CN114890928B - Isothiocyanate derivative and preparation method and application thereof - Google Patents
Isothiocyanate derivative and preparation method and application thereof Download PDFInfo
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- CN114890928B CN114890928B CN202210283523.6A CN202210283523A CN114890928B CN 114890928 B CN114890928 B CN 114890928B CN 202210283523 A CN202210283523 A CN 202210283523A CN 114890928 B CN114890928 B CN 114890928B
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- hydrogen atom
- isothiocyanate derivative
- isothiocyanate
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- halogen
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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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- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- 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
-
- 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
- C07C303/40—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 reactions not involving the formation of sulfonamide groups
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The application discloses an isothiocyanate derivative, a preparation method and application thereof, and relates to the field of medical technology; wherein, an isothiocyanate derivative has the following structural formula:wherein R1 and R2 are independently selected from one of a hydrogen atom, halogen, alkyl and haloalkyl, and n represents different carbon chain lengths. The isothiocyanate derivative provided by the application has strong inhibition activity on hematological malignant tumors and solid malignant tumors, can be used for preparing antitumor drugs, and provides candidate compounds 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, a preparation method and application thereof.
Background
Tumor refers to a new organism formed by local tissue cell proliferation under the action of various tumorigenic factors; depending on the cellular nature of the neoplasm and the degree of damage to the body, it can be classified into benign and malignant tumors. Malignant tumors, also called cancers, are the most serious diseases endangering human health, and cancer cells are significantly different from normal cells in vivo or in vitro in morphology, growth and proliferation, genetic traits and the like.
The sulforaphane is also called as sulforaphane, belongs to one of isothiocyanates, and is extracted from cruciferous vegetables. Sulforaphane is the 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, and the PhaseII enzymes can destroy the active center of a cancerogenic factor or combine the cancerogenic factor with an endogenous ligand to reduce the change of the cancerogenic factor on normal intracellular genetic materials.
Disclosure of Invention
In order to design an isothiocyanate derivative and provide a novel anticancer drug, the application provides an isothiocyanate derivative and a preparation method and application thereof.
In a first aspect, the present application provides an isothiocyanate derivative according to the following technical scheme:
an isothiocyanate derivative having the structural formula shown below:
wherein R1 and R2 are independently selected from one of a hydrogen atom, a halogen, an alkyl group and a haloalkyl group, and n represents different carbon chain lengths.
Preferably, the haloalkyl is methyl trifluoride.
Preferably, the alkyl group is methyl.
Preferably, n is 1, R1 is halogen and R2 is a hydrogen atom.
Preferably, n is 2, R1 is independently selected from one of a hydrogen atom, halogen, alkyl and haloalkyl, and R2 is independently selected from one of a 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 preparation method of the isothiocyanate derivative provided by the application adopts the following technical scheme:
a method for preparing 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 a hydrogen atom, halogen, alkyl and haloalkyl, and n represents different carbon chain lengths.
In a third aspect, the present application provides a pharmaceutical formulation according to the following technical scheme:
a pharmaceutical formulation comprising a therapeutically effective amount of an isothiocyanate derivative as described above and a pharmaceutically acceptable carrier or excipient, said pharmaceutical formulation being an oral formulation or an injectable formulation.
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 inhibition activity on hematological malignant tumors and solid malignant tumors, can be used for preparing antitumor drugs, and provides candidate compounds for researching and developing new antitumor drugs;
(2) Compared with the sulforaphane, the isothiocyanate derivative provided by the application has stronger anti-tumor activity on SKM-1, and can be used for researching and developing medicines for treating myelodysplastic syndrome to provide candidate compounds.
Drawings
FIG. 1 is a graph of compound C plasma concentration versus time for individuals following a single intravenous administration of 1mg/kg of compound C to SD rats;
FIG. 2 is a graph of compound C plasma concentration versus time for individuals following a single oral administration of 3mg/kg of compound C to SD rats;
FIG. 3 is a most significant pathway diagram of a differentially expressed gene KEGG assay;
FIG. 4 is a cluster of highly expressed gene KEGG in SKM-1 cells cultured with Compound C.
