluent to afford 6b as a yellow solid (1.8 g, 62.1%). (5) (6-Oxocyclohex-1-en-1-yl)methyl (1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate (Ii) or di(6-oxocyclohex-1-en-1-yl)methyl (1-(3,4,5 trimethoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)carbamate(IIi) Compound 6b (2.9 g, 10 mmol) and compound 4a (3.49 g, 10 mmol) were dissolved in 20 mL of dry CH2 Cl2 at 0 °C, and DIPEA (505 mg, 5.0 mmol) was added to the above solution, and the mixture was stirred at room temperature for 4 h. The solvent was evaporated under vacuum. The crude solid was purified with a silica gel column using petroleum ether/EtOAc (2:1, v/v) as the eluent to obtain HJTA (1.8 g, 35.6%) and HJTB (1.1 mg, 21.9%). Analytical data for Ii: ESI-MS (m/z): 524
[M+Na]*; 'H NMR (d-DMSO, 400 MHz): 610.83 (s, 1H, NH), 8.07 (d, J= 7.8 Hz, 1H, NH), 7.46 (q, J= 8.0 Hz, 2H, Ar-H), 7.21 (s, 2H, Ar-H), 7.13 - 7.09 (m, 2H, Ar H), 6.99 (s, 1H, Ar-H), 6.15 (d, J= 19.6 Hz, 1H, CH), 4.10 (s, 2H, CH2), 3.91 (s, 6H, CH 3), 3.76 (s, 3H, CH 3), 2.43 - 2.36 (m, 2H, CH 2), 2.36 - 2.30 (m, 2H, CH 2 ), 1.95 1.87 (m, 2H, CH2 ). 13C NMR (d6 -DMSO, 101 MHz): 6 199.32, 153.40, 152.53, 145.79, 143.03, 138.17, 137.03, 128.37, 127.91, 126.62, 121.98, 121.31, 112.48, 106.11, 95.58, 60.54, 56.32, 38.55, 25.67, 23.18. Analytical data for IIi: ESI-MS (m/z): 654 [M+H]*; 'H NMR (d6 -DMSO, 400 MHz): 610.89 (s, 1H, NH), 8.15 (d, J= 8.1 Hz, 1H, Ar-H), 7.50 - 7.43 (m, 2H, Ar-H), 7.23 (s, 2H, Ar-H), 7.18 (s, 1H, Ar-H), 7.13 - 7.09 (m, 1H, Ar-H), 6.73 (s, 2H, CH), 4.35 (s, 4H, CH2), 3.89 (s, 6H, CH 3 ), 3.76 (s, 3H, CH3), 2.42 - 2.37 (m, 4H, CH2 ), 2.31 (s, 4H, CH 2 ), 1.92 - 1.90 (m, 4H, CH 2 ). 13C NMR (d6-DMSO, 101 MHz): 6199.83, 153.35, 151.48, 145.43, 142.93,
138.40, 137.96, 134.78, 134.66, 134.06, 128.45, 127.45, 122.32, 105.78, 56.14, 47.57, 38.57, 25.66, 23.16. Example 2 Synthesis of (6-oxocyclohex-1-en-1-yl)methyl (1-(p-tolyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate (12) or di(6-oxocyclohex-1-en-1-yl)methyl (1-(p-tolyl)-9H pyrido[3,4-b]indol-3-yl)carbamate (112) 1-(P-tolyl)-9H-pyrido[3,4-b]indole-3-carbohydrazide (2b) Referring to the synthesis of (2a) in Example 1, (lb) was substituted for (la) in the method, and finally a light yellow solid (2b) was obtained with a yield of 80.9%. 1-(P-tolyl)-9H-pyrido[3,4-b]indole-3-carbonyl azide (3b) Referring to the synthesis of (3a) in Example 1, (2b) was substituted for (2a) in the method, and finally a light yellow solid (3b) was obtained with a yield of 87.5%. 1-(P-tolyl)-9H-pyrido[3,4-b]indole-3-amine (4b) With reference to the synthesis of (4a) in Example 1, (3b) was substituted for (3a) in the method, and finally a light yellow solid (4b) was obtained with a yield of 50.7%. ESI-MS (m/z): 274 [M + H]*. (6-Oxocyclohex-1-en-1-yl)methyl (1-(p-tolyl)-9H-pyrido[3,4-b]indol-3-yl)carbamate (12) or di(6-oxocyclohex-1-en-1-yl)methyl (1-(p-tolyl)-9H-pyrido[3,4-b]indol-3 yl)carbamate (112) Referring to the synthesis method of (Ii) in Example 1, replacing (4a) in the method by (4b), and finally obtaining light yellow solids (12) and (112), with yields of 34.1% and 22.3%, respectively. Analytical data for 12: ESI-MS (m/z): 426 [M+H]*; 1 H NMR (d-DMSO, 400 MHz): 610.78 (s, 1H, NH), 8.11 (d, J= 7.8 Hz, 1H, NH), 7.50 - 7.36 (m, 2H, Ar-H), 7.28 - 7.20 (m, 3H, Ar-H), 7.11 - 7.02 (m, 3H, Ar-H), 6.94 (s, 1H, Ar-H), 6.19 (d, J= 19.5 Hz, 1H, CH), 4.16 (s, 2H, CH 2), 3.03 (s, 3H, CH 3),2.45 2.38 (m, 2H, CH 2), 2.36 - 2.32 (m, 2H, CH2 ), 1.96 - 1.84 (m, 2H, CH 2). Analytical data for 112: ESI-MS (m/z): 578 [M+H]*; 'H NMR (d-DMSO, 400 MHz): 610.80 (s, 1H, NH), 8.11 (d, J= 8.1 Hz, 1H, Ar-H), 7.59 - 7.47 (m, 2H, Ar-H), 7.38 - 7.25 (m, 3H, Ar-H), 7.21 (s, 1H, Ar-H), 7.15 - 7.11 (m, 2H, Ar-H), 6.79 (s, 2H, CH), 4.39 (s, 4H, CH2 ), 3.16 (s, 3H, CH 3), 2.41 - 2.35 (m, 4H, CH 2), 2.28 (s, 4H, CH2 ), 1.95 - 1.92 (m, 4H, CH 2 ). Example 3 Synthesis of (6-oxocyclohex-1-en-1-yl)methyl (1-(3-methoxyphenyl)-9H pyrido[3,4-b]indol-3-yl)carbamate (13) or di(6-oxocyclohex-1-en-1-yl)methyl (1-(3 methoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)carbamate (113)
