CN104529972B - Kinases inhibitor cumarin and preparation method thereof and medical applications - Google Patents
Kinases inhibitor cumarin and preparation method thereof and medical applications Download PDFInfo
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- CN104529972B CN104529972B CN201510026529.5A CN201510026529A CN104529972B CN 104529972 B CN104529972 B CN 104529972B CN 201510026529 A CN201510026529 A CN 201510026529A CN 104529972 B CN104529972 B CN 104529972B
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- trifluoromethyl
- hydroxyl
- chlorocoumarin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Kinases inhibitor cumarin and preparation method thereof and medical applications, belong to pharmaceutical chemistry technical field. 4 San Fu Jia Ji 7 Qiang Ji 8 the structural formula of chlorocoumarin as follows:
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, the target that is specifically related to kinases inhibitor cumarin is establishedMeter, and preparation method thereof with and application in anti-tumour cell proliferative.
Background technology
Protein kinase is one of protein family maximum in cell, contains altogether more than 500 albumen in human genomeKinase gene. It wants function is that the γ phosphate of ATP is transferred on the specific amino acid of substrate protein, and thenRegulate the activity of substrate protein, rise at aspects such as regulating metabolism, gene expression, Growth of Cells, division and differentiationKey effect. Closely related with tumorigenesis, become popular anticancer target spot, and existing more than ten plant eggWhite inhibitors of kinases successfully goes on the market as cancer therapy drug. Protein kinase C K2 is a kind of multi-functional serine/Soviet UnionPropylhomoserin albuminoid kinases, by the multiple substrate of phosphorylation, participates in inducing cell growth, inhibited apoptosis and tuneThe physiology course such as the activity of oncogene and tumor suppressor gene in joint signal path, has short growth and the characteristic of anti-apoptosisForm as important anticancer target. People source CK2 holoenzyme structure is by two catalytic subunits (α and/or α ') and two tuneThe heterogeneity tetramer that joint subunit β forms. Wherein CK2 α is by the N end that is rich in beta sheet, is rich in alpha-helix knotThe C end of structure and the composition of the catalytic activity pocket between two domains.
Coumarin kind compound and derivative thereof distribute extremely extensive at occurring in nature, have antibacterial, anti-inflammatory, anti-The biologically active such as tumour, anti-agglomeration, has potential medical value, is identified as important medicine guide chemical combinationThing. Prior art shows, umbelliferone compounds only forms single polarity effect with active pocket,Therefore protein kinase C K2 is shown to moderate inhibition activity. For umbelliferone compound boneFrame, selects appropriate the position of substitution to carry out modified with functional group, suppresses active and anti-swollen to obtaining having high CK2The compound of tumor cell proliferation activity.
Summary of the invention
The present invention relates to 4-trifluoromethyl-7-hydroxyl-8-chlorocoumarin and preparation method thereof, and press down at protein kinaseApplication in preparation and anti-tumour cell proliferative field of medicaments.
ATP competitive inhibitor is brought into play inhibit feature by being attached to catalytic activity pocket. Wherein this target enzymeCatalytic activity pocket mainly by hinge area (Glu114, Val116), electropositive district (Lys68, Glu81With hydrone 1) and three sublocus compositions of hydrophobic region (Val66, F113, Met163 and Ile174). ForOnly form single polarity effect umbelliferone compounds with CK2 catalytic activity pocket electropositive district, thisA person of good sense propose can with the each sublocus formation of binding pocket effect (especially can be simultaneously and hinge area and electropositive district shapeBecome polarity effect) be to ensure that compound has the high active important structure basis that suppresses. Therefore, inventor's baseIn umbelliferone skeleton structure, for increasing the polarity of compound and hinge area amino acid Glu114 and Val116Effect, selects appropriate the position of substitution to carry out suitable modified with functional group, proposes at R4CF is introduced in position3Substituting group,To obtain the thering is compound that high protein kinase c K2 suppresses activity and anti-tumour cell proliferative activity.
The invention provides the trifluoromethyl-7-hydroxyl-8-chlorocoumarin of 4-shown in structural formula 1 or its officinal salt (this4-trifluoromethyl-7-hydroxyl-8-chlorocoumarin of invention, in the time that its hydroxyl exists with negative oxygen ion form, can be withCation is in conjunction with forming compound salt, as sodium salt, sylvite, ammonium salt etc.).