Detailed Description
The present application is described in further detail below in conjunction with figures 1-4.
Example 1: 3-chloro-4-isothiocyanato methyl benzenesulfonamide (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-isothiocyanato methyl benzenesulfonamide (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) ethyl benzenesulfonamide (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) ethyl benzenesulfonamide (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) ethyl benzenesulfonamide (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) ethyl benzenesulfonamide (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) ethyl benzenesulfonamide (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) ethyl benzenesulfonamide (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) ethyl benzenesulfonamide (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 preparing isothiocyanate derivatives
This example provides a general synthetic route for the compounds described in preparation examples 1-10, as follows:
wherein R1 and R2 are independently selected from one of a hydrogen atom, halogen, alkyl and halogenated alkyl, and n represents different carbon chain lengths.
1. 3-chloro-4-isothiocyanato methyl benzene sulfonamide
S1, synthesizing a structural formula 2: 10g (70.08 mmol) of 3-chlorobenzylamine and 13g (1.56 eq,128.73 mmol) of triethylamine are added into a 250ml single-mouth eggplant type bottle, after the mixture is stirred uniformly at room temperature, 8.4g (82.52 mmol) of acetic anhydride is added dropwise, after the dropwise addition, the mixture is stirred overnight at room temperature, 30ml of water is added under ice bath for quenching reaction, 10% of dilute hydrochloric acid is used for regulating pH to be 5-6, DCM is used for extraction, the organic phases are combined for drying, filtration and concentration are carried out to obtain 7g of a product, and the product is directly used for the next reaction;
s2, synthesizing a structural formula 3: into a 250ml single-mouth eggplant type bottle, 10g (85.82 mmol) of chlorosulfonic acid is added, the temperature is reduced to minus 10 ℃, 2.6g (15.60 mmol) of the product obtained in the step S1 is added dropwise into the solution, after the dropwise addition is finished, the reaction is carried out for 1.5h at 100 ℃, the temperature is cooled to room temperature, and crushed ice is slowly added. Extracting with DCM, mixing the organic phases, drying, filtering, concentrating to obtain 3g of product, and directly using for the next reaction;
s3, synthesizing a structural formula 4: 3g of the product obtained in the step S2 is dissolved in 70ml of ammonia water in a 250ml single-mouth eggplant type bottle, stirred at room temperature overnight, the solvent is dried by spin, methanol is added, and the product is obtained by sample column chromatography;
s4, synthesizing a structural formula 5: 700mg (2.89 mmol) of the product of step S3 was dissolved in 24ml (2N KOH (aq)) in a 1L single-neck eggplant-type bottle and reacted at 100℃for 4h. Cooled to room temperature and ph=7 was adjusted with 2N HCl (aq). The residue after spinning the aqueous phase was dissolved in 500ml (4% MeOH in DCM) and stirred overnight. Filtering, concentrating the filtrate to obtain 300mg of product, and directly using the product in the next reaction;
s5, synthesizing a structural formula 6: 309mg DCC (1.5 mmol) and 1.14. 1.14gCS were combined in 250ml single-neck eggplant bottle 2 (15 mmol) in 20ml acetonitrile. Cooling to-10deg.C, mixing, dissolving 300mg of the product of step S4 in 50ml acetonitrile (basically insoluble) in another 100ml single-mouth eggplant bottle, adding dropwise the solution of the dissolved product of step S4 into another acetonitrile solution, reacting at room temperature for 3 hr after the dropwise addition is completed, gradually clarifying the reaction solution, concentrating the filtrate to dryness, adding diethyl ether, filtering to remove solid, and subjecting the filtrate to column chromatography to obtain white solid 150mg.