1-(3-Methoxyphenyl)-9H-pyrido[3,4-b]indole-3-carbohydrazide (2c) Referring to the synthesis of (2a) in Example 1, (1c) was substituted for (la) in the method, and finally a light yellow solid (2c) was obtained with a yield of 81.3%. 1-(3-Methoxyphenyl)-9H-pyrido[3,4-b]indole-3-carbonyl azide (3c) Referring to the synthesis of (3a) in Example 1, (2c) was substituted for (2a) in the method, and finally a light yellow solid (3c) was obtained with a yield of 88.4%. 1-(3-Methoxyphenyl)-9H-pyrido[3,4-b]indole-3-amine (4c) Referring to the synthesis of (4a) in Example 1, (3c) was substituted for (3a) in the method, and finally a light yellow solid (4c) was obtained with a yield of 52.3%. ESI-MS (m/z): 290 [M + H]*. (6-Oxocyclohex-1-en-I-yl)methyl (1-(3-methoxyphenyl)-9H-pyrido[3,4-b]indol-3 yl)carbamate (13) or di(6-oxocyclohex-1-en-1-yl)methyl (1-(3-methoxyphenyl)-9H pyrido[3,4-b]indol-3-yl)carbamate (113) Referring to the synthesis method of (Ii) in Example 1, replacing (4a) in the method by (4c), and finally obtaining light yellow solids (13) and (113) with yields of 30.4% and 21.8%, respectively. Analytical data for 13: ESI-MS (m/z): 442 [M+H]* ; H NMR (d-DMSO, 400 MHz): 610.79 (s, 1H, NH), 8.04 (s, 1H, NH), 7.43 - 7.39 (m, 3H, Ar-H), 7.23 - 7.18 (m, 3H, Ar-H), 7.15 (s, 2H, Ar-H), 6.97 (s, 1H, Ar-H), 6.13 (d, J= 19.6 Hz, 1H, CH), 4.08 (s, 2H, CH 2), 3.88 (s, 3H, CH3), 2.41 - 2.35 (m, 2H, CH 2), 2.33 - 2.29 (m, 2H, CH2 ), 1.94 - 1.85 (m, 2H, CH2). Analytical data for113: ESI-MS (m/z): 594 [M+H] ; 'H NMR (d-DMSO, 400 MHz): 610.87 (s, 1H, NH), 8.14 (d, J= 8.0 Hz, 1H, Ar-H), 7.48 - 7.42 (m, 3H, Ar-H), 7.25 (s, 2H, Ar-H), 7.19 (s, 1H, Ar-H), 7.11 - 7.08 (m, 2H, Ar-H), 6.71 (s, 2H, CH), 4.33 (s, 4H, CH2), 3.85 (s, 6H, CH3), 2.41 - 2.35 (m, 4H, CH2), 2.31 - 2.19 (m, 4H, CH 2 ), 1.94 - 1.89 (m, 4H, CH 2 ). Example 4 Synthesis of (6-oxocyclohex-1-en-1-yl)methyl (1-(4-methoxyphenyl)-9H pyrido[3,4-b]indol-3-yl)carbamate (14) or di(6-oxocyclohex-1-en-1-yl)methyl (1-(4 methoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)carbamate (114) 1-(4-Methoxyphenyl)-9H-pyrido[3,4-b]indole-3-carbohydrazide (2d) Referring to the synthesis of (2a) in Example 1, (1d) was substituted for (la) in the method, and finally a light yellow solid (2d) was obtained with a yield of 82.0%. 1-(4-Methoxyphenyl)-9H-pyrido[3,4-b]indole-3-carbonyl azide (3d) Referring to the synthesis of (3a) in Example 1, (2d) was substituted for (2a) in
the method, and finally a light yellow solid (3d) was obtained with a yield of 87.4%. 1-(4-Methoxyphenyl)-9H-pyrido[3,4-b]indole-3-amine (4d) Referring to the synthesis of (4a) in Example 1, (3d) was substituted for (3a) in the method, and finally a light yellow solid (4d) was obtained with a yield of 52.5%. ESI-MS (m/z): 290 [M + H]*. (6-Oxocyclohex-1-en-I-yl)methyl (1-(4-methoxyphenyl)-9H-pyrido[3,4-b]indol-3 yl)carbamate (14) or di(6-oxocyclohex-1-en-1-yl)methyl (1-(4-methoxyphenyl)-9H pyrido[3,4-b]indol-3-yl)carbamate (114) Referring to the synthesis of (Ii) in Example 1, (4d) was substituted for (4a) in the method, and finally light yellow solids (14)and (114) were obtained, and the yields were 35.1% and 22.6%, respectively. Analytical data for 14: ESI-MS (m/z): 442
[M+H]* ; 'H NMR (d6-DMSO, 400 MHz): 610.83 (s, 1H, NH), 8.04 (d, J= 7.8 Hz, 1H, NH), 7.44 - 7.39 (m, 2H, Ar-H), 7.24 - 7.17 (m, 3H, Ar-H), 7.14 - 7.08 (m, 2H, Ar-H), 6.97 (s, 2H, Ar-H), 6.12 (d, J= 19.6 Hz, 1H, CH), 4.12 (s, 2H, CH 2), 3.83 (s, 3H, CH3), 2.41 - 2.34 (m, 2H, CH2), 2.35 - 2.32 (m, 2H, CH 2 ), 1.98 - 1.87 (m, 2H, CH 2). Analytical data for 114: ESI-MS (m/z): 594 [M+H]* ; 'H NMR (d-DMSO, 400 MHz): 610.90 (s, 1H, NH), 8.17 (s, 1H, Ar-H), 7.55 - 7.48 (m, 2H, Ar-H), 7.33 - 7.29 (m, 2H, Ar-H), 7.22 (s, 2H, Ar-H), 7.18 - 7.10 (m, 2H, Ar-H), 6.77 (s, 2H, CH), 4.37 (s, 4H, CH 2), 3.80 (s, 6H, CH3 ), 2.41 - 2.37 (m, 4H, CH 2), 2.30 - 2.19 (m, 4H, CH 2 ), 1.94 - 1.90 (m, 4H, CH 2 ). Example 5 Synthesis of (6-oxocyclohex-1-en-I-yl)methyl (1-(4 (dimethylamino)phenyl)-9H-pyrido[3,4-b]indol-3-yl)carbamate (15) or di(6 oxocyclohex-1-en-1-yl)methyl (1-(4-(dimethylamino)phenyl)-9H-pyrido[3,4-b]indol 3-yl)carbamate (IIs) 1-(4-(dimethylamino)phenyl)-9H-pyrido[3,4-b]indole-3-carbohydrazide (2e) Referring to the synthesis of (2a) in Example 1, replacing (la) in the method by (le), and finally obtain a red solid (2e) with a yield of 8.1% 1-(4-(dimethylamino)phenyl)-9H-pyrido[3,4-b]indole-3-carbonyl azide (3e) Referring to the synthesis of (3a) in Example 1, (2e) was substituted for (2a) in the method, and finally a brown solid (3e) was obtained with a yield of 80.9%. 1-(4-(dimethylamino)phenyl)-9H-pyrido[3,4-b]indole-3-amine (4e) Referring to the synthesis of (4a) in Example 1, (3e) was substituted for (3a) in the method, and finally a red solid (4e) was obtained with a yield of 45.8%. ESI-MS