The structural formula of 4-trifluoromethyl-7-hydroxyl-8-chlorocoumarin is as follows:
Coumarin compound preparation method shown in structural formula 1: compound 2 (the chloro-Resorcinol of 2-) is scattered inIn inorganic acid aqueous solution, add subsequently compound 3 (trifluoroacetic ethyl acetoacetate), this reactant liquor under agitation addsUnder the condition of heat, react, after reacting completely, return to room temperature, separatory. Washing, dry, separate, obtain systemObtain structural formula 1.
The preferably mass concentration 60%-80% of inorganic acid aqueous solution. The temperature to 60 of heating DEG C-90 DEG C; React 1 littleTime-3 hour.
Preferred compound 2: inorganic acid aqueous solution: compound 3 is (0.2-0.6) g:(1-3) mL:(0.20-0.40)mL。
Chemical equation is as follows:
Further, described inorganic acid is any in hydrochloric acid, sulfuric acid and perchloric acid, with saturated sodium bicarbonate andEthyl acetate separatory. Organic phase is with after saturated common salt water washing, and with anhydrous magnesium sulfate drying, column chromatography for separation (justHexane: ethyl acetate=2:1).
Coumarin compound shown in structural formula 1 or its officinal salt are as preparing kinases inhibitor medicineApplication.
Further, the coumarin compound shown in structural formula 1 or its officinal salt are as preparing protein kinase C K2Inhibitor medicaments, its IC50Value is 0.4 μ M, the coumarin kind compound that is better than not replaced by trifluoromethyl.
Coumarin compound shown in structural formula 1 or its officinal salt are as preparing antineoplastic application.
Further, the coumarin compound shown in structural formula 1 has the activity of certain anti-tumour cell proliferative. SwollenOncocyte comprises a kind of or several in lung cell A549, cervical cancer cell Hela and breast cancer cell MCF-7Kind.
Detailed description of the invention
Below in conjunction with embodiment the present invention will be further described book, but the present invention is not limited to following examples.
Embodiment 1
The preparation method of compound shown in structural formula 1
Compound 2 (the chloro-Resorcinol of 2-) (0.400g) is scattered in the perchloric acid of 1.5mL70%, withAfter add compound 3 (trifluoroacetic ethyl acetoacetate) (0.36mL). This reactant liquor is under agitation heated to 80DEG C, after 2 hours, return to room temperature, with saturated sodium bicarbonate and ethyl acetate separatory. Organic phase saturated common saltAfter water washing, with anhydrous magnesium sulfate drying, column chromatography for separation (n-hexane: ethyl acetate=2:1), to obtain final productMaking compound 1 (0.39g) is light yellow solid, and productive rate is 72%.1HNMR(400MHz,DMSO-d6):11.74(brs,1H),7.52(dd,1H,J＝1.9Hz,J＝9.0Hz),7.10(d,1H,J＝9.0Hz),6.86(s,1H).HRMS(ESI)m/zcalculatedforC10H4O3F3Cl[M+H]+:263.9801,found:263.9733。
Perchloric acid is replaced with to other the inorganic acid such as hydrochloric acid, sulfuric acid, can obtain equally same compound.
Compound CKIs kinase c K2 determination of activity shown in embodiment 2 structural formulas 1.
Adopt the on-radiation method of the luminous detection kit of Kinase-Glo kinases (production of Promega company)The inhibition activity of detection compound to CK2. By kinase buffer liquid (0.1 μ g/L protein kinase C K2,1mMPeptide substrate HRRRDDD-SDDD-NH2、2mMMnCl2,2mMDTTand100μMNaVO3) establishBe set to negative control, to the structure of the present invention that adds respectively kinase buffer liquid to dilute in 96 hole microtest platesCompound solution shown in formula 1 and positive inhibitor (compound 4) contrast solution. Add 10 μ MATP to start anti-Should, hatch 30min in 30 DEG C. Every hole adds 25 μ LADP-Glo reagent cessation reactions, adds 50 μ L kinases inspectionsTest agent changes into ADP ATP and hatches 1h, uses the luminous detector of microwell plate to measure and record sending out of every holeLight value. Taking the logarithm of concentration as abscissa, respective concentration inhibiting rate is ordinate, draws and changes with drug concentrationActivity of protein kinase CK 2 suppress curve, try to achieve IC50Value, the results are shown in Table 1.
Embodiment 3
Compound anti-tumour cell proliferative activity shown in structural formula 1 is measured.