2. 4- (2-isothiocyanato) ethyl benzene sulfonamide
S1, synthesizing a structural formula 2: 10g (82.52 mmol) of phenylethylamine and 13g (1.56 eq,128.73 mmol) of triethylamine are added into a 250ml single-mouth eggplant-shaped bottle, after being stirred uniformly at room temperature, 8.4g of acetic anhydride is added dropwise, 82.52mmol is stirred overnight at room temperature after the dropwise addition, 30ml of water is added under ice bath for quenching reaction, 10% of dilute hydrochloric acid is used for regulating pH=5-6, DCM is used for extraction, the organic phases are combined for drying, filtration and concentration are carried out, and 7g of product is obtained and is directly used for the next reaction;
s2, synthesizing a structural formula 3: into a 250ml single-mouth eggplant type bottle, 10g (85.82 mmol) of chlorosulfonic acid is added, the temperature is reduced to minus 10 ℃, 2.6g (15.60 mmol) of the product obtained in the step S1 is added dropwise into the solution, after the dropwise addition is finished, the reaction is carried out for 1.5h at 100 ℃, the temperature is cooled to room temperature, and crushed ice is slowly added. Extracting with DCM, mixing the organic phases, drying, filtering, concentrating to obtain 3g of product, and directly using for the next reaction;
s3, synthesizing a structural formula 4: 3g of the product obtained in the step S2 is dissolved in 70ml of ammonia water in a 250ml single-mouth eggplant type bottle, stirred at room temperature overnight, the solvent is dried by spin, methanol is added, and the product is obtained by sample column chromatography;
s4, synthesizing a structural formula 5: 700mg (2.89 mmol) of the product of step S3 was dissolved in 24ml (2N KOH (aq)) in a 1L single-neck eggplant-type bottle and reacted at 100℃for 4h. Cooled to room temperature and ph=7 was adjusted with 2N HCl (aq). The residue after spinning the aqueous phase was dissolved in 500ml (4% MeOH in DCM) and stirred overnight. Filtering, concentrating the filtrate to obtain 300mg of product, and directly using the product in the next reaction;
s5, synthesizing a structural formula 6: 309mg DCC (1.5 mmol) and 1.14. 1.14gCS were combined in 250ml single-neck eggplant bottle 2 (15 mmol) in 20ml acetonitrile. Cooling to-10deg.C, mixing, dissolving 300mg of the product of step S4 in 50ml acetonitrile (basically insoluble) in another 100ml single-mouth eggplant bottle, adding dropwise the solution of the dissolved product of step S4 into another acetonitrile solution, reacting at room temperature for 3 hr after the dropwise addition is completed, gradually clarifying the reaction solution, concentrating the filtrate to dryness, adding diethyl ether, filtering to remove solid, and subjecting the filtrate to column chromatography to obtain white solid 150mg.
3. 4- (3-isothiocyanato) propylbenzenesulfonamide
S1, synthesizing a structural formula 2: raw materials of 10g (73.96 mmol) of 3-phenyl-1-propylamine and 13g (1.56 eq,128.73 mmol) of triethylamine are added into a 250ml single-mouth eggplant type bottle, after the mixture is stirred uniformly at room temperature, 8.4g of acetic anhydride is added dropwise, 82.52 mmol) is added dropwise, after the dropwise addition is finished, the mixture is stirred overnight at room temperature, 30ml of water is added under ice bath for quenching reaction, 10% of diluted hydrochloric acid is used for regulating pH to = 5-6, DCM is used for extraction, the organic phases are combined for drying, filtration and concentration are carried out, and 7g of a product is obtained and is directly used for the next reaction;
s2, synthesizing a structural formula 3: into a 250ml single-mouth eggplant type bottle, 10g (85.82 mmol) of chlorosulfonic acid is added, the temperature is reduced to minus 10 ℃, 2.6g (15.60 mmol) of the product obtained in the step S1 is added dropwise into the solution, after the dropwise addition is finished, the reaction is carried out for 1.5h at 100 ℃, the temperature is cooled to room temperature, and crushed ice is slowly added. Extracting with DCM, mixing the organic phases, drying, filtering, concentrating to obtain 3g of product, and directly using for the next reaction;
s3, synthesizing a structural formula 4: 3g of the product obtained in the step S2 is dissolved in 70ml of ammonia water in a 250ml single-mouth eggplant type bottle, stirred at room temperature overnight, the solvent is dried by spin, methanol is added, and the product is obtained by sample column chromatography;
