CN113648294B - Application of beta-disulfonimide substituted ketone compound in treatment of cancer - Google Patents
Application of beta-disulfonimide substituted ketone compound in treatment of cancer Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
The invention belongs to the technical field of medicines, and discovers that beta-disulfonimide substituted ketone compounds show double targeting inhibition effects on a WNT signal channel and a HIF signal channel for the first time, and can be used as inhibitors of the two signal channels. Because the two pathways are closely related to the occurrence and development of tumors, further experiments also prove that the compounds can be used as bifunctional inhibitors to inhibit the proliferation of cancer cells under two-dimensional (2D) and three-dimensional (3D) cell culture conditions, and the compounds are suggested to have the efficacy of treating malignant tumors. The compound not only has wide application prospect in the aspect of treating cancers related to the two paths, but also provides a new thought for the development of multi-target antitumor drugs.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a novel application of a beta-disulfonimide substituted ketone compound, in particular to an application of the beta-disulfonimide substituted ketone compound in treating WNT signal channels or diseases related to HIF signal channels, especially cancers.
Background
HIF (hypoxia inducible factor) is a transcription factor that regulates the adaptation of cells to reduced oxygen or to a hypoxic environment, depending on the change in available oxygen in the cellular environment. Studies have shown that HIF is essential for cell differentiation and development. HIF is not only capable of regulating human metabolism, but also plays an important role in the survival and growth of chondrocytes in a hypoxic environment. Because of the large amount of oxygen required for malignant tumor proliferation, the tumor microenvironment is typically in an anoxic environment. Studies have demonstrated that HIF is often overexpressed in tumors, with unlimited growth, invasion and metastasis of tumors, and with angiogenesis in tumors. Development of new HIF inhibitors for malignancy treatment has been a hotspot area of research.
It has been found that the WNT signaling pathway plays an important role in embryonic development and limb formation in young animals, and that the classical WNT/β -catenin signaling pathway is closely related to the generation and development of malignant tumors. The abnormal accumulation of the beta-catenin can reduce the cell surface adhesiveness, and accelerate the infiltration and metastasis of tumors to cause death of malignant tumor patients. The beta-catenin is enriched in a large amount in most human epithelial cell cancers (including colorectal cancer, esophageal cancer, renal cancer, colon cancer, breast cancer and the like). The development of new WNT signaling pathway inhibitors for the treatment of malignant tumors has been the leading international research hotspot.
Both WNT signaling pathway and HIF signaling pathway are closely related in the development and progression of cancer, and these two single pathway inhibitors have been studied very intensively and successfully in the treatment of malignant tumors. However, as the drug resistance of tumors increases, the anticancer drug effect of a single signal pathway target will be difficult to meet the requirements of anticancer drug development. Further development of novel multifunctional signaling pathway inhibitors is of great importance for cancer treatment. The beta-bissulfonylimide substituted ketone compound is a lead compound which is designed by the inventor in earlier stage to inhibit the activity of novel coronaviruses, and further research discovers that the compound can be used as a high-efficiency inhibitor of a WNT signal channel and a HIF signal channel at the same time, can obviously inhibit the replication of cancer cells, and has wide application prospect in preparing high-efficiency anticancer drugs.
Disclosure of Invention
Aiming at the prior art, the invention aims to provide a novel medical application of the beta-disulfonimide substituted ketone compound. The research of the invention discovers that the beta-disulfonimide substituted ketone compound can obviously inhibit the transcription of HIF and WNT related genes and inhibit the replication of cancer cells. Can be used for preparing medicines for treating malignant tumors related to HIF and WNT pathways.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the invention provides application of beta-bissulfonylimide substituted ketone compounds in cancer treatment.
In the application, the beta-bissulfonylimide substituted ketone compound has a structural general formula shown in the following formula I:
wherein: r is R 1 Selected from the group consisting of hydrogen, alkyl, substituted and unsubstituted aryl;
R 2 selected from the group consisting of hydrogen, alkyl, substituted and unsubstituted aryl;
R 3 and R is 4 Each independently selected from substituted and unsubstituted aryl and alkyl groups.
The beta-disulfonimide substituted ketone compound, wherein R 1 Alkyl groups, substituted and unsubstituted aryl groups in (a) include, but are not limited to
Either one.
The beta-disulfonimide substituted ketone compound and the R 2 Alkyl groups, substituted and unsubstituted aryl groups in (a) include, but are not limited toEither one.
The beta-disulfonimide substituted ketone compound and the R 3 And R is 4 Alkyl groups, substituted and unsubstituted aryl groups in (a) include and are notIs limited toEither one.