(m/z): 303 [M + H]*. (6-Oxocyclohex-1-en-I-yl)methyl (1-(4-(dimethylamino)phenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate (15) or di(6-oxocyclohex-1-en-I-yl)methyl (1-(4 (dimethylamino)phenyl)-9H-pyrido[3,4-b]indol-3-yl)carbamate(IIs) Referring to the synthesis of (Ii) in Example 1, replacing (4a) in the method by (4e), and finally obtaining light red solids (Is) and (IIs), with yields of 32.7% and 19.1%, respectively. Analytical data forIs: ESI-MS (m/z): 455 [M+H]* ; 'H NMR (d6 DMSO, 400 MHz): 610.88 (s, 1H, NH), 8.09 (s, 1H, NH), 7.51 - 7.44 (m, 3H, Ar-H), 7.26 - 7.18 (m, 3H, Ar-H), 7.12 (s, 2H, Ar-H), 6.99 (s, 1H, Ar-H), 6.19 (d, J= 19.6 Hz, 1H, CH), 4.14 (s, 2H, CH 2), 3.99 (s, 6H, CH 3),2.45 - 2.37 (m, 2H, CH 2),2.38 2.32 (m, 2H, CH 2 ), 1.97 - 1.89 (m, 2H, CH 2). Analytical data for Is: ESI-MS (m/z): 607 [M+H]* ; 'H NMR (d6 -DMSO, 400 MHz): 610.95 (s, 1H, NH), 8.18 (s, 1H, Ar H), 7.50 - 7.43 (m, 3H, Ar-H), 7.30 - 7.24 (m, 2H, Ar-H), 7.19 (s, 2H, Ar-H), 7.14 7.10 (m, 1H, Ar-H), 6.79 (s, 2H, CH), 4.41 (s, 4H, CH 2), 4.04 (s, 6H, CH3),2.46 (s, 4H, CH2 ),2.31 - 2.25 (m, 4H, CH2 ), 1.94 - 1.85 (m, 4H, CH 2 ). Example 6 Synthesis of (6-oxocyclohex-1-en-1-yl)methyl (1-(2,4-dimethoxyphenyl) 9H-pyrido[3,4-b]indol-3-yl)carbamate (16) or di(6-oxocyclohex-1-en-1-yl)methyl (1 (2,4-dimethoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)carbamate(116) 1-(2,4-Dimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-carbohydrazide (2f) Referring to the synthesis of (2a) in Example 1, (if) was substituted for (la) in the method, and finally a light yellow solid (2f) was obtained with a yield of 87.1 %. 1-(2,4-Dimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-carbonyl azide (3f) Referring to the synthesis of (3a) in Example 1, (2f) was substituted for (2a) in the method, and finally a light yellow solid (3f) was obtained with a yield of 86.2%. 1-(2,4-Dimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-amine (4f) Referring to the synthesis of (4a) in Example 1, (3a) in the method was replaced by (3f), and finally a light yellow solid (4f) was obtained with a yield of 55.2%. ESI MS (m/z): 320 [M + H]*. (6-Oxocyclohex-1-en-1-yl)methyl (1-(2,4-dimethoxyphenyl)-9H-pyrido[3,4-b]indol 3-yl)carbamate (16) or di(6-oxocyclohex-1-en-1-yl)methyl (1-(2,4-dimethoxyphenyl) 9H-pyrido[3,4-b]indol-3-yl)carbamate(116) Referring to the synthesis of (Ii) in Example 1, (4f) was substituted for (4a) in the method, and finally light yellow solids (16) and(116)were obtained, and the yields
were 34.2% and 20.7%, respectively. Analytical data for 16: ESI-MS (m/z): 472
[M+H]+ ; 'H NMR (d6 -DMSO, 400 MHz): 610.79 (s, 1H, NH), 8.10 (s, 1H, NH), 7.47 - 7.36 (m, 3H, Ar-H), 7.28 (s, 1H, Ar-H), 7.19 - 7.10 (m, 3H, Ar-H), 7.02 (s, 1H, Ar H), 6.18 (d, J= 19.6 Hz, 1H, CH), 4.19 (s, 2H, CH2), 3.93 (s, 3H, CH 3), 3.78 (s, 3H, CH 3), 2.37 - 2.30 (m, 2H, CH 2),2.27 - 2.21 (m, 2H, CH2 ), 1.93 - 1.82 (m, 2H, CH 2 ). Analytical data for1I6: ESI-MS (m/z): 624 [M+H] ; 'H NMR (d-DMSO, 400 MHz): 610.95 (s, 1H, NH), 8.05 (s, 1H, Ar-H), 7.55 - 7.46 (m, 3H, Ar-H), 7.26 (s, 1H, Ar-H), 7.19 (s, 1H, Ar-H), 7.16 - 7.11 (m, 2H, Ar-H), 6.78 (s, 2H, CH), 4.39 (s, 4H, CH 2 ), 3.93 (s, 3H, CH3), 3.80 (s, 3H, CH3),2.45 - 2.36 (m, 4H, CH 2), 2.23 - 2.15 (m, 4H, CH 2 ), 1.90 - 1.82 (m, 4H, CH2 ). Example 7 Synthesis of (6-oxocyclohex-1-en-1-yl)methyl (1-(2,5-dimethoxyphenyl) 9H-pyrido[3,4-b]indol-3-yl)carbamate (17) or di(6-oxocyclohex-1-en-1-yl)methyl (1 (2,5-dimethoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)carbamate(117) 1-(2,5-Dimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-carbohydrazide (2g) Referring to the synthesis of (2a) in Example 1, (1g) was substituted for (la) in the method, and finally a light yellow solid (2g) was obtained with a yield of 85.1%. 1-(2,5-Dimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-carbonyl azide (3g) Referring to the synthesis of (3a) in Example 1, (2g) was substituted for (2a) in the method, and finally a light yellow solid (3g) was obtained, and the yield was 86.9%. 1-(2,5-Dimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-amine(4g) Referring to the synthesis of (4a) in Example 1, (3g) was substituted for (3a) in the method, and finally a light yellow solid (4g) was obtained with a yield of 52.4%. ESI-MS (m/z): 320 [M + H]*. (6-Oxocyclohex-1-en-1-yl)methyl (1-(2,5-dimethoxyphenyl)-9H-pyrido[3,4-b]indol 3-yl)carbamate (17) or di(6-oxocyclohex-1-en-1-yl)methyl (1-(2,5-dimethoxyphenyl) 9H-pyrido[3,4-b]indol-3-yl)carbamate(117) Referring to the synthesis method of (Ii) in Example 1, replacing (4a) in the method by (4g), and finally obtaining light yellow solids (17)and(117), the yields were 35.7% and 18.4%, respectively. Analytical data for 17: ESI-MS (m/z): 472 [M+H]* ; H NMR (d-DMSO, 400 MHz): 610.82 (s, 1H, NH), 8.04 (s, 1H, NH), 7.45 - 7.34 (m, 3H, Ar-H), 7.23 (s, 2H, Ar-H), 7.14 - 7.02 (m, 2H, Ar-H), 6.98 (s, 1H, Ar-H), 6.27 (d, J= 19.6 Hz, 1H, CH), 4.21 (s, 2H, CH2), 3.92 (s, 3H, CH 3), 3.79 (s, 3H, CH 3 ),