s4, synthesizing a structural formula 5: 700mg (2.89 mmol) of the product of step S3 was dissolved in 24ml (2N KOH (aq)) in a 1L single-neck eggplant-type bottle and reacted at 100℃for 4h. Cooled to room temperature and ph=7 was adjusted with 2N HCl (aq). The residue after spinning the aqueous phase was dissolved in 500ml (4% MeOH in DCM) and stirred overnight. Filtering, concentrating the filtrate to obtain 300mg of product, and directly using the product in the next reaction;
s5, synthesizing a structural formula 6: 309mg DCC (1.5 mmol) and 1.14. 1.14gCS were combined in 250ml single-neck eggplant bottle 2 (15 mmol) in 20ml acetonitrile. Cooling to-10deg.C, mixing, dissolving 300mg of the product of step S4 in 50ml acetonitrile (basically insoluble) in another 100ml single-mouth eggplant bottle, adding dropwise the solution of the dissolved product of step S4 into another acetonitrile solution, reacting at room temperature for 3 hr after the dropwise addition is completed, gradually clarifying the reaction solution, concentrating the filtrate to dryness, adding diethyl ether, filtering to remove solid, and subjecting the filtrate to column chromatography to obtain white solid 150mg.
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 test drug: dissolving isothiocyanate derivative described in examples 1-10 with a certain mass in 0.5mL of 5% DMSO, swirling for 1min, performing ultrasonic treatment for 4min, adding 4mL of PEG400, swirling for 1min, adding 5.5mL of physiological saline, and swirling for 1min to prepare a test medicament of colorless clear liquid.
(2) Cell proliferation inhibition assay
a549, MCF7, and HEPG2 cells: preparing single cell suspension with culture solution (DMEM) containing 1% diabody and 10% foetal calf serum, and heating to 37deg.C and 5% CO 2 Is cultured under saturated humidity for 2 days, and cells are inoculated into 96-well plates after expansion, wherein the cell density of each well is 1×10 4 100 μl, overnight attached. Setting different drug gradient concentrations to treat cells for 72h, discarding drug-containing culture medium, adding newly prepared toxicity detection solution CCK8 containing 10 μL into each hole, placing into an incubator, continuously incubating for 1h, measuring OD value at 450nm with an ELISA reader, and calculating half of the effective values with Bliss methodConcentration-inhibiting IC 50 Experiments were performed in parallel 4 times.
Hl-60, SKM-1 cells: taking logarithmic growth phase cells, centrifuging, diluting with RPMI1640 culture solution to concentration of 3×10 5 Cell suspensions at each/mL were seeded in 96-well plates. After culturing at 37deg.C overnight, adding test drugs with different concentrations, incubating for 72 hr, adding fresh 10 μL toxicity detection solution CCK8 into each well, culturing in incubator for 1 hr, measuring OD value at 450nm with enzyme-labeled instrument, and calculating half effective inhibitory concentration IC with Bliss method 50 Experiments were performed in parallel 4 times.
2. Experimental results
The results of the cell proliferation inhibition experiments are shown in table 1:
TABLE 1 half inhibition concentration of isothiocyanate derivatives on cancer cells
As shown in Table 1, the compounds A-K described in examples 1-10 have an inhibitory effect on proliferation of human cancer cells HL-60, SKM-1, A549, MCF-7 and HepG2, have a high in vitro antitumor activity, and have a stronger inhibitory effect on proliferation of hematological malignant cells HL-60 and SKM-1 than that of solid malignant cells A549, MCF-7 and HepG2.
The sulforaphane has strong inhibition effect on hematological malignancy, but has no obvious inhibition effect on proliferation of solid malignancy; however, compound C provided in example 3 has the strongest antitumor activity in vitro, and half-effective inhibitory concentration IC 50 The minimum is 1.71 mu M, the maximum is 9 mu M, and the inhibition effect on proliferation of blood malignant tumor and solid malignant tumor is strong; the inhibition effect of the compound D, E, F, G and H obtained by changing the functional group on the benzene ring of the compound C on the hematological malignancy cells is close to that of the compound C, but the inhibition effect on the solid malignancy is reduced.
