CN114890928A - Isothiocyanate derivative and preparation method and application thereof - Google Patents
Isothiocyanate derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN114890928A CN114890928A CN202210283523.6A CN202210283523A CN114890928A CN 114890928 A CN114890928 A CN 114890928A CN 202210283523 A CN202210283523 A CN 202210283523A CN 114890928 A CN114890928 A CN 114890928A
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- Prior art keywords
- isothiocyanate derivative
- hydrogen atom
- alkyl
- compound
- halogen
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Images
Classifications
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- C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
- C07C331/16—Isothiocyanates
- C07C331/18—Isothiocyanates having isothiocyanate groups bound to acyclic carbon atoms
- C07C331/22—Isothiocyanates having isothiocyanate groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C331/24—Isothiocyanates having isothiocyanate groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- A61P35/02—Antineoplastic agents specific for leukemia
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
- C07C303/04—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by substitution of hydrogen atoms by sulfo or halosulfonyl groups
- C07C303/08—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by substitution of hydrogen atoms by sulfo or halosulfonyl groups by reaction with halogenosulfonic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
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Abstract
The application discloses an isothiocyanate derivative and a preparation method and application thereof, relating to the field of medical technology; the isothiocyanate derivative has the structural formula shown as follows:
wherein R1 and R2 are independently selected from one of hydrogen atom, halogen, alkyl and halogenated alkyl, and n represents different carbon chain lengths. The isothiocyanate derivative provided by the application has stronger inhibitory activity on hematologic malignant tumors and solid malignant tumors, can be used for preparing antitumor drugs, and provides a candidate compound for researching and developing new antitumor drugs.
Description
Technical Field
The application relates to the field of medical technology, in particular to an isothiocyanate derivative and a preparation method and application thereof.
Background
Tumor refers to a new organism formed by local histiocyte hyperplasia under the action of various tumorigenic factors; according to the cellular characteristics of the new organism and the degree of harm to the organism, the new organism can be divided into two main categories, namely benign tumor and malignant tumor. Malignant tumor, also called cancer, is the most serious disease to endanger human health, and cancer cells have significant difference in morphology, growth and proliferation, genetic traits and the like compared with normal cells in vivo, whether in vivo or in vitro.
Sulforaphane, also known as sulforaphane, belongs to one of isothiocyanates, and is extracted from vegetables of Brassicaceae. Sulforaphane is a natural active substance with the strongest anticancer capability in vegetables, and can induce the production of PhaseII enzymes, such as glutathione-S-transferase, epoxide enzyme, quinone reductase and the like, which can destroy the active center of carcinogenic factors or combine the carcinogenic factors with endogenous ligands to reduce the change of the carcinogenic factors to normal intracellular genetic materials.
Disclosure of Invention
In order to design an isothiocyanate derivative and provide a novel anti-cancer drug, the application provides the isothiocyanate derivative and a preparation method and application thereof.
In a first aspect, the isothiocyanate derivative provided by the application adopts the following technical scheme:
an isothiocyanate derivative having the formula:
wherein R1 and R2 are independently selected from one of hydrogen atom, halogen, alkyl and halogenated alkyl, and n represents different carbon chain lengths.
Preferably, the haloalkyl group is methyl trifluoride.
Preferably, the alkyl group is methyl.
Preferably, n is 1, R1 is halogen, and R2 is hydrogen atom.
Preferably, n is 2, R1 is independently selected from one of hydrogen atom, halogen, alkyl and haloalkyl, and R2 is independently selected from one of hydrogen atom and halogen.
Preferably, n is 3, R1 is a hydrogen atom, and R2 is a hydrogen atom.
Preferably, n is 2, R1 is a hydrogen atom, and R2 is a hydrogen atom.
In a second aspect, the present application provides a method for preparing an isothiocyanate derivative as described above, which adopts the following technical scheme:
a process for producing an isothiocyanate derivative as described above, comprising a synthetic route for synthesizing an isothiocyanate derivative, the synthetic route being as follows:
wherein R1 and R2 are independently selected from one of hydrogen atom, halogen, alkyl and halogenated alkyl, and n represents different carbon chain lengths.
In a third aspect, the present application provides a pharmaceutical preparation, which adopts the following technical scheme:
a pharmaceutical preparation comprises a therapeutically effective amount of the isothiocyanate derivative and a pharmaceutically acceptable carrier or adjuvant, and the pharmaceutical preparation is an oral preparation or an injection preparation.