2.43 - 2.35 (m, 2H, CH2), 2.33 - 2.21 (m, 2H, CH2 ), 1.96 - 1.86 (m, 2H, CH2 ). Analytical data for 117: ESI-MS (m/z): 624 [M+H]* ; 'H NMR (d-DMSO, 400 MHz): 610.89 (s, 1H, NH), 8.12 (s, 1H, Ar-H), 7.62 - 7.51 (m, 2H, Ar-H), 7.31 - 7.22 (m, 3H, Ar-H),7.11 - 7.05 (m, 2H, Ar-H), 6.81 (s, 2H, CH), 4.29 (s, 4H, CH 2), 3.92 (s, 3H, CH 3), 3.66 (s, 3H, CH 3), 2.52 - 2.46 (m, 4H, CH2), 2.30 - 2.18 (m, 4H, CH 2 ), 1.93 - 1.89 (m, 4H, CH 2 ). Example 8 Synthesis of (6-oxocyclohex-1-en-1-yl)methyl (1-(3,4-dimethoxyphenyl) 9H-pyrido[3,4-b]indol-3-yl)carbamate (18) or di(6-oxocyclohex-1-en-1-yl)methyl (1 (3,4-dimethoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)carbamate (118) 1-(3,4-Dimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-carbohydrazide (2h) Referring to the synthesis of (2a) in Example 1, (1h) was substituted for (la) in the method, and finally a light yellow solid (2h) was obtained with a yield of 84.5%. 1-(3,4-Dimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-carbonyl azide (3h) Referring to the synthesis method of (3a) in Example 1, (2h) was substituted for (2a) in the method, and finally a light yellow solid (3h) was obtained with a yield of 86.7%. 1-(3,4-Dimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-amine (4h) Referring to the synthetic of (4a) in Example 1, (3a) in the method was replaced by (3h), and finally a light yellow solid (4h) was obtained with a yield of 51.7%. ESI MS (m/z): 320 [M + H]*. (6-Oxocyclohex-1-en-1-yl)methyl (1-(3,4-dimethoxyphenyl)-9H-pyrido[3,4-b]indol 3-yl)carbamate (18) or di(6-oxocyclohex-1-en-1-yl)methyl (1-(3,4-dimethoxyphenyl) 9H-pyrido[3,4-b]indol-3-yl)carbamate (118) Referring to the synthesis method of (Ii) in Example 1, (4a) in the method was replaced by (4h), and finally light yellow solids (18) and (118) were obtained, and the yields were 36.1% and 16.7%, respectively. Analytical data for 18: ESI-MS (m/z): 472
[M+H]* ; 'H NMR (d6-DMSO, 400 MHz): 610.77 (s, 1H, NH), 8.01 (d, J= 7.8 Hz, 1H, NH), 7.50 - 7.39 (m, 3H, Ar-H), 7.27 (s, 2H, Ar-H), 7.15 - 7.09 (m, 2H, Ar-H), 6.98 (s, 1H, Ar-H), 6.16 (d, J= 19.6 Hz, 1H, CH), 4.22 (s, 2H, CH2), 3.93 (s, 3H, CH 3), 3.78 (s, 3H, CH 3), 2.42 - 2.35 (m, 2H, CH 2), 2.31 - 2.23 (m, 2H, CH 2 ), 1.93 1.87 (m, 2H, CH2). Analytical data for 118: ESI-MS (m/z): 624 [M+H] ; 'H NMR (d6 DMSO, 400 MHz): 610.98 (s, 1H, NH), 8.09 (s, 1H, Ar-H), 7.55 - 7.46 (m, 3H, Ar H), 7.28 (s, 2H, Ar-H), 7.19 (s, 1H, Ar-H), 7.15 - 7.08 (m, 1H, Ar-H), 6.81 (s, 2H,
CH), 4.33 (s, 4H, CH2 ), 3.84 (s, 3H, CH3), 3.73 (s, 3H, CH3), 2.41 - 2.36 (m, 4H, CH 2), 2.29 - 2.24 (s, 4H, CH 2 ), 1.92 - 1.88 (m, 4H, CH2 ). Example 9 Synthesis of (6-oxocyclohex-1-en-1-yl)methyl (1-(3,5-dimethoxyphenyl) 9H-pyrido[3,4-b]indol-3-yl)carbamate (19) or di(6-oxocyclohex-1-en-1-yl)methyl (1 (3,5-dimethoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)carbamate (119) 1-(3,5-Dimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-carbohydrazide (2i) Referring to the synthesis of (2a) in Example 1, (li) was substituted for (la) in the method, and finally a light yellow solid (2i) was obtained with a yield of 81.0%. 1-(3,5-Dimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-carbonyl azide (3i) Referring to the synthesis of (3a) in Example 1, (2i) was used to replace (2a) in the method, and finally a light yellow solid (3i) was obtained with a yield of 85.7%. 1-(3,5-Dimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-amine (4i) Referring to the synthesis of (4a) in Example 1, (3i) was substituted for (3a) in the method, and finally a light yellow solid (4i) was obtained with a yield of 53.2%. ESI-MS (m/z): 320 [M + H]*. (6-Oxocyclohex-1-en-1-yl)methyl (1-(3,5-dimethoxyphenyl)-9H-pyrido[3,4-b]indol 3-yl)carbamate (19) or di(6-oxocyclohex-1-en-1-yl)methyl (1-(3,5-dimethoxyphenyl) 9H-pyrido[3,4-b]indol-3-yl)carbamate (119) Referring to the synthesis of (Ii) in Example 1, (4a) in the method was replaced by (4i), and finally light yellow solids (19) and (119) were obtained, and the yields were 34.4% and 24.1%, respectively. Analytical data for 19: ESI-MS (m/z): 472 [M+H]* ; H NMR (d-DMSO, 400 MHz): 610.82 (s, 1H, NH), 8.06 (d, J= 7.8 Hz, 1H, NH), 7.49 - 7.39 (m, 3H, Ar-H), 7.24 (s, 2H, Ar-H), 7.13 - 7.08 (m, 2H, Ar-H), 6.98 (s, 1H, Ar-H), 6.52 (d, J= 19.6 Hz, 1H, CH), 4.09 (s, 2H, CH 2), 3.92 (s, 6H, CH3), 2.43 2.35 (m, 2H, CH 2), 2.36 - 2.31 (m, 2H, CH2 ), 1.96 - 1.87 (m, 2H, CH 2). Analytical data for 119: ESI-MS (m/z): 624 [M+H] ; 'H NMR (d-DMSO, 400 MHz): 610.85 (s, 1H, NH), 8.12 (d, J= 8.0 Hz, 1H, Ar-H), 7.52 - 7.46 (m, 3H, Ar-H), 7.22 (s, 2H, Ar H), 7.19 (s, 1H, Ar-H), 7.14 - 7.08 (m, 1H, Ar-H), 6.76 (s, 2H, CH), 4.38 (s, 4H, CH 2), 3.87 (s, 6H, CH 3), 2.42 - 2.36 (m, 4H, CH2), 2.27 - 2.19 (s, 4H, CH2), 1.91 1.86 (m, 4H, CH 2 ). Example 10 Synthesis of (5-oxocyclopent-1-en-1-yl)methyl (1-(3,4,5 trimethoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)carbamate (Iio)or di(5-oxocyclopent 1-en-1-yl)methyl (1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)carbamate