The beta-bissulfonylimide substituted ketone compound includes, but is not limited to, any one of the following compounds:
in the application of the compounds, the WNT signal channel inhibitor and the HIF signal channel inhibitor are therapeutic drugs for diseases related to the WNT and the HIF signal channels.
The cancers for treatment include, but are not limited to, colon cancer, colorectal cancer, liver cancer, gastric cancer, lung cancer, prostate cancer, pancreatic cancer, breast cancer, ovarian cancer, and osteosarcoma, particularly colon cancer, that are closely related to HIF and WNT signaling pathways.
The dosage forms of the medicines related to the HIF and WNT channels are tablets, capsules, oral liquid, granules, pills or injections.
The invention has the beneficial effects that:
the invention discovers that the beta-disulfonimide substituted ketone compound has double targeting inhibition effect on two signal paths of HIF and WNT closely related to malignant tumor for the first time. The compound can further inhibit the proliferation of tumor cells, and has the effect of treating malignant tumors. The compound not only has wide application prospect in the aspect of treating cancers related to the two paths, but also provides a new thought for the development of multi-target antitumor drugs.
Drawings
The inhibition effect of the compounds 3g, 3h, 3i, 3p, 3v, 3w, 3x, 3af, 3aq and 4i in FIG. 1 on the luciferase activity related to the WNT and HIF channels shows that the compounds have obvious inhibition effect on the WNT and HIF channels.
FIG. 2 shows the inhibition efficiency of compound 3g on WNT and HIF pathway-related luciferase activity and EC at various concentrations 50 And (5) measuring.
FIG. 3 shows the efficiency of compound 3g in inhibiting HCT116 cell proliferation and IC at various concentrations 50 And (5) measuring.
Figure 4 in vivo environment was simulated by three-dimensional (3D) cell culture, 3g of compound significantly inhibited HCT116 cell spheroid formation and growth.
Detailed Description
The following describes in detail the technical solutions of the embodiments of the present invention, and the provided embodiments are merely representative examples of the present invention. All other embodiments, which are obtained by a person of ordinary skill in the art without making any inventive effort, are intended to fall within the scope of the present invention.
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the present application. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
The test materials used in the examples of the present invention, which are not specifically described, are all conventional in the art, and can be synthesized by simple procedures or purchased commercially.
Wherein: the structural formulas of compounds 3g, 3h, 3i, 3p, 3v, 3w, 3x, 3af, 3aq and 4i are shown below:
the preparation of compounds 3g, 3h, 3i, 3p, 3v, 3w, 3x, 3af and 3aq can be referred to the method described in chinese patent application (CN 113024423 a), the reaction formula (taking compound 3g as an example):
example 1: the preparation method of the compound 4i comprises the following steps:
the synthesis steps and processes are as follows: to a 5mL reaction tube equipped with a magnetic stirrer, 1a (0.1 mmol,18.8 mg), NFSI (0.25 mmol,78.8 mg), cuprous iodide (0.02 mmol) and 2, 3-butanedione (0.02 mmol) were added, then 0.1-1mL acetonitrile was added, the reaction tube was fixed on a 6w photoreactor under inert gas protection, the wavelength range was 460-470 nm, the reaction was carried out for 20 hours, and after completion, the solvent was removed by a rotary evaporator, the crude product was purified by column chromatography (petroleum ether: ethyl acetate=3:1) to obtain the target product N- (2-methyl-4-oxo-3- ((N- (phenylsulfonyl) phenylsulfamoyl) methyl) -4- (4- (trifluoromethyl) phenyl) butan-2-yl) acetamide (N- (2-methyl-4-oxo-3- ((N- (phenylsulfonyl) phenyl) methyl) -4- (4- (triphenylmethyl) sulfonyl) phenyl) methyl) ketone-2-amide yield of 0.45%.
Compound 4i nuclear magnetic data: 1 H NMR(600MHz,Chloroform-d)δ8.03–7.99(m,6H),7.63–7.60(m,4H),7.52(dd,J＝8.4,7.4Hz,4H),5.69(brs,NH,1H),5.03(dd,J＝8.9,1.7Hz,1H),4.19(dd,J＝15.3,8.9Hz,1H),4.08(dd,J＝15.3,1.7Hz,1H),1.89(s,3H),1.35(s,3H),1.33(s,3H).；
13 C NMR(151MHz,Chloroform-d)δ200.81,170.74,141.03,138.84,134.2(q,J＝32.5Hz),134.08,130.42,129.05,128.61,125.52(q,J＝3.8Hz),123.57(q,J＝272.7Hz),55.73,50.60,47.86,25.97,24.38,24.16；
19 F NMR(565MHz,Chloroform-d)δ-63.16；
example 2: cell culture
Human colon cancer cell line (HCT 116) was purchased from American Type Culture Collection (ATCC). HCT116 was maintained in 5A medium to which 10% Fetal Bovine Serum (FBS), penicillin (100 IU/ml) and streptomycin (100 mg/ml) were added. HCT116 cells contained 5% CO at 37deg.C 2 Is cultured in a humidified atmosphere of CoCl 2 And simulating an anoxic model.