In a fourth aspect, the present application also provides the use of a pharmaceutical formulation as described above in the treatment of cancer.
In summary, the present application includes at least one of the following beneficial technical effects:
(1) The isothiocyanate derivative provided by the application has stronger inhibitory activity on hematologic malignant tumors and solid malignant tumors, can be used for preparing antitumor drugs, and provides a candidate compound for researching and developing new antitumor drugs;
(2) compared with sulforaphane, the isothiocyanate derivative provided by the application has stronger antitumor activity on SKM-1, and can be used for researching and developing a medicament for treating myelodysplastic syndrome, so that a candidate compound is provided.
Drawings
FIG. 1 is a plot of individual compound C plasma concentration versus time following a single intravenous administration of 1mg/kg compound C to SD rats;
FIG. 2 is a plot of individual compound C plasma concentration versus time following a single oral administration of 3mg/kg compound C to SD rats;
FIG. 3 is a graph of the most significant pathway for the differentially expressed gene KEGG analysis;
FIG. 4 is a KEGG cluster diagram of high expression genes in SKM-1 cells cultured by compound C.
Detailed Description
The present application is described in further detail below with reference to figures 1-4.
Example 1: 3-chloro-4-isothiocyanatomethylbenzenesulfonamide (a, n ═ 1, R1 ═ Cl, R2 ═ H)
1 H-NMR((CD 3 ) 2 CO,400MHz)δ：8.07(s,1H),7.91(d,1H,J＝8.28Hz),7.72(d,1H,J＝8.24),6.80(s,1H),5.12(s,2H),2.80(s,H)。
Example 2: 3-fluoro-4-isothiocyanatomethylbenzenesulfonamide (B, n ═ 1, R1 ═ F, R2 ═ H)
1 H-NMR((CD 3 ) 2 CO,400MHz)δ：8.05(d,1H,J＝6.68Hz),7.97(s,H),7.41(t,1H,J＝9.08Hz),6.74(s,H),5.08(s,2H),2.80(s,1H)。
Example 3: 4- (2-isothiocyanato) ethylbenzenesulfonamide (C, n ═ 2, R1 ═ H, R2 ═ H)
1 H-NMR((CD 3 ) 2 CO，400MHz)δ：7.85(d,2H,J＝2Hz),7.52(d,2H,J＝8.32Hz),6.58(s,2H),3.97(t,2H,J＝6.64Hz),3.15(t,2H,J＝13.3Hz)。
Example 4: 3-chloro-4- (2-isothiocyanato) ethylbenzenesulfonamide (D, n ═ 2, R1 ═ Cl, R2 ═ H)
1 H-NMR((CD 3 ) 2 CO,400MHz)δ：7.96(s,1H),7.81(d,1H,J＝8.48Hz),7.65(d,1H,J＝8.44Hz),6.66(s,1H),4.0(t,2H,J＝5.64Hz),3.29(t,2H,J＝6.32Hz),2.79(s,1H)。
Example 5: 3-fluoro-4- (2-isothiocyanato) ethylbenzenesulfonamide (E, n ═ 2, R1 ═ F, R2 ═ H)
1 H-NMR((CD 3 ) 2 CO,400MHz)δ：7.95(d,1H,J＝6.92Hz),7.87(s,1H),7.34(t,1H,J＝9.32Hz),6.59(s,1H),3.98(t,2H,J＝6.6Hz),3.18(t,2H,J＝6.64Hz),2.77(s,1H)。
Example 6: 3-methyl-4- (2-isothiocyanato) ethylbenzenesulfonamide (F, n ═ 2, R1 ═ CH 3 ，R2＝H)
1 HNMR((CD 3 ) 2 CO,400MHz)δ：7.78(s,1H),7.68(d,1H,J＝7.36Hz),7.38(d,1H,J＝7.08Hz),6.43(s,1H),3.94(t,2H),3.17(t,2H),2.76(s,1H),2.45(s,3H)。
Example 7: 2-chloro-4- (2-isothiocyanato) ethylbenzenesulfonamide (G, n ═ 2, R1 ═ H, R2 ═ Cl)
1 H-NMR((CD 3 ) 2 CO,400MHz)δ：8.01(d,1H,J＝8.32Hz),7.62(s,1H),7.51(d,1H),6.94(s,2H),4.0(t,2H,J＝6.64Hz),3.48(t,2H)。
Example 8: 2-fluoro-4- (2-isothiocyanato) ethylbenzenesulfonamide (H, n ═ 2, R1 ═ H, R2 ═ F)
1 H-NMR((CD 3 ) 2 CO,400MHz)δ：8.08(t,1H,J＝6.4Hz),7.38(d,1H),7.22(t,1H),6.89(s,1H),4.01(t,2H,J＝6.32Hz),3.49(t,2H),2.8(s,1H)。
Example 9: 3-trifluoromethyl- (2-isothiocyanato) ethylbenzenesulfonamide (I, n ═ 2, R1 ═ CF) 3 ，R2＝H)
1H-NMR((CD3)2CO,400MHz)δ：8.21(s,1H),8.14(d,1H,J＝9.32Hz),7.85(d,1H,J＝8.28Hz),6.84(s,1H),4.05(t,2H,J＝6.76Hz),3.33(t,2H,J＝6.68Hz),2.79(s,1H)。