(IIio) 4-Nitrophenyl ((5-oxocyclopent-1-en-1-yl)methyl) carbonate (6a) Referring to the synthesis of (6b) in Example 1, replaced (5b) in the method by (5a), and finally obtaining a light yellow liquid (6a) with a yield of 85.1%. (5-Oxocyclopent-1-en-I-yl)methyl (1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate (Iio) or di(5-oxocyclopent-1-en-1-yl)methyl (1-(3,4,5 trimethoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)carbamate(Ilio) Referring to the synthesis of (Ii) in Example 1, (6a) replaced (6b) in the method and finally obtained light yellow solids (Iio) and (Iio) with yields of 30.7% and 19.6%, respectively. Analytical data for Iio: ESI-MS (m/z): 488 [M+H]* ; 'H NMR (d-DMSO, 400 MHz): 610.83 (s, H, NH), 8.08 (d, J= 7.8 Hz, 1H, NH), 7.45 - 7.36 (m, 2H, Ar-H), 7.24 (s, 2H, Ar-H), 7.16 - 7.09 (m, 2H, Ar-H), 6.99 (s, 1H, Ar-H), 6.18 (d, J= 19.6 Hz, 1H, CH), 4.14 (s, 2H, CH 2), 3.92 (s, 6H, CH 3), 3.78 (s, 3H, CH 3 ), 2.35 - 2.29 (m, 2H, CH2 ), 1.96 - 1.87 (m, 2H, CH 2). Analytical data for Ilio: ESI-MS (m/z): 626 [M+H]*. Example 11 Synthesis of (5-oxocyclopent-1-en-1-yl)methyl (1-(4 (dimethylamino)phenyl)-9H-pyrido[3,4-b]indol-3-yl)carbamate (Iii) or di(5 oxocyclopent-1-en-1-yl)methyl(1-(4-(dimethylamino)phenyl)-9H-pyrido[3,4-b]indol 3-yl)carbamate (Iii) Referring to the synthesis of (Ii) in Example 1, replaced (4a) in the method with (4e), and replaced (6b) with (6a). Finally, light red solids (Iii) and (IIn) were obtained with yields of 31.2% and 18.4%, respectively. Analytical data for In: ESI-MS (m/z): 441 [M+H]* ; 1 H NMR (d-DMSO, 400 MHz): 610.87 (s, 1H, NH), 8.04 (d, J= 7.8 Hz, 1H, NH), 7.44 - 7.37 (m, 3H, Ar-H), 7.24 (s, 2H, Ar-H), 7.16 - 7.11 (m, 3H, Ar H), 6.98 (s, 1H, Ar-H), 6.17 (d, J= 19.6 Hz, 1H, CH), 4.19 (s, 2H, CH 2), 4.11 (s, 6H, CH3), 2.38 - 2.32 (m, 2H, CH2 ), 1.97 - 1.88 (m, 2H, CH 2). Analytical data for IIi: ESI-MS (m/z): 579 [M+H]*. Example 12 Synthesis of (7-oxocyclohept-1-en-I-yl)methyl (1-(3,4,5 trimethoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)carbamate (112) or di(7-oxocyclohept 1-en-1-yl)methyl (1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)carbamate (1112) 4-Nitrophenyl ((7-oxocyclohept-1-en-I-yl)methyl) carbonate (6c) Referring to the synthesis of (6c) in Example 1, (5c) was substituted for (5b) in
the method, and finally a light yellow liquid (6c) was obtained with a yield of 84.0%. (7-Oxocyclohept-1-en-I-yl)methyl (1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate (112) or di(7-oxocyclohept-1-en-1-yl)methyl (1-(3,4,5 trimethoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)carbamate(1112) Referring to the synthesis of (Ii) in Example 1, replaced (6b) with (6c) ,and finally light red solids (112) and (1112) were obtained with yields of 29.8% and 18.0%, respectively. Analytical data for 112: ESI-MS (m/z): 516 [M+H]*; 'H NMR (CDC 3
, 400 MHz): 6 8.11 (s, 1H, NH), 8.03 (d, J= 7.8 Hz, 1H, Ar-H), 7.50 - 7.46 (m, 1H, Ar-H), 7.40 (d, J= 8.1 Hz, 1H, Ar-H), 7. 22 - 7.19 (m, 1H, Ar-H), 7.14 (s, 2H, Ar-H), 6.93 (s, 1H, Ar-H), 6.87 - 6.84 (m, 1H, CH), 4.21 (s, 2H, CH2), 3.95 (s, 6H, CH 3 ), 3.92 (s, 3H, CH 3), 2.70 - 2.58 (m, 2H, CH2), 2.44 - 2.40 (m, 2H, CH2 ), 1.82 - 1.71 (m, 4H, CH 2 ). 13C NMR (CDCl3 , 101 MHz): 6 205.05, 153.77, 152.78, 143.12, 141.80, 140.13, 138.52, 134.37, 133.69, 128.47, 128.22, 122.01, 121.90, 119.45, 111.45, 105.48, 94.46, 60.99, 56.44, 45.35, 42.90, 27.65, 25.18, 21.49. Analytical data for 1112: ESI-MS (m/z): 682 [M+H]*. Example 13 Synthesis of (7-oxocyclohept-1-en-I-yl)methyl (1-(4 (dimethylamino)phenyl)-9H-pyrido[3,4-b]indol-3-yl)carbamate (113) or di(7 oxocyclohept-1-en-1-yl)methyl(1-(4-(dimethylamino)phenyl)-9H-pyrido[3,4-b]indol 3-yl)carbamate(1113) Referring to the synthesis of (Ii) in Example 1, replaced (4a) in the method with (4e), and replaced (6b) with (6c). Finally, light red solids (113)and (1113)were obtained with yields of 27.7% and 16.9%, respectively. Analytical data for 113: 'H NMR (d6 DMSO, 400 MHz): 610.94 (s, 1H, NH), 8.08 (d, J= 7.8 Hz, 1H, NH), 7.47 - 7.39 (m, 3H, Ar-H), 7.23 (s, 2H, Ar-H), 7.15 - 7.10 (m, 3H, Ar-H), 7.01 (s, 1H, Ar-H), 6.18 (d, J= 19.6 Hz, 1H, CH), 4.23 (s, 2H, CH2), 4.16 (s, 6H, CH3 ), 2.73 - 2.66 (m, 2H, CH 2 ), 2.46 - 2.40 (m, 2H, CH 2 ), 1.89 - 1.82 (m, 4H, CH 2).ESI-MS (m/z): 469 [M+H]*. Analytical data for 1113: ESI-MS (m/z): 635 [M+H]*. Example 14 The determination of tumor cells proliferation inhibition rates of the compounds by MTT method The antiproliferative effects on four human cancer cell lines were evaluated by using the tetramethylazol blue colorimetric method (MTT). COMC-6 was used as a positive control drug. Human cancer cell line: HepG2, Hela, HCT116, HT29, and HGC-27 cells.