From table 1 and the above analysis, the structure-activity relationship of isothiocyanate derivatives can be deduced. 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 isocyanoalkyl has little influence on the antitumor activity of the compound; for SKM-1 cell line, the compound with the chain length of isocyanoalkyl being 2 or 3 has higher anti-tumor activity, but when the substituent at the 3-position of the benzene ring is fluorine atom or trifluoromethyl, the anti-tumor activity of the compound is reduced. For solid malignant cells, the antitumor activity of the compound with the chain length of 2 of isocyanoalkyl is higher than that of the compound with the chain length of 1 or 3; wherein, for the A459 cell line, when fluorine atom or trifluoromethyl is introduced into benzene ring, the antitumor activity of the compound is reduced; for the MCF-7 cell line, the influence of introducing chlorine atoms on the 2 nd position of the benzene ring on the antitumor activity of the compound is not great; for HepG2 cell lines, when the substituent at position 3 of the benzene ring is a fluorine atom or a trifluoromethyl group, the antitumor activity of the compound decreases. Through analysis of the structure-activity relationship of isothiocyanate derivatives, valuable information can be provided for searching more effective and more selective anticancer drugs by taking isothiocyanato alkyl benzene sulfonamide as a basic framework.
Example 13: in the research and development of medicines, the pharmacokinetic experiment of the isothiocyanate derivative 4- (2-isothiocyanamide) ethyl benzene sulfonamide has important significance in the pharmacokinetic research before the clinical experiment, and the pharmacokinetics is that the dynamic change rule of the medicines in vivo is revealed through the research methods in vivo, in vitro and in vitro of animals, the basic pharmacokinetic parameters of the medicines are obtained, and the absorption, distribution, metabolism and excretion processes and characteristics of the medicines are clarified.
The pharmacokinetic study of the compound C4- (2-isothiocyanamide) ethyl benzene sulfonamide was performed using female SD rats; wherein female SD rats were purchased from Shanghai Sipuler-BiKai laboratory animal Co., ltd; and the concentration of compound C in the plasma of experimental rats was determined using LC/MS and relevant parameters were calculated.
1. Configuration of pharmaceutical formulations
(1) Injection (IV) of pharmaceutical formulation: 1.99mg of compound C is weighed, dissolved in 0.5% DMSO, vortexed for 1min, sonicated for 4min, then 4mL PEG400 is added, vortexed for 1min, then 5.5mL physiological saline is added, vortexed for 1min, and finally colorless clear liquid with the concentration of 0.2mg/mL is prepared.
(2) Pharmaceutical preparation for oral administration (PO): 2.69mg of Compound C was weighed, dissolved in 9mL of 0.5% CMC-Na, vortexed for 2min, sonicated for 10min, and finally a white homogeneous suspension was prepared at a concentration of 0.3 mg/mL.
2. Grouping and administration
6 female SD rats were randomly divided into 2 groups, respectively an injection group and an oral group, and were dosed according to Table 2; and, the oral group took food 16-17 hours before administration, and was resumed after administration for 4 hours.
Table 2.
3. Sample collection and processing
(1) Sample collection: rats in the injection group were subjected to jugular vein blood collection 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h and 24h before administration; oral rats were subjected to jugular vein blood collection before dosing for 15min, 30min, 1h, 2h, 4h, 6h, 8h and 24h at the dosing port.
(2) Sample treatment: performing anticoagulation treatment on the collected blood sample by using heparin sodium, centrifuging at 8000r/min and 6min at 2-8deg.C to obtain plasma, and storing at-80deg.C.
5. Experimental results
The results of the data on blood concentration of female SD rats after single injection administration of the pharmaceutical preparation are shown in FIG. 1, and the results of the data on blood concentration after single oral administration of the pharmaceutical preparation are shown in FIG. 2.