Example 10: 4- (3-isothiocyanato) propylbenzenesulfonamide (K, n ═ 3, R1 ═ H, R2 ═ H)
1H-NMR((CD3)2CO,400MHz)δ：7.83(d,2H,J＝8.32Hz),7.45(d,2H,J＝8.24Hz),6.52(s,2H),3.69(t,2H,J＝6.52Hz),2.83(dt,2H,J＝12.7Hz),2.05(t,2H,J＝2.16Hz)。
Example 11: process for producing isothiocyanate derivative
This example provides a general synthetic route to the compounds described in examples 1-10, as follows:
wherein, R1 and R2 are independently selected from one of hydrogen atom, halogen, alkyl and halogenated alkyl, and n represents different carbon chain lengths.
1. 3-chloro-4-isothiocyanatomethylbenzenesulfonamide
S1, synthesis of structural formula 2: adding 10g (70.08mmol) of raw material 3-chlorobenzylamine and 13g (1.56eq,128.73mmol) of triethylamine into a 250ml single-mouth eggplant-shaped bottle, stirring uniformly at room temperature, dropwise adding 8.4g (82.52mmol) of acetic anhydride, stirring overnight at room temperature after dropwise adding, adding 30ml of water under ice bath for quenching reaction, adjusting pH to 5-6 by 10% diluted hydrochloric acid, extracting by DCM, combining organic phases for drying, filtering, concentrating to obtain 7g of product, and directly using the product in the next reaction;
S2, synthesis of structural formula 3: adding 10g (85.82mmol) of chlorosulfonic acid into a 250ml single-mouth eggplant-shaped bottle, cooling to-10 ℃, dropwise adding 2.6g (15.60mmol) of the product obtained in the step S1 into the solution, reacting at 100 ℃ for 1.5h after dropwise adding, cooling to room temperature, and slowly adding crushed ice. DCM is used for extraction, organic phases are combined, dried, filtered and concentrated to obtain 3g of a product, and the product is directly used for the next reaction;
s3, synthesis of structural formula 4: dissolving 3g of the product obtained in the step S2 in 70ml of ammonia water in a 250ml single-mouth eggplant-shaped bottle, stirring overnight at room temperature, spin-drying the solvent, adding methanol, and carrying out sample mixing column chromatography to obtain 700mg of the product;
s4, synthetic structural formula 5: 700mg (2.89mmol) of the product of step S3 were dissolved in 24ml (2N KOH (aq)) in a 1L single-neck eggplant-type flask and reacted at 100 ℃ for 4 h. Cool to room temperature and adjust pH to 7 with 2N HCl (aq). The residue after the water phase had been spun down was dissolved in 500ml (4% MeOH in DCM) and stirred overnight. Filtering, concentrating the filtrate to obtain 300mg of a product, and directly using the product in the next reaction;
s5, synthetic structural formula 6: 309mg of DCC (1.5mmol) and 1.14gCS mg in a 250ml single-neck eggplant-shaped flask 2 (15mmol) was dissolved in 20ml acetonitrile. Cooling to-10 deg.C, mixing, dissolving the product 300mg obtained in step S4 in 50ml acetonitrile (basically insoluble) in another 100ml single-neck eggplant-shaped bottle, adding dropwise the solution containing the product obtained in step S4 into another acetonitrile solution, reacting at room temperature for 3h after dropwise addition, clarifying the reaction solution gradually, concentrating the filtrate to dryness, adding diethyl ether, filtering to remove the solid, and performing column chromatography to obtain 150mg of white solid.
