Application of sulfonylurea compounds in preparation of antitumor drugs
阅读说明：本技术 一类磺酰脲类化合物在制备抗肿瘤药物中的应用 (Application of sulfonylurea compounds in preparation of antitumor drugs ) 是由 周莎 吕鑫屹 郭宸辰 李正名 魏巍 于 2021-06-18 设计创作，主要内容包括：一类磺酰脲类化合物或者其可药用的盐在制备抗乳腺癌药物中的应用,其中磺酰脲类化合物的化学结构式如下通式所示：式中X是H,卤素,SCN,氰基,硝基；R-(1)是卤素,硝基,羟基,C-(1)-C-(6)烷基；R-(2)是卤素,H；R-(3)是H,C-(1)-C-(6)烷基,C-(2)-C-(6)链烯基,C-(2)-C-(6)炔基或C-(3)-C-(6)环烷基；Y是O或者S；M是O,S。实验结果表明：化合物H对乳腺癌和神经母瘤细胞表现明显的抑制作用,且肿瘤细胞的特异性选择较好,具有成为新一代抗乳腺癌药物的研发前景。(The application of a sulfonylurea compound or medicinal salt thereof in preparing anti-breast cancer medicaments is disclosed, wherein the chemical structural formula of the sulfonylurea compound is shown as the following general formula: wherein X is H, halogen, SCN, cyano, nitro; r 1 Is halogen, nitro, hydroxy, C 1 ‑C 6 An alkyl group; r 2 Is halogen, H; r 3 Is H, C 1 ‑C 6 Alkyl radical, C 2 ‑C 6 Alkenyl radical, C 2 ‑C 6 Alkynyl or C 3 ‑C 6 A cycloalkyl group; y is O or S; m is O, S. The experimental results show that: the compound H has obvious inhibition effect on breast cancer and neuroblastoma cells, has better specificity selection of tumor cells, and has research and development prospect of becoming a new generation of anti-breast cancer drugs.)
1. The application of a sulfonylurea compound or medicinal salt thereof in preparing anti-breast cancer medicaments is disclosed, wherein the chemical structural formula of the sulfonylurea compound is shown as the following general formula:
wherein X is H, halogen, SCN, cyano, nitro, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C1-C6Haloalkyl, C1-C4Alkoxyalkyl radical, C1-C4Hydroxyalkyl radical, C1-C4Alkoxy radical, C1-C4Halogenoalkoxy, C1-C4Alkylthio radical, C2-C6Alkoxycarbonyl radical, C2-C6Alkylcarbonyl group, C1-C4Alkylsulfonyl radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfinylimino radical, C1-C4Alkylthio radical, C1-C4Alkylamino radical, C2-C8Dialkylamino radical, C3-C6Cycloalkylamino, C3-C6Trialkylsilyl group, C2-C6Alkylaminocarbonyl radical, C3-C8Dialkylaminocarbonyl, phenyl, phenoxy, benzyl, a five-or six-membered heteroaromatic ring optionally substituted with 1-3 substituents each independently selected from halogen, SCN, CN, nitro, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C4Halogenoalkoxy, C1-C4Alkylthio radical, C1-C4A hydroxyalkyl group;
R1is H, halogen, SCN, CN, nitro, hydroxy, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl or C3-C6A cycloalkyl group;
R2is halogen, H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkenoxy radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C4-C7Alkyl cycloalkyl radical, C1-C6Haloalkyl, C1-C6Halogenoalkoxy, C2-C6Haloalkenyl, C2-C6Haloalkynyl group, C3-C6Halocycloalkyl radical, C4-C7Haloalkyl cycloalkyl, C2-C6Alkoxycarbonyl radical, C2-C6A haloalkoxycarbonyl group;
R3is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl or C3-C6A cycloalkyl group;
y is O or S;
m is O, S, NR4；
R4Is a compound of H, a halogen,cyano, nitro, thiocyanate, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkenoxy radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C4-C7Alkyl cycloalkyl radical, C1-C6Haloalkyl, C1-C6Halogenoalkoxy, C2-C6Haloalkenyl, C2-C6Haloalkynyl group, C3-C6Halocycloalkyl radical, C2-C6Alkylcarbonyl group, C2-C6Alkoxycarbonyl radical, C2-C6Alkylaminocarbonyl radical, C2-C6The alkylsilyl, phenyl, five-membered heteroaromatic ring or six-membered heteroaromatic ring is optionally substituted by 1 to 3 substituents which are independently halogen, SCN, CN, nitro, hydroxyl or C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Halogenoalkoxy, C1-C4A haloalkyl group.