Adopt CCK-8 reagent method to measure that it is thin to lung cancer A549, cervical cancer cell strain Hela and breast cancer MCF-7The inhibitory action of born of the same parents' strain. Tumour cell in cell log growth period is made into cell suspension, with every hole 7500Individual cell concentration is inoculated in 96 orifice plates. Hatch and cultivate 24h, negative control 3 holes are set, every hole, other holes adds notWith the testing compound (being respectively compound 1 and compound 4) of concentration, cultivate 48h. Every hole adds CCK-8Reagent, continues to cultivate 4h, stops cultivating. Add DMSO dissolving crystallized to every hole, use ELIASA to existIn 490-570nm wave-length coverage, measure its absorbance value curve plotting, indirect reaction cell survival quantity.
Table 1 coumarin compound CKIs kinase c K2 activity and anti-tumour cell proliferative activity (μ M)
By the compound 1 in contrast table 1 and 4 and suppress activity data can find, R in the present invention4For CF3The R that only forms single polarity effect with electropositive district that obtains of compound 1 and prior art4For CH3Compound 4 compare, all there is stronger CKIs kinase c K2 and suppressing lung cancer A 549, uterine neckCancer Hela and proliferation of MCF-7 cells activity. Its reasons in structure is mainly due to R4CH3ConversionFor CF3After, increase and the polarity effect of CK2 catalytic activity pocket hinge area, thereby improved compound1 suppresses active.
Claims (10)
1.4-trifluoromethyl-7-hydroxyl-8-chlorocoumarin or its officinal salt, the wherein knot of 4-trifluoromethyl-7-hydroxyl-8-chlorocoumarinStructure formula is as follows:
2. the preparation method of 4-trifluoromethyl-7-hydroxyl-8-chlorocoumarin as claimed in claim 1, is characterized in that: by chemical combinationThe chloro-Resorcinol 2 of thing 2-is scattered in inorganic acid aqueous solution, adds subsequently compound trifluoroacetic ethyl acetoacetate 3, this reactant liquorUnder agitation under the condition of heating, react, after reacting completely, return to room temperature, separatory, washing, dry, separate, to obtain final product,Reaction equation is as follows:
3. the preparation method of 4-trifluoromethyl-7-hydroxyl-8-chlorocoumarin as claimed in claim 2, is characterized in that inorganic acidThe mass concentration 60%-80% of the aqueous solution; The temperature to 60 of heating DEG C-90 DEG C; React 1 hour-3 hours.
4. the preparation method of 4-trifluoromethyl-7-hydroxyl-8-chlorocoumarin as claimed in claim 2, is characterized in that inorganic acidFor any in hydrochloric acid, sulfuric acid and perchloric acid.
5. the preparation method of 4-trifluoromethyl-7-hydroxyl-8-chlorocoumarin as claimed in claim 2, is characterized in that compound 2:Inorganic acid aqueous solution: compound 3 is (0.2-0.6) g:(1-3) mL:(0.20-0.40) mL.
6. the preparation method of 4-trifluoromethyl-7-hydroxyl-8-chlorocoumarin as claimed in claim 2, is characterized in that, with saturatedSodium acid carbonate and ethyl acetate separatory, organic phase is used after saturated common salt water washing, with anhydrous magnesium sulfate drying, n-hexane: acetic acidVolume ratio=the 2:1 of ethyl ester carries out column chromatography for separation.
7. 4-trifluoromethyl-7-hydroxyl-8-chlorocoumarin as claimed in claim 1 or its officinal salt press down as preparing protein kinaseThe application of preparation medicine.
8. 4-trifluoromethyl-7-hydroxyl-8-chlorocoumarin as claimed in claim 7 or its officinal salt press down as preparing protein kinaseThe application of preparation medicine, is characterized in that, protein kinase is CK2.
9. 4-trifluoromethyl-7-hydroxyl-8-chlorocoumarin as claimed in claim 1 or its officinal salt are as preparing antineoplasticApplication.
10. 4-trifluoromethyl-7-hydroxyl-8-chlorocoumarin as claimed in claim 9 or its officinal salt are as preparing answering of antineoplasticWith, it is characterized in that, wherein tumour cell comprises lung cell A549, cervical cancer cell Hela and breast cancer cell MCF-7In one or more.
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| CN104606186B (en) * | 2014-11-19 | 2017-09-12 | 北京工业大学 | Application of the hydroxy coumarin compound of fluoro 7 in kinases inhibitor or/and antineoplastic |
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