2. 4- (2-isothiocyanato) ethyl benzenesulfonamide
S1, synthesis of structural formula 2: adding 10g (82.52mmol) of phenethylamine and 13g (1.56eq,128.73mmol) of triethylamine into a 250ml single-opening eggplant-shaped bottle, uniformly stirring at room temperature, dropwise adding 8.4g 82.52mmol of acetic anhydride, stirring at room temperature overnight after dropwise adding, adding 30ml of water under ice bath to quench the reaction, adjusting the pH value to 5-6 by 10% of dilute hydrochloric acid, extracting by DCM, combining organic phases, drying, filtering, concentrating to obtain 7g of a product, and directly using the product in the next reaction;
s2, synthesis of structural formula 3: adding 10g (85.82mmol) of chlorosulfonic acid into a 250ml single-mouth eggplant-shaped bottle, cooling to-10 ℃, dropwise adding 2.6g (15.60mmol) of the product obtained in the step S1 into the solution, reacting at 100 ℃ for 1.5h after dropwise adding, cooling to room temperature, and slowly adding crushed ice. DCM is used for extraction, organic phases are combined, dried, filtered and concentrated to obtain 3g of a product, and the product is directly used for the next reaction;
s3, synthesis of structural formula 4: dissolving 3g of the product obtained in the step S2 in 70ml of ammonia water in a 250ml single-mouth eggplant-shaped bottle, stirring overnight at room temperature, spin-drying the solvent, adding methanol, and carrying out sample mixing column chromatography to obtain 700mg of the product;
s4, synthetic structural formula 5: 700mg (2.89mmol) of the product of step S3 were dissolved in 24ml (2N KOH (aq)) in a 1L single-neck eggplant-type flask and reacted at 100 ℃ for 4 h. Cool to room temperature and adjust pH to 7 with 2N HCl (aq). The residue after the water phase had been spun down was dissolved in 500ml (4% MeOH in DCM) and stirred overnight. Filtering, concentrating the filtrate to obtain 300mg of a product, and directly using the product in the next reaction;
S5, synthesis structural formula 6: 309mg of DCC (1.5mmol) and 1.14gCS mg in a 250ml single-neck eggplant-shaped flask 2 (15mmol) was dissolved in 20ml acetonitrile. Cooling to-10 deg.C, mixing, dissolving the product 300mg obtained in step S4 in 50ml acetonitrile (basically insoluble) in another 100ml single-neck eggplant-shaped bottle, adding dropwise the solution containing the product obtained in step S4 into another acetonitrile solution, reacting at room temperature for 3h after dropwise addition, clarifying the reaction solution gradually, concentrating the filtrate to dryness, adding diethyl ether, filtering to remove the solid, and performing column chromatography to obtain 150mg of white solid.
3. 4- (3-isothiocyanato) propylbenzenesulfonamide
S1, synthesis of structural formula 2: adding 10g (73.96mmol) of raw material 3-phenyl-1-propylamine and 13g (1.56eq,128.73mmol) of triethylamine into a 250ml single-opening eggplant-shaped bottle, uniformly stirring at room temperature, dropwise adding 8.4g 82.52mmol of acetic anhydride, stirring at room temperature overnight after dropwise adding, adding 30ml of water under ice bath to quench the reaction, adjusting the pH value to 5-6 by 10% diluted hydrochloric acid, extracting by DCM, combining organic phases, drying, filtering, concentrating to obtain 7g of product, and directly using the product in the next reaction;
s2, synthesis of structural formula 3: adding 10g (85.82mmol) of chlorosulfonic acid into a 250ml single-mouth eggplant-shaped bottle, cooling to-10 ℃, dropwise adding 2.6g (15.60mmol) of the product obtained in the step S1 into the solution, reacting at 100 ℃ for 1.5h after dropwise adding, cooling to room temperature, and slowly adding crushed ice. DCM is used for extraction, organic phases are combined, dried, filtered and concentrated to obtain 3g of a product, and the product is directly used for the next reaction;