Take a bottle of cells that are in good condition in the exponential growth phase, add 0.25% trypsin to digest, so that the adherent cells are shed, and make a suspension containing 2x10 4 -4x104 cells per ml. Take the cell suspension and inoculate it in 96 well plate, 180 L per well, incubate in a constant temperature C02 incubator for 24 hours. Change the medium and add test compounds 1-113 and 111-1113 (compounds are dissolved in DMSO and diluted with PBS). The concentrations of the test compounds are respectively 6.25x10-6, 1.25x10-5, 2.5x10-5, 5x10-5 mol/L), 20 L per well, culture for 72 hours. After MTT medium removal, the formazan crystals were dissolved in DMSO and the absorbance was measured at 570 nm using a BioTek Microplate Absorbance Reader according to the protocol. The inhibitory effect was expressed as percentage. Corresponding IC 5 o values were then calculated through corresponding software (Graph-PadPrism Version 4.03). The experimental results are shown in Table 2. The compounds of the present invention have undergone a series of tumor cell anti-proliferation activity tests, and the results of pharmacological experiments show in Table 2. It is found that they own strong inhibitory effects on the proliferation of most tumor cells. Especially, some compounds have a stronger inhibitory effect and the positive control drug COMC-6 is slightly stronger or equivalent. Table 2 Inhibition rate of some compounds on human tumor cells (12.5 mol/L) Compounds HepG2 HCT116 HT29 HGC-27 COMC-6 58.1 65.1 68.1 72.3 Ii 78.4 83.1 87.9 80.6 12 67.2 72.7 78.6 77.2 13 83.8 82.3 79.8 80.1 14 82.2 78.7 80.3 71.7 15 77.1 80.2 81.9 72.1 16 75.7 ND 70.4 71.5 17 74.2 ND 73.0 70.3 18 77.2 79.1 77.8 83.2 19 76.8 74.9 79.1 81.6 Iio 74.4 ND 73.2 71.5 Iii 65.9 ND 69.7 68.8 112 80.3 86.2 84.6 82.4 113 78.1 83.6 88.2 79.3 Ii 77.8 80.1 82.3 85.5 113 79.6 81.4 78.2 79.2 114 81.3 73.2 79.7 ND IIs 70.8 ND 78.9 74.9 117 70.7 74.4 77.6 73.7 119 68.4 73.4 ND 72.6
Iii 71.0 ND 71.7 70.2 1112 85.3 80.7 86.1 79.9 1113 80.9 84.4 83.8 82.2 ND: Not detected Example 15 pH Responsive fluorescence of -carbolines/cycloketene derivatives Ultraviolet-visible spectrophotometer and fluorescence spectrometer are used to determine the ultraviolet absorption wavelength of the I or II series compounds and the change of fluorescence with pH. The selected pH range is 3 ~ 8. pH-Dependent Absorption Spectra. Solutions (100 M) of compounds were prepared in deionized water containing 1% (v/v) DMSO with pH ranging from 8 to 3. All absorption spectra were recorded at room temperature (r.t.), and the scanning wavelength range was 350-700 nm with a scanning speed of 1.0 nm/s. pH-Dependent Emission Spectra. Solutions (1.0 M) of compounds were prepared in deionized water containing 1% (v/v) DMSO with pH ranging from 8 to 3. All emission spectra were performed at r.t., excited at 450 nm, and recorded from 460 to 650 nm. The characteristic ultraviolet absorption wavelengths of the compounds11-113 and 111-1113 are between 390~420nm, and with the decrease of pH value, the peak value gradually decreases, and the peak value at 430 ~ 470nm gradually rises. And its fluorescence spectrum shows that the fluorescence intensity at 480-520 nm also increases significantly as the pH value decreases. The ultraviolet fluorescence spectrum represented by compound Ii is shown in Figure 1. As the pH decreased from 7.63 to 3.19, the absorption band of Ii gradually shifted from 398 to 445 nm, with a distinct isosbestic point observed at 416 nm.The fluorescence intensity at 490 nm underwent a concomitant monotonic increase. However, the fluorescence was fully quenched in an aqueous solution with neutral pH. A quantitative analysis of the fluorescence intensity at 490 nm vs pH revealed a 65-fold (from 845.348 12.47 to 13.035 1.26) increase as the pH was lowered from 7.67 to 3.17 (Figure lb and Id, Ex=445nm). Example 16 GSH responsive fluorescence of -carbolines/cycloketene derivatives The changes of the ultraviolet and fluorescence of the I-II series compounds with the concentration of GSH are judged by extracellular fluorescence experiments.. GSH-Dependent Absorption Spectra. Solutions (100 [M or 200 [M) of compounds were prepared with deionized water containing 1% (v/v) DMSO with
GSH (0 ~ 20 equiv) and cat. GSTt. All absorption spectra were recorded at 37 °C for 0.5 h, and the scanning wavelength range was 350-700 nm with a scanning speed of 1.0 nm/s. GSH-Dependent Emission Spectra. Solutions (1.0 M) of compounds were prepared in deionized water containing 1% (v/v) DMSO with GSH (0-100 M) and cat. GST. All emission spectra were performed at 37 °C for 0.5 h, excited at 440 nm, and recorded from 450 to 650 nm. Compounds 11-13 and 111-1113 at a concentration of 1 M, with the increase of GSH, the absorption bands between 385~430 nm gradually decrease, and the bands at 435~470 nm gradually increase. And its fluorescence spectrum shows that the fluorescence intensity at 470-530 nm also increases gradually with the increase of GSH. As shown in Figure 2, no detectable change in fluorescence was observed with 6 after the addition of GSH. However, the absorption of the Ii solution rapidly increased to above 440 nm (Figure 2a). Furthermore, the solution showed a marked enhancement of fluorescence intensity at around 492 nm in a dose-dependent manner. The fluorescent signal of HJTA after the addition of GSH was stable and lasted over 1 h at 37 °C (Figure 2d, Ex=440nm). Example 17 Selective GSH-Response of compounds. To confirm that the response of compouds toward GSH/GSTi were selective, a variety of physiological environment relevant species, including inorganic metal ions, amino acids, reductants, and oxidants, were analyzed at pH 7.4. Solutions (1 M) of compounds with cat. GST and various biological analytes (lysine, histidine, alanine, cysteine, glutamic acid, serine, glycine, and arginine, H 2 0 2 ,