Compound C was administered to female SD rats by injection, the peak time of the plasma concentration was short, the metabolic rate of compound C in plasma was rapid to gradual gentle, and the concentration of drug in plasma was low after 24 hours of administration; compound C was administered orally to female SD rats with longer peak plasma concentration times and faster compound C metabolism in plasma, and 24h after administration, the concentration of drug in plasma was lower.
Pharmacokinetic parameters for compound C were calculated from the blood concentration data using the pharmacokinetic calculation software winnolin6.2.1 non-compartmental model, respectively, and the results are shown in tables 3 and 4.
TABLE 3 pharmacokinetic parameters of injection groups
TABLE 4 oral group pharmacokinetic parameters
Where "-" indicates no calculated value and "NA" indicates inapplicability.
Oral administration of C in rat plasma max Compared with C administered by injection max Compound C is hydrolyzed in the rat body after oral administration, and the availability of oral absorption is poor, and the antitumor activity of compound C can be better exerted by administration in an injection manner, thus realizing better drug effect.
Example 14: the SKM-1RNA-seq protein cultured by the isothiocyanate derivative 4- (2-isothiocyanato) ethyl benzene sulfonamide is a main carrier for performing cell functions, the protein is the most direct description of the cell functions and states, the transcriptome is a necessary tie for connecting genome genetic information and a proteome with biological functions, and the research on cell gene expression is realized by sequencing the transcriptome.
Transcriptomes are the sum of all RNAs transcribed by a particular tissue or cell at a certain developmental stage or functional state, mainly including mRNA and non-coding RNAs, and RNA sequencing technology (RNA-seq) is currently an important tool in transcriptomic studies. The RNA-seq utilizes the new generation high throughput sequencing to sequence the genome cDNA, calculates the expression quantity of different mRNAs by counting the related Reads, analyzes the structure and the expression level of transcripts, simultaneously discovers unknown transcripts and rare transcripts, accurately identifies variable cleavage sites and nucleotide polymorphism of coding sequences, and provides the most comprehensive transcriptome information.
In this example, SKM-1 cells were used as the subject, a pharmaceutical preparation containing Compound C was added during cell culture, and after a period of cell culture, the transcriptome of the SKM-1 cells was sequenced using the RNA-seq technique; and the difference of SKM-1 cells cultured by the compound C and the cells cultured by the sulforaphane in gene expression and the like is analyzed by taking the sulforaphane as a control and analyzing the structure and the expression level of transcripts, so that effective information can be provided for specific molecular mechanism research of the anticancer effect of the compound C.
The expression levels of AACSP1, AAK1 and AAMP genes in SKM-1 cells were calculated by calculating the gene expression levels (RPKM), and the results are shown in Table 5.
TABLE 5 differential gene expression results of Compound C and sulforaphane
As can be seen from Table 5, the expression of AAK1 gene and sulforaphane in SKM-1 cells cultured with Compound C is greatly different, and the expression of AAK1 gene in SKM-1 cells cultured with Compound C is down-regulated, AAK1 refers to adaptor protein kinase 1 which regulates the endocytosis process mediated by intracellular lattice protein by binding with adaptor protein complex 2 (AP-2); AAK1 can activate SKM-1 intracellular replication related proteins through kinase action, and the expression of AAK1 genes can be reduced by using the compound C, so that an anticancer effect is realized, and the compound C has a better anticancer effect compared with sulforaphane.
The SKM-1 cells were analyzed for biological pathways using KEGG biological pathway database, and the analysis results are shown in fig. 3 and 4.
As can be seen from FIG. 3, the BCR-ABL1 gene is a fusion gene formed by fusion of the ABL1 gene on chromosome 9 and the BCR gene on chromosome 22; the p210 fusion protein is the coded protein of the BCR-ABL1 gene, belongs to one of tyrosine protein kinases, and the coiled-coil domain at the N end of the p210 fusion protein has the functions of promoting dimerization and autophosphorylation, so that the p210 fusion protein has continuously activated tyrosine protein kinase activity, and CRKL can be connected with p210 to regulate and control downstream metabolic pathways. Wherein, p210 protein end p-Tyr activation promotes the combination of GRB2 and Sos, carries out GTP/GDP exchange with RAS and activates RAS, and meanwhile, recruits PI3K and SHP2 through CRKL, CBL and CRK to realize activation of serine-threonine protein kinase; activation of serine-threonine protein kinase can inhibit the activity of transcription factor FOXO, thereby inhibiting apoptosis, and simultaneously promote cell proliferation by up-regulating Skp2 protein expression, skp2 protein degrading cell regulatory factor p 27; BCR-ABL1 can also be directly phosphorylated to activate STAT5, and activation of STAT5 is beneficial to proliferation and survival of cells. The BCR-ABL1 signal channel in the SKM-1 cells is expressed in a high degree, so that the survival and the diffusion of the SKM-1 cells are realized.