S3, synthesis of structural formula 4: dissolving 3g of the product obtained in the step S2 in 70ml of ammonia water in a 250ml single-mouth eggplant-shaped bottle, stirring overnight at room temperature, spin-drying the solvent, adding methanol, and carrying out sample mixing column chromatography to obtain 700mg of the product;
s4, synthetic structural formula 5: 700mg (2.89mmol) of the product of step S3 were dissolved in 24ml (2N KOH (aq)) in a 1L single-neck eggplant-type flask and reacted at 100 ℃ for 4 h. Cool to room temperature and adjust pH to 7 with 2N HCl (aq). The residue after the water phase had been spun down was dissolved in 500ml (4% MeOH in DCM) and stirred overnight. Filtering, concentrating the filtrate to obtain 300mg of a product, and directly using the product in the next reaction;
s5, synthetic structural formula 6: 309mg of DCC (1.5mmol) and 1.14gCS mg in a 250ml single-neck eggplant-shaped flask 2 (15mmol) was dissolved in 20ml acetonitrile. Cooling to-10 deg.C, mixing, dissolving the product 300mg obtained in step S4 in 50ml acetonitrile (basically insoluble) in another 100ml single-neck eggplant-shaped bottle, adding dropwise the solution containing the product obtained in step S4 into another acetonitrile solution, reacting at room temperature for 3h after dropwise addition, clarifying the reaction solution gradually, concentrating the filtrate to dryness, adding diethyl ether, filtering to remove the solid, and performing column chromatography to obtain 150mg of white solid.
Example 12: in vitro antitumor activity of isothiocyanate derivatives
The human cells used are as follows: human liver cancer cell HepG2, human non-small cell lung cancer cell A549, breast cancer cell MCF-7, human acute myelogenous leukemia cell HL-60 and human myelodysplastic syndrome cell SKM-1.
1. Experimental method
(1) Preparation of the tested drugs: dissolving a certain mass of the isothiocyanate derivative described in examples 1-10 in 0.5mL of 5% DMSO, vortexing for 1min, sonicating for 4min, adding 4mL of PEG400, vortexing for 1min, adding 5.5mL of physiological saline, and vortexing for 1min to prepare the test drug as a colorless clear liquid.
(2) Cell proliferation inhibition assay
a.A549. MCF7 and HEPG2 cells: preparing single cell suspension with culture medium (DMEM) containing 1% double antibody and 10% fetal calf serum, and culturing at 37 deg.C under 5% CO 2 Culturing under saturated humidity for 2 days, amplifying for one time, inoculating the cells into 96-well plate, and culturing at cell density of 1 × 10 per well 4 Per 100. mu.L, overnight adherence. Setting different drug gradient concentration to treat cells for 72h, discarding the drug-containing culture medium, adding freshly prepared toxicity detection solution CCK8 containing 10 μ L into each well, placing in an incubator for incubation for 1h, measuring OD value at 450nm with an enzyme-labeling instrument, and calculating half effective inhibition concentration IC by Bliss method 50 Parallel experiments were performed 4 times.
HL-60, SKM-1 cells: taking cells in logarithmic growth phase, centrifuging, and diluting with RPMI1640 culture solution to obtain 3 × 10 concentration 5 Cell suspension per mL, seeded in 96-well plates. Culturing at 37 deg.C overnight, adding test drugs with different concentrations, incubating for 72h, adding 10 μ L toxicity detection solution CCK8 into each well, placing in incubator, incubating for 1h, measuring OD value at 450nm with enzyme-labeling instrument, and calculating half effective inhibitory concentration IC by Bliss method 50 Parallel experiments were performed 4 times.
2. Results of the experiment
The results of the cell proliferation inhibition experiments are shown in table 1:
TABLE 1 half inhibitory concentration of isothiocyanate derivatives on cancer cells
As is clear from Table 1, the compounds A-K described in examples 1-10 have inhibitory activities on the proliferation of human cancer cells HL-60, SKM-1, A549, MCF-7 and HepG2, have high in vitro antitumor activities, and have stronger inhibitory activities on the proliferation of hematological malignant cells HL-60 and SKM-1 than solid malignant cells A549, MCF-7 and HepG 2.