In the definitions of the above compounds, the terms used, whether used alone or in compound words, represent the following substituents:
halogen: fluorine, chlorine, bromine or iodine;
alkyl groups: a linear or branched alkyl group such as methyl, ethyl, propyl, isopropyl, or tert-butyl;
halogenated alkyl groups: straight-chain or branched alkyl groups, the hydrogen atoms on which may be partially or fully substituted by halogen atoms, for example, haloalkyl groups such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl or trifluoromethyl.
Alkenyl: linear or branched and may have a double bond present in any position, for example a vinyl or allyl group;
alkynyl: straight or branched chain and may have a triple bond at any position, for example ethynyl or propargyl.
2. The use of the sulfonylurea compound or its pharmaceutically acceptable salt according to claim 1 for the preparation of an anti-breast cancer drugCharacterized in that R is1H, halogen, SCN, CN, nitro, hydroxyl, methyl, ethyl, isopropyl, tert-butyl and the like.
3. The use of a sulfonylurea compound or a pharmaceutically acceptable salt thereof according to claim 1 for the preparation of a drug for treating breast cancer, wherein R is2And R3Are respectively selected from H, halogen, SCN, CN, nitro and C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl or C3-C6Cycloalkyl groups, and the like.
4. Use of a sulfonylurea compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating breast cancer according to claim 1, wherein the sulfonylurea compound is selected from the group consisting of N- ((5-bromo-4- (thiophen-2-yl) pyrimidin-2-yl) carbamoyl) -2-chloro-5-vinylbenzenesulfonamide, 2-chloro-N- (((4- (furan-2-yl) pyrimidin-2-yl) carbamoyl) -5-vinylbenzenesulfonamide, N- ((5-bromo-4- (furan-2-yl) pyrimidin-2-yl) carbamoyl) -2-chloro-5-vinylbenzenesulfonamide, 2-chloro-N- (((4- (thiophen-2-yl) pyrimidin-2-yl) carbamoyl) -5-vinylbenzenesulfonamide, 2-chloro-N- (((4-methoxy-6- (thiophen-2-yl) pyrimidin-2-yl) carbamoyl) -5-vinylbenzenesulfonamide.
Technical Field
The invention relates to an application of sulfonylurea compounds in preparing antitumor drugs
Background
Malignant tumors are one of the most feared diseases in the world, and with great progress made in the medical field, the cure rate of malignant tumors is greatly improved, but cancer remains the second leading cause of death after heart disease in the world. There are many methods for treating cancer, including surgical therapy, radiation therapy, biological therapy, gene therapy, chemotherapy, and traditional Chinese medicine therapy, among which chemotherapy is one of the most important. Although the number of the antitumor drugs is large at present, the ideal drugs are few, so that the search for the antitumor drugs with good curative effect and small side effect has profound significance. The sulfonylurea compounds are widely used in the fields of pesticide and medicine as herbicide and hypoglycemic agent, and in the research process of the action mechanism of sulfonylurea hypoglycemic agent, people find that the second generation hypoglycemic agent has potential tumor inhibiting effect. With the continuous and intensive research of people, more sulfonylurea compounds are found to show strong antitumor activity, such as on lung cancer, breast cancer, colon cancer, ovarian cancer, gastric cancer and the like, so that some sulfonylurea structures gradually become the focus of people for developing new-generation antitumor drugs. Actively searching and designing a novel structure with anticancer effect, and having very important clinical significance and wide application prospect.