Example 3: the inhibition effect of beta-disulfonimide substituted ketone compounds on HIF and WNT signals is evaluated by detecting luciferase activity.
The present example evaluates the effect of different β -bissulfonylimide substituted ketone small molecule compounds in inhibiting HIF and WNT signaling pathways, first constructing a corresponding luciferase reporter cell line. The inhibition of these compounds is detected by decreasing luciferase activity, and the results indicate that the compounds generally have obvious inhibition on WNT and HIF signal channels. Of these, compounds 3g and 3aq exhibited better inhibition (FIG. 1). Wherein compound 3g inhibited luciferase activity of HIF and WNT signaling with EC50 values of 11.37 μm and 9.17 μm, respectively (fig. 2).
The specific operation is as follows: human colon cancer cells (HCT 116) were stably transfected with a TCF/LEF luciferase reporter plasmid (genome editech, GM-021042), a HIF-1 luciferase reporter plasmid (genome editech, GM-021020), and a P53 luciferase reporter plasmid (GM-021040), respectively, to construct HCT116 luciferase reporter plasmids. Transfection with lipofectamine3000 (Invitrogen) was performed according to the manufacturer's protocol. 48 hours after transfection, cells were screened with 500. Mu.g/ml G418 (Sigma). Positive clones were taken after 3 weeks for analysis. Reporter cells (10000 per well) were seeded into white 96-well plates and incubated with different β -bissulfonylimide substituted ketones at 10 μm concentration or compound 3g at gradient concentration, respectively. After 24h, luciferase assay reagent (Promega) was added to each well usingAnd detecting the fluorescence value by an L enzyme label instrument. Wherein the compounds are tested for their inhibitory effect by a decrease in luciferase activity.
Example 3: compound 3g at different concentrations inhibited HCT116 cell proliferation efficiency and IC under two-dimensional (2D) cell culture conditions 50 Measurement (FIG. 3).
The specific operation is as follows: to evaluate the inhibitory effect on cancer cells of 3g, 3000 HCT116 cells were seeded in 96 Kong Baiban and cultured overnight. Adding 3g with different concentrations for 72 hr, and usingAnd (3) measuring cell count by using an enzyme-labeled instrument, and calculating the half-inhibition concentration.
Example 4: in vivo environment was simulated by three-dimensional (3D) cell culture, under which 3g of compound could significantly inhibit the formation and growth of spheres of human colon cancer cells (HCT 116).
Experimental results: as shown in fig. 4, the size of spheroids formed was significantly reduced after treatment with 3g of compound and the inhibition was dose dependent (fig. 4). Sphere size distribution was measured using Image J software (fig. 4). At concentrations of 10. Mu.M and 20. Mu.M, the average spherical diameters of the medium containing 3g were 46.5 μm and 32.7. Mu.m, respectively, and the spherical diameters after 6d of culture in the vector group were about 102.4. Mu.m. Quantitative analysis of total protein also showed that 3g had an inhibitory effect on cell growth. 3g of the cells were dispersed in the initial stage of culture, and the formation and growth of cell spheres were inhibited.
The specific operation is as follows: 80000 cells were seeded per well and HCT116 cells were cultured using the 3D intercalating assay method. HCT116 cells were cultured in 24 well plates for 8 days with or without 3g treatment in the culture medium, and the culture medium was changed every 2 days. The spheres were observed using a 20 Xmagnification microscope on days 2, 4, 6 and 8. Finally, the total cell proteins were extracted with BCA protein assay kit (Solarbio) and quantified. Sphere diameter was analyzed with photoshop and quantified with Image J software. Error bars represent mean ± SD.
The foregoing description is only of the preferred embodiments of the present application and is not intended to limit the present application. Any modifications or the like, which do not depart from the spirit and principles of the present application, are intended to be included within the scope of the present application.
Claims (1)
1. Application of beta-disulfonimide substituted ketone compound serving as dual-function inhibitor of WNT signal pathway and HIF signal pathway in preparation of medicine for treating colon cancer
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