Sulforaphane has strong inhibitory action on hematological malignant tumors, but has no obvious inhibitory action on proliferation of solid malignant tumors; however, compound C provided in example 3 had the most in vitro anti-tumor activity Potent, half-effective inhibitory concentration IC 50 The minimum is 1.71 mu M, the maximum is 9 mu M, and the inhibitor has strong inhibition effect on the proliferation of hematologic malignant tumor and solid malignant tumor; furthermore, the inhibitory effect of compound D, E, F, G and H obtained by changing the functional group on the benzene ring of compound C on hematological malignant cells is close to that of compound C, but the inhibitory effect on solid malignant cells is weakened.
The structure-activity relationship of the isothiocyanate derivatives can be inferred from Table 1 and the above analysis. For HL-60 cell lines, the change of the carbon chain length of the substituent groups on the 2 and 3 positions of the benzene ring and the isocyano alkyl has little influence on the antitumor activity of the compound; in the case of the SKM-1 cell line, a compound having an isocyanoalkyl group with a chain length of 2 or 3 has a high antitumor activity, but when the substituent at the 3-position of the benzene ring is a fluorine atom or a methyl trifluoride group, the antitumor activity of the compound is decreased. For solid malignant tumor cells, the compound with the chain length of isocyano alkyl group being 2 has higher anti-tumor activity than the compound with the chain length being 1 or 3; wherein, for A459 cell line, when fluorine atoms or methyl trifluoride are introduced on a benzene ring, the antitumor activity of the compound is reduced; for MCF-7 cell lines, chlorine atoms introduced to the No. 2 position of a benzene ring have little influence on the antitumor activity of the compound; in the case of the HepG2 cell line, when the substituent at the 3-position of the benzene ring is a fluorine atom or a methyl trifluoride group, the antitumor activity of the compound is decreased. Through the analysis of the structure-activity relationship of the isothiocyanate derivatives, valuable information can be provided for searching for more effective and more selective anti-cancer drugs by taking the isothiocyanic benzene sulfonamide as a basic skeleton.
Example 13: the pharmacokinetics experiment of isothiocyanate derivative 4- (2-isothiocyanic) ethyl benzene sulfonamide is of great significance in the research and development of medicine, and the pharmacokinetics research before clinical experiment reveals the dynamic change rule of medicine in vivo through the research methods of animal in vivo, animal in vitro and human in vitro, obtains the basic pharmacokinetic parameters of medicine, and clarifies the processes and characteristics of medicine absorption, distribution, metabolism and excretion.
This example uses female SD rats for pharmacokinetic studies of the compound C4- (2-isothiocyanato) ethylbenzenesulfonamide; wherein, female SD rats were purchased from Shanghai Sphall-Bikay laboratory animals Co., Ltd.; and the concentration of compound C in the plasma of experimental rats was determined using LC/MS and the relevant parameters were calculated.
1. Formulation of pharmaceutical preparations
(1) Pharmaceutical formulation for Injection (IV): weighing 1.99mg of compound C, dissolving in 0.55% DMSO, vortexing for 1min, performing ultrasound for 4min, adding 4mL of PEG400, vortexing for 1min, adding 5.5mL of physiological saline, and vortexing for 1min to obtain colorless clear liquid with concentration of 0.2 mg/mL.
(2) Pharmaceutical preparation for oral administration (PO): weighing 2.69mg of compound C, dissolving in 9mL of 0.5% CMC-Na, vortexing for 2min, and performing ultrasonic treatment for 10min to finally prepare a white uniform suspension with the concentration of 0.3 mg/mL.
2. Grouping and administration of drugs
Taking 6 female SD rats, randomly dividing into 2 groups, namely an injection group and an oral group, and administering according to the table 2; furthermore, the oral group had a meal for 16-17h before administration and was returned to meal 4h after administration.
Table 2.
3. Sample collection and processing
(1) Collecting samples: the rats in the injection group are subjected to jugular vein blood sampling before administration and 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h and 24h after administration; the rats in oral group were subjected to jugular vein blood sampling before administration and 15min, 30min, 1h, 2h, 4h, 6h, 8h and 24h at the administration port.
(2) Sample treatment: performing anticoagulation treatment on the collected blood sample by using heparin sodium, performing centrifugal separation at 8000r/min and 6min at 2-8 ℃ to obtain plasma, and storing the plasma at-80 ℃.
5. Results of the experiment
The data results of the blood concentration of female SD rats after a single injection administration of the drug preparation are shown in figure 1, and the data results of the blood concentration of female SD rats after a single oral administration of the drug preparation are shown in figure 2.