Disclosure of Invention
The invention aims to provide an application of sulfonylurea compounds or medicinal salts thereof in preparing anti-breast cancer medicaments, wherein the chemical structural formula of the sulfonylurea compounds is shown as the following general formula:
wherein X is H, halogen, SCN, cyano, nitro, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C1-C6Haloalkyl, C1-C4Alkoxyalkyl radical, C1-C4Hydroxyalkyl radical, C1-C4Alkoxy radical, C1-C4Halogenoalkoxy, C1-C4Alkylthio radical, C2-C6Alkoxycarbonyl radical, C2-C6Alkylcarbonyl group, C1-C4Alkylsulfonyl radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfinylimino radical, C1-C4Alkylthio radical, C1-C4Alkylamino radical, C2-C8Dialkylamino radical, C3-C6Cycloalkylamino, C3-C6Trialkylsilyl group, C2-C6Alkylaminocarbonyl radical, C3-C8Dialkylaminocarbonyl, phenyl, phenoxy, benzyl, a five-membered or six-membered heteroaromatic ring optionally substituted with 1-3 substituents each independently selected from halogen, SCN, CN, nitro, hydroxy, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C4Halogenoalkoxy, C1-C4Alkylthio radical, C1-C4A hydroxyalkyl group;
R1is H, halogen, SCN, CN, nitro, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl or C3-C6A cycloalkyl group;
R2is halogen, H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkenoxy radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C4-C7Alkyl cycloalkyl radical, C1-C6Haloalkyl, C1-C6Halogenoalkoxy, C2-C6Haloalkenyl, C2-C6Haloalkynyl group, C3-C6Halocycloalkyl radical, C4-C7Haloalkyl cycloalkyl, C2-C6Alkoxycarbonyl radical, C2-C6A haloalkoxycarbonyl group;
R3is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl or C3-C6A cycloalkyl group;
y is O or S;
m is O, S, NR4；
R4Is H, halogen, cyano, nitro, thiocyanate, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkenoxy radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C4-C7Alkyl cycloalkyl radical, C1-C6Haloalkyl, C1-C6Halogenoalkoxy, C2-C6Haloalkenyl, C2-C6Haloalkynyl group, C3-C6Halocycloalkyl radical, C2-C6Alkylcarbonyl group, C2-C6Alkoxycarbonyl radical, C2-C6Alkylaminocarbonyl radical, C2-C6The alkylsilyl, phenyl, five-membered heteroaromatic ring or six-membered heteroaromatic ring is optionally substituted by 1 to 3 substituents, and the substituents are independently selected from halogen, SCN, CN, nitro, hydroxyl and C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Halogenoalkoxy, C1-C4A haloalkyl group.
In the definitions of the above compounds, the terms used, whether used alone or in compound words, represent the following substituents:
halogen: fluorine, chlorine, bromine or iodine;
alkyl groups: a linear or branched alkyl group such as methyl, ethyl, propyl, isopropyl, or tert-butyl;
halogenated alkyl groups: straight-chain or branched alkyl groups in which the hydrogen atoms may be partially or completely replaced by halogen atoms,
for example, a haloalkyl group such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, or trifluoromethyl.
Alkenyl: linear or branched and may have a double bond present in any position, for example a vinyl or allyl group;
alkynyl: straight or branched chain and may have a triple bond at any position, for example ethynyl or propargyl.
In a preferred embodiment, R is1H, halogen, SCN, CN, nitro, hydroxyl, methyl, ethyl, isopropyl, tert-butyl and the like;
in a preferred embodiment, R is2And R3Are respectively selected from H, halogen, SCN, CN, nitro and C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl or C3-C6Cycloalkyl groups and the like;
in a further preferred embodiment, the N- ((5-bromo-4- (thiophen-2-yl) pyrimidin-2-yl) carbamoyl) -2-chloro-5-vinylbenzenesulfonamide, 2-chloro-N- (((4- (furan-2-yl) pyrimidin-2-yl) carbamoyl) -5-vinylbenzenesulfonamide, N- ((5-bromo-4- (furan-2-yl) pyrimidin-2-yl) carbamoyl) -2-chloro-5-vinylbenzenesulfonamide, 2-chloro-N- (((4- (thiophen-2-yl) pyrimidin-2-yl) carbamoyl) -5-vinylbenzenesulfonamide, 2-chloro-N- (((4-methoxy-6- (thiophen-2-yl) pyrimidin-2-yl) carbamoyl) -5-vinylbenzenesulfonamide.
The invention further performs biological activity determination on the sulfonylurea derivatives, and the result shows that the sulfonylurea derivatives have different degrees of inhibition effects on breast cancer and neuroblastoma on a cellular level.
Therefore, the present invention also claims the inhibitory effect of the sulfonylurea compound or its usable salt containing potassium salt, sodium salt, calcium salt, magnesium salt, etc. on breast cancer and neuroblastoma
The invention also claims the application of the sulfonylurea compound or the available salt thereof in preparing medicines for resisting breast cancer and neuroblastoma.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
the invention reports that the sulfonylurea compound and the salt thereof have obvious inhibition effect on proliferation of breast cancer cells and neuroblastoma for the first time, and can be used for preparing medicines for resisting breast cancer and neuroblastoma.