Ca2+, K+, Mg2+, Na*, Zn2+, Fe2+, Cu2+, Na2S, A13+, Vc, NADH, and GSH, 20 M) were prepared at pH = 4.0 with deionized water containing 1% (v/v) DMSO at 37 °C for 0.5 h. All emission spectra were excited at 440 nm and recorded from 450 to 650 nm. As shown in Figure 3, inorganic salts (K+, Na*, Ca2+, Mg2+, Zn2+, A13*, Cu2+, and Fe2+), amino acids (Lys, His, Ala, Cys, Glu, Ser, Gly, Arg), reductants (vitamin C and Na2S), H 2 0 2 , and NADH did not cause any apparent change of the fluorescence intensity. These results show that Ii is highly selective in specific response to GSH. Example 18 Tumor cells imaging with confocal microscope
The intracellular fluorescence of compounds were subsequently evaluated in cancer HT29 cells with high expression of GSTi to evaluate their cellular uptake. HT29 cells (2 x 10' cells/well) were seeded into 35 mm glassbottom cell culture dishes in 2.0 mL of culture medium, respectively. The cells were incubated in DMEM containing compounds (1 M) for 30 min. The fluorescence image were obtained with a Leica TCS SP5 LSM confocal microscope using 40X objective water lenses. The green fluorescence of compounds were obtained by using a 405 nm laser. Filter set: 480-530 nm. The confocal fluorescence images indicate that the uptake of 1-113 and 111-1113
were rapid and increased comparably for HT29 cells within the first 10 min. A most efficient accumulation showed at 1h and lasted for 2h. Figure 4 shows the cellular fluorescence imaging pictures of representative compoundsIi, 13, 16, 19, o, 113, 112, 114, 117, 119, 1Iii, and 1112 in HT29 cells at 1 h. These studies clearly demonstrate that the compounds can accumulate excellently in tumor cells with high intracellular fluorescence intensity. Example 19 Ex Vivo Fluorescence Imaging and Tissue Biodistribution. HT29 tumor-bearing mice were used for fluorescence imaging, and before imaging, the tumor-bearing mice were i.v. injected with compounds Ii, 13, 16, 19,
Iio, 13, II2, II 4 , II7, II 9 , 1ii, 1112 (40 mg/kg). First, the mice were placed onto the warmed stage inside of an IVIS light-tight chamber, and anesthesia was maintained with 1% pentobarbital. All the image acquisitions were performed with a Caliper IVIS Lumina II in vivo optical imaging system equipped with an excitation filter (465 nm) and emission filter (GFP) when the mice were anesthetized at 0, 1, 2, 4, 8, and 24 h postinjection. Then, the mice were sacrificed after imaging. The major organs including the heart, lung, liver, kidney, spleen, colon, and tumor were collected and imaged with the fluorescence imaging system as described above. The results showed that the compoundsIi I33,I6, 9, Iio, I13, II2, II 4 , II7
119, Iii, 1112 selectively displayed stronger fluorescent signal in tumor tissues than that of major organs, including heart, lungs, liver, kidneys and spleen. Figure 5 shows the in vivo fluorescence imaging distribution result of compound Ii. It confirmed the efficient retention of compounds in the tumor with promising selectivity and visualization in vivo, which could assist fluorescence-guided surgical removal of tumors.
Example 20 In Vivo Tumor Growth Inhibition. All animal experimental protocols were approved by the Animal Research and Care Committee of Nantong University. Female BALB/c nude mice at an age of 5 to 6-week-old were inoculated subcutaneously with 1 x 106 HT29 cells. When tumor volumes reached 100 mm 3 , the mice were randomly administered with11-113 or Ii 1113, COMC-6, and the vehicle, respectively. The body weight of all animals was monitored throughout the study, and animals were euthanized if they incurred 20% weight loss between observations. Two axes (mm) of a tumor (L, longest axis; W, shortest axis) were measured with a Vernier caliper. Tumor volume (mm 3) was calculated using a formula of 'tumor volume = 1/2 (LxW 2 ). Progression of tumors was monitored every 2 days up to 21 days posttreatment. At the end of the experiment, the mice were sacrificed, and their tumors were dissected out and weighed. As shown in Figure 6, a sustainable tumor growth was observed with the saline treated group. In contrast, the intraperitoneal treatment of HJTA apparently diminished the volumes of xenograft tumors. HJTA also led to greater tumor reduction than COMC-6 at the end of the treatment period. The tumor weight (0.48 0.07 g) in mice injected with HJTA at 40 mg/kg was diminished by 67.7% (w/w), compared to the saline groups (1.49 0.27 g), and was lower than the tumor weight (0.81 0.12 g) of COMC-6 groups at 40 mg/kg. Together, these data clearly confirm that HJTA possessed remarkable inhibitory potency of the tumor growth in vivo.
Claims (9)
1. A class of p-carboline/cycloalkenone derivatives with the general structure shown in the following general formula:
R4 oO N
NO R .----- N /
Ri R 1 represents one or more substituents on the corresponding substituted ring, selected from one or more of H, C-C6 alkoxy, Cl-C6 alkyl, C-C6 alkylamino. When R1 represents multiple substituents, each substituent is same or different. R2 represents one or more substituents on the corresponding substituted ring, selected from H or C-C6 alkyl. When R2 represents multiple substituents, each substituent is same or different. R3 is selected from H or C1-C6 alkyl. 0 0 R4 is selected from H, C1-C6 alkyl or n n= 1, 2, or 3.
2. The p-carboline/cycloketene derivatives according to claim 1, wherein R1 is selected from one or more of H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methyl amino group, ethylamino group, methylethylamino group, N,N-dimethylamino
group; R2 is selected from one or more of H, methyl, ethyl, propyl, and isopropyl; R3 is selected from H, methyl, ethyl, propyl or isopropyl; 0
R4 is selected from H, methyl, ethyl, propyl, isopropyl or n , n=1, 2 or 3.