The compound C is administrated to female SD rats by injection, the peak time of the blood concentration is short, the metabolism speed of the compound C in plasma is gradually gentle from fast, and the concentration of the medicine in the plasma is low after 24 hours of administration; compound C is orally administered to female SD rats, the peak time of the blood concentration is longer, the metabolism speed of the compound C in the blood plasma is higher, and the concentration of the medicine in the blood plasma is lower after 24 hours of administration.
Pharmacokinetic parameters of compound C were calculated from the plasma concentration data using pharmacokinetic calculation software winnolin6.2.1 non-compartmental model, respectively, and the results are shown in tables 3 and 4.
TABLE 3 injection group pharmacokinetic parameters
TABLE 4 oral group pharmacokinetic parameters
Where "-" indicates no calculated value and "NA" indicates not applicable.
Orally administered rat plasma C max Compared with C administered by injection max The compound C is hydrolyzed in a rat body after oral administration, the oral absorption utilization degree is poor, and the antitumor activity of the compound C can be better played by using an injection mode for administration, so that better drug effect is realized.
Example 14: the SKM-1RNA-seq protein cultured by isothiocyanate derivative 4- (2-isothiocyano) ethyl benzenesulfonamide is a main undertaker for performing cell functions, the protein is the most direct description of the cell functions and states, the transcriptome is a necessary link for connecting genome genetic information and a proteome with biological functions, and the research on cell gene expression is realized by sequencing the transcriptome.
The transcriptome is the sum of all RNAs transcribed from a specific tissue or cell in a certain developmental stage or functional state, mainly including mRNA and non-coding RNA, and currently, the RNA sequencing technology (RNA-seq) is an important means for transcriptomics research. The RNA-seq utilizes a new generation high-throughput sequencing to sequence the genome cDNA, calculates the expression quantity of different mRNA by counting related Reads, analyzes the structure and the expression level of a transcript, finds unknown transcripts and rare transcripts at the same time, accurately identifies variable shearing sites and coding sequence nucleotide polymorphism, and provides the most comprehensive transcriptome information.
In this example, SKM-1 cells were used as the study subject, and a pharmaceutical preparation containing Compound C was added during the cell culture, and after a period of cell culture, the transcriptome of SKM-1 cells was sequenced using RNA-seq technique; and the difference between SKM-1 cells cultured by the compound C and cells cultured by the sulforaphen in the aspects of gene expression and the like can be analyzed by analyzing the structure and the expression level of the transcript by taking the sulforaphen as a control, so that effective information can be provided for the research on the specific molecular mechanism of the anticancer effect of the compound C.
The expression levels of AACSP1, AAK1, and AAMP genes in SKM-1 cells were obtained by calculating the gene expression levels (RPKM), and the results are shown in Table 5.
TABLE 5 differential expression Gene results for Compound C and sulforaphane
As can be seen from Table 5, the difference between the expression of AAK1 gene and sulforaphane in SKM-1 cells cultured by compound C is large, the expression of AAK1 gene in SKM-1 cells cultured by compound C is reduced, AAK1 refers to adaptor protein kinase 1, which is combined with adaptor protein complex 2(AP-2) to regulate the endocytosis process mediated by intracellular lattice protein; AAK1 can also activate SKM-1 intracellular replication-related protein through the kinase action, and the compound C can reduce the expression of AAK1 gene, thereby realizing the anticancer effect, and has better anticancer effect compared with sulforaphane.
The results of the analysis of the biological pathway of SKM-1 cells using the KEGG biological pathway database are shown in FIGS. 3 and 4.
As can be seen from FIG. 3, the BCR-ABL1 gene is a fusion gene formed by fusing the ABL1 gene on chromosome 9 with the BCR gene on chromosome 22; the p210 fusion protein is a protein coded by a BCR-ABL1 gene and belongs to one of tyrosine protein kinases, a coiled-coil domain at the N terminal of the p210 fusion protein has the functions of promoting dimerization and autophosphorylation, so that the protein has the activity of continuously activated tyrosine protein kinase, and CRKL can be connected with p210 to further regulate and control a downstream metabolic pathway. Wherein, the activation of p-Tyr at the end of p210 protein promotes the combination of GRB2 and Sos, performs GTP/GDP exchange with RAS and activates RAS, and simultaneously recruits PI3K and SHP2 through CRKL, CBL and CRK to realize the activation of serine-threonine protein kinase; activation of serine-threonine protein kinase can inhibit activity of transcription factor FOXO, further inhibit apoptosis, and simultaneously, through up-regulating expression of Skp2 protein, Skp2 protein degrades cell regulatory factor p27, promote cell proliferation; BCR-ABL1 can also activate STAT5 by direct phosphorylation, and activation of STAT5 is beneficial for cell proliferation and survival. The BCR-ABL1 signal channel in the SKM-1 cell is presented with high expression, thereby realizing the survival and the diffusion of the SKM-1 cell.