The compound C is used for treating SKM-1 cells, so that BCR-ABL1 signal paths in the SKM-1 cells can be inhibited, p-Tyr activation of the tail end of p210 protein is inhibited, the activity of a transcription factor FOXO is improved, and apoptosis is promoted; the Skp2 protein expression is reduced, the degradation of a regulatory factor p27 is reduced, and the proliferation of cells is inhibited, so that the proliferation, invasion, migration and other processes of SKM-1 cells are inhibited; in addition, compound C can also modulate VEGF signaling pathways, as well as proliferation, invasion and metastasis of SKM-1 cells; the compound C has better anticancer prospect in hematopoietic stem cell malignant clonal diseases by influencing the processes of cell proliferation, apoptosis, invasion, metastasis and the like of SKM-1 cells.
The present embodiment is merely illustrative of the present application and is not intended to be limiting, and those skilled in the art, after having read the present specification, may make modifications to the present embodiment without creative contribution as required, but is protected by patent laws within the scope of the claims of the present application.
Claims (8)
1. An isothiocyanate derivative having the structural formula:
wherein R is 1 And R is 2 Independently selected from one of a hydrogen atom, a halogen, a methyl group and a halogenated methyl group,
n represents different carbon chain lengths, and n is 1-3;
and when n=1 or 2, R 1 And R is 2 Not both hydrogen atoms.
2. An isothiocyanate derivative according to claim 1, wherein said halomethyl group is methyl trifluoride.
3. An isothiocyanate derivative according to claim 1, wherein n is 1, R 1 Is halogen, R 2 Is a hydrogen atom.
4. An isothiocyanate derivative according to claim 1, wherein n is 2, r 1 Independently selected from one of hydrogen atom, halogen, methyl and halogenated methyl, R 2 Independently selected from one of a hydrogen atom and a halogen, and R 1 And R is 2 Not both hydrogen atoms.
5. An isothiocyanate derivative according to claim 1, wherein n is 3, r 1 Is a hydrogen atom, R 2 Is a hydrogen atom.
6. A process for the preparation of isothiocyanate derivatives according to any of claims 1-5, comprising the synthetic route for the synthesis of isothiocyanate derivatives, said synthetic route being as follows:
wherein R is 1 And R is 2 Independently selected from one of a hydrogen atom, a halogen, a methyl group and a halogenated methyl group,
n represents different carbon chain lengths, and n is 1-3;
and when n=1 or 2, R 1 And R is 2 Not both hydrogen atoms.
7. A pharmaceutical formulation characterized in that: comprising a therapeutically effective amount of an isothiocyanate derivative of any of claims 1-5 in combination with a pharmaceutically acceptable carrier or excipient, wherein the pharmaceutical formulation is an oral formulation or an injectable formulation.
8. Use of a pharmaceutical formulation according to claim 7 for the preparation of a composition for the treatment of cancer.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
| 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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| US8211402B2 (en) * | 2008-12-05 | 2012-07-03 | Molecular Insight Pharmaceuticals, Inc. | CA-IX specific radiopharmaceuticals for the treatment and imaging of cancer |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Non-Patent Citations (1)
| Title |
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| Hypoxia-Targeting Carbonic Anhydrase IX Inhibitors by a New Series of Nitroimidazole-Sulfonamides/Sulfamides/Sulfamates;Marouan Rami 等;Journal of Medicinal Chemistry;第56卷;第8513页Scheme 2 * |
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