3. The p-carboline/cycloketene derivatives according to claim 1, wherein R1 represents 3,4,5-Tri-OCH 3, 4-CH 3, 3-OCH 3, 4-OCH 3, 4-N,N-dimethyl, 2,4-Di-OCH 3 ,
2,5-Di-OCH 3 , 3,4-Di-OCH 3 or 3,5-Di-OCH 3. R2 or R3 represents H. R4 represents H 0
or n ,n=1,2,or3.
4. According to the p-carboline/cycloketene derivatives of claim 1, the structure characterization of p-carboline/cycloketene derivatives is selected from the following compounds: (6-oxocyclohex-1-en-1-yl)methyl(1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4-b]indol 3-yl)carbamate; Di(6-oxocyclohex-1-en-I-yl)methyl (1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; (6-oxocyclohex-1-en-1-yl)methyl(1-(p-tolyl)-9H-pyrido[3,4-b]indol-3-yl)carbamate; Di(6-oxocyclohex-1-en-I-yl)methyl (1-(p-tolyl)-9H-pyrido[3,4-b]indol-3 yl)carbamate; (6-oxocyclohex-I-en-I-yl)methyl (1-(3-methoxyphenyl)-9H-pyrido[3,4-b]indol-3 yl)carbamate; Di(6-oxocyclohex-I-en-I-yl)methyl (1-(3-methoxyphenyl)-9H-pyrido[3,4-b]indol-3 yl)carbamate; (6-oxocyclohex-I-en-I-yl)methyl (1-(4-methoxyphenyl)-9H-pyrido[3,4-b]indol-3 yl)carbamate; Di(6-oxocyclohex-I-en-I-yl)methyl (1-(4-methoxyphenyl)-9H-pyrido[3,4-b]indol-3 yl)carbamate; (6-oxocyclohex-I-en-I-yl)methyl (1-(4-(dimethylamino)phenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; Di(6-oxocyclohex-I-en-I-yl)methyl (1-(4-(dimethylamino)phenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; (6-oxocyclohex-i-en-1-yl)methyl(1-(2,4-dimethoxyphenyl)-9H-pyrido[3,4-b]indol-3 yl)carbamate; Di(6-oxocyclohex-I-en-I-yl)methyl (1-(2,4-dimethoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; (6-oxocyclohex-i-en-1-yl)methyl(1-(2,5-dimethoxyphenyl)-9H-pyrido[3,4-b]indol-3 yl)carbamate; Di(6-oxocyclohex-I-en-I-yl)methyl (1-(2,5-dimethoxyphenyl)-9H-pyrido[3,4
b]indol-3-yl)carbamate; (6-oxocyclohex-1-en-1-yl)methyl (1-(3,4-dimethoxyphenyl)-9H-pyrido[3,4-b]indol-3 yl)carbamate; Di(6-oxocyclohex-1-en-I-yl)methyl (1-(3,4-dimethoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; (6-oxocyclohex-1-en-1-yl)methyl (1-(3,5-dimethoxyphenyl)-9H-pyrido[3,4-b]indol-3 yl)carbamate; Di(6-oxocyclohex-1-en-I-yl)methyl (1-(3,5-dimethoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; (5-oxocyclopent-I-en-I-yl)methyl (1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; Di(5-oxocyclopent-I-en-I-yl)methyl (1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; (5-oxocyclopent-I-en-I-yl)methyl (1-(4-(dimethylamino)phenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; Di(5-oxocyclopent-I-en-I-yl)methyl (1-(4-(dimethylamino)phenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; (7-oxocyclohept-I-en-I-yl)methyl (1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; Di(7-oxocyclohept-I-en-I-yl)methyl (1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; (7-oxocyclohept-I-en-I-yl)methyl (1-(4-(dimethylamino)phenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate; Di(7-oxocyclohept-I-en-I-yl)methyl (1-(4-(dimethylamino)phenyl)-9H-pyrido[3,4 b]indol-3-yl)carbamate.
5. A method for preparing p-carboline/cycloketene derivatives according to any one of claims 1-4 comprises the following steps: (1) Compound 1 is reacted with hydrazine hydrate to obtain compound 2, preferably reacted with 85% hydrazine hydrate in methanol,
0 / 0N. NH2 R 2 R NH \/N NH 2 NH 2 H2 0 \/N N N R3 /\ R3 /\
1 R1 2 R
. (2) Compound 2 is reacted with NaNO2 under acidic conditions, preferably under dilute hydrochloric acid conditions to obtain compound 3
0NH 2 N N3 \ NNaNO 2 N ; N R3 /R,
2 R1 3 R
. (3) Compound 3 is reacted under acidic conditions, preferably aqueous acetic acid, to obtain compound 4,
0 N3 NH 2 R \ N R N
N N R, / R 3%/
3 R, 4 R1
(4) Compound 5 is reacted with p-nitrophenyl chloroformate under the condition of alkaline, preferably DIPEA, to obtain compound 6,
o O NO 2 O 0 NO 2 OH A 0,0 1, 0 0
5 O 6 (5) Compounds 4 and 6 are reacted under the condition of alkaline, preferably DIPEA, to obtain compound 7 and/or compound 8,
0
0 0 0--r
NH 2 H O n R, \N 6 0 N N0 N \ N + N R, /\N N RR 4 R1
7 8
Alternatively, the above synthesis step also includes step (6): compound 7 reacts with C1-C6 alkyl bromide under the condition of sodium hydrogen to obtain compound 9.
0 H OO
N 0/2/ N N
N N R3 -R 3
Ri
7 9
Ri represents one or more substituents on the corresponding substituted ring, selected from one or more of H, amino, halogen, hydroxyl, nitro, C1-C6 alkoxy, C1 C6 alkyl, and Cl-C6 alkylamino. When R1 represents multiple substituents, each substituent is same or different; R2 represents one or more substituents on the corresponding substituted ring, selected from one or more of H, C-C6 alkyl. When R2 represents multiple substituents, each substituent is same or different; R3 is selected from H or C1-C6 alkyl; R4 is selected from C1-C6 alkyl; n=l, 2 or 3.
6. The application of the p-carboline/cycloketene derivatives according to any one of claims 1-4 in the preparation of drugs and/or probes targeting GSTxr.
7. The application according to claim 6, wherein the drug targeting GSTR is for treatment and/or preventation of cancer.
8. The application according to claim 7, wherein the cancer is selected from liver cancer, colon cancer, cervical cancer, or gastric cancer.
9. The application according to claim 6, characterized in that probes targeting GST7U have pH and GSH dual response and selective effect on tumor imaging.
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