The SKM-1 cell is treated by the compound C, so that a BCR-ABL1 signal channel in the SKM-1 cell can be inhibited, p-Tyr activation at the tail end of a p210 protein is inhibited, the activity of a transcription factor FOXO is improved, and apoptosis is promoted; the expression of Skp2 protein is reduced, the degradation of regulatory factor p27 is reduced, and the cell proliferation is inhibited, so that the inhibition of processes such as proliferation, invasion, migration and the like of SKM-1 cells is realized; in addition, compound C can also be used to modulate VEGF signaling pathway, as well as proliferation, invasion and metastasis of SKM-1 cells; the compound C has better anticancer prospect in malignant clonal diseases of hematopoietic stem cells by influencing the processes of cell proliferation, apoptosis, invasion, metastasis and the like of SKM-1 cells.
The present embodiment is only for explaining the present application, and it is not limited to the present application, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present application.
Claims (10)
1. An isothiocyanate derivative having the formula:
wherein R1 and R2 are independently selected from one of hydrogen atom, halogen, alkyl and halogenated alkyl, and n represents different carbon chain lengths.
2. The isothiocyanate derivative of claim 1, wherein the alkyl halide is methyl trifluoride.
3. The isothiocyanate derivative of claim 1, wherein said alkyl group is a methyl group.
4. The isothiocyanate derivative of claim 1, wherein n is 1, R1 is halogen, and R2 is a hydrogen atom.
5. The isothiocyanate derivative of claim 1, wherein n is 2, R1 is independently selected from the group consisting of hydrogen, halogen, alkyl, and haloalkyl, and R2 is independently selected from the group consisting of hydrogen and halogen.
6. The isothiocyanate derivative according to claim 1, wherein n is 3, R1 is a hydrogen atom, and R2 is a hydrogen atom.
7. The isothiocyanate derivative according to claim 1, wherein n is 2, R1 is a hydrogen atom, and R2 is a hydrogen atom.
8. A process for producing an isothiocyanate derivative according to any one of claims 1 to 7, comprising a synthetic route for synthesizing an isothiocyanate derivative, the synthetic route being as follows:
wherein R1 and R2 are independently selected from one of hydrogen atom, halogen, alkyl and halogenated alkyl, and n represents different carbon chain lengths.
9. A pharmaceutical formulation characterized by: comprising a therapeutically effective amount of the isothiocyanate derivative according to any one of claims 1-7 and a pharmaceutically acceptable carrier or excipient, wherein the pharmaceutical preparation is an oral preparation or an injection preparation.
10. Use of a pharmaceutical formulation according to claim 9 in the treatment of cancer.
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Citations (3)
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|---|---|---|---|---|
| US20100178247A1 (en) * | 2008-12-05 | 2010-07-15 | Molecular Insight Pharmaceuticals, Inc. | Ca-ix specific radiopharmaceuticals for the treatment and imaging of cancer |
| CN102083427A (en) * | 2008-01-09 | 2011-06-01 | 分子洞察制药公司 | Inhibitors of carbonic anhydrase IX |
| CN103443083A (en) * | 2010-12-24 | 2013-12-11 | 马斯特里赫特放射肿瘤学基金会"Maastro诊所" | Cancer targeting using carbonic anhydrase isoform IX inhibitors |
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| CN102083427A (en) * | 2008-01-09 | 2011-06-01 | 分子洞察制药公司 | Inhibitors of carbonic anhydrase IX |
| US20100178247A1 (en) * | 2008-12-05 | 2010-07-15 | Molecular Insight Pharmaceuticals, Inc. | Ca-ix specific radiopharmaceuticals for the treatment and imaging of cancer |
| CN103443083A (en) * | 2010-12-24 | 2013-12-11 | 马斯特里赫特放射肿瘤学基金会"Maastro诊所" | Cancer targeting using carbonic anhydrase isoform IX inhibitors |
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