Drawings
FIG. 1 shows the inhibitory effect of the inhibitor compound N- ((5-bromo-4- (thiophen-2-yl) pyrimidin-2-yl) carbamoyl) -2-chloro-5-vinylbenzenesulfonamide (H) on MDA-231 cells (influence of concentration gradient of sulfonylurea compound H on viability of MCF-7 cell line, results showing three biological replicates)
FIG. 2 Effect of the inhibitor compound N- ((5-bromo-4- (thiophen-2-yl) pyrimidin-2-yl) carbamoyl) -2-chloro-5-vinylbenzenesulfonamide (H) on the inhibition of MCF-7 cells in example one (influence of concentration gradient of sulfonylurea compound H on viability of MDA-MB-231 cell line, results showing three biological replicates)
FIG. 3 Effect of the inhibitor compound N- ((5-bromo-4- (thiophen-2-yl) pyrimidin-2-yl) carbamoyl) -2-chloro-5-vinylbenzenesulfonamide (H) on the inhibition of SH-SY5Y cells in example one (influence of concentration gradient of sulfonylurea compound H on viability of SH-SY5Y cell line, results showing three biological replicates)
Detailed Description
The invention is further described with reference to the following figures and examples:
the first embodiment is as follows: compound H N- ((5-bromo-4- (thiophen-2-yl) pyrimidin-2-yl) carbamoyl) -2-chloro-5-vinylbenzenesulfonamide was analyzed for its inhibitory effect on breast cancer cells and neuroblastoma cells.
Experimental methods
Compound configuration
(1) The appropriate amount of the novel compound was weighed into a 1.5mL enzyme-free sterile EP tube and the name of the compound was marked on the side wall of the EP tube, and the volume of DMSO added was calculated to give a final concentration of 10 mM based on the relative molecular mass of the compound.
(2) Add the corresponding volume of DMSO in the cell room clean bench with a pipette and blow and mix well to allow complete dissolution of the compound.
(3) A1.5 mL EP tube was placed in a 95 ℃ metal bath and heated for 10 minutes, after which the compound solution was dispensed into small tubes for use.
(4) The compound solution was stored in a refrigerator-20.
Preparation of MTT solution
(1) A50 mL centrifuge tube was removed from the clean bench and sterilized 20mL PBS was added.
(2) Open 100mg MTT package, add 1mL PBS from 50mL centrifuge tube into EP tube with MTT solid, blow and beat evenly, transfer all liquid into 50mL centrifuge tube, shake and mix evenly. This process needs to be repeated several times so that no MTT solids remain in the EP tube.
(3) At this time, the MTT solution concentration in the 50mL centrifuge tube was 5mg/mL, and the MTT solution was dispensed into a new 1.5mL EP tube, and the MTT solution concentration, preparation time and preparation time were marked.
(4) And storing the subpackaged MTT solution-20 in a refrigerator in a dark place.
Note that: since MTT is unstable under light, the above preparation process should be carried out in the dark all the time, and also in the using time, if MTT solution is found to change from yellow to grey green, it is not available at this time, and it should be replaced in time.
Experiment for determining cell viability by MTT method
(1) The growth of the cells in the 12-well plate was observed, one of the wells was digested when the cells had grown to the appropriate density, and the cell suspension was transferred to a 1.5mL EP tube after termination of the digestion.
(2) The cells were counted and the density of the cell suspension was determined and transferred to a 15mL centrifuge tube and diluted with medium to a concentration of 50000 cells/mL.
(3) Taking out the 96-well plate, placing the 96-well plate on a super clean bench for cell planting, wherein the operation of cell planting is as follows: cells in a 15mL centrifuge tube were pipetted evenly and then a volume of 100 μ L of cell suspension (approximately 5000 cells per well) was added to each well in a 96 well plate and placed in a 37 degree incubator overnight.
(4) And on the next day, after the cells are attached to the wall, changing the culture medium, namely, absorbing the culture medium in each hole, adding a new control culture medium or a culture medium with the corresponding compound concentration, and putting the culture medium into a 37-degree culture box for culture.
(5) During the compound treatment, the liquid needs to be changed every day, namely, the culture medium containing the compound with the corresponding concentration needs to be changed every day, so that the treatment of the compound can be ensured to be continuously effective.
(6) After the compound treatment for the corresponding time, 15. mu.L of 5mg/mL MTT solution was added to each well and incubated for 4 hours in a 37-degree cell incubator without light.
(7) After the 96-well plate was taken out to a clean bench and the culture medium in each well was aspirated away from light, 150. mu.L of DMSO was added to each well to dissolve formazan, and the plate was shaken on a shaker for 10 minutes at a medium speed.
(8) The microplate reader was ordered to detect the absorbance of each well of the 96-well plate at a wavelength of 490 nm.
The experimental results show that: compound H showed significant inhibitory effects on breast cancer and neuroma cells (FIGS. 1 to 3), with its EC50The values are shown in Table 1. And the tumor cells have better specificity selection, and have the research and development prospect of becoming a new generation of anti-breast cancer drugs.
TABLE 1 IC50(μ M) for inhibition of three tumor cells by Compound H