CN112010852A - Compound for inhibiting PCa cell transfer and application - Google Patents
Compound for inhibiting PCa cell transfer and application Download PDFInfo
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- CN112010852A CN112010852A CN202010809032.1A CN202010809032A CN112010852A CN 112010852 A CN112010852 A CN 112010852A CN 202010809032 A CN202010809032 A CN 202010809032A CN 112010852 A CN112010852 A CN 112010852A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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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
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
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- Medicinal Chemistry (AREA)
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Abstract
The invention discloses a compound for inhibiting PCa cell transfer and application thereof; the structural formula of the compound is
Wherein X is NH or S; r1Selected from the group consisting of lower branched alkyl, R2Selected from lower alkyl or H, R3Selected from lower alkyl, R4Is selected from lower alkyl or-NRyRw, Ry and Rw are respectively selected from lower alkyl, or Ry and Rw form 4-8 rings, and the rings contain 0-3 substituents of O, N, S, Cl and F. Detection of PC3 fine particle of each compound by CCK8 methodThe result shows that the cell has no obvious killing effect on the cell activity; further tumor cell migration experiments prove that the compound can be used for inhibiting the migration of prostate cancer cells.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a compound for inhibiting PCa cell transfer and application thereof.
Background
With the increase of the global tumor morbidity, China becomes a big country with tumor morbidity and death in the world. It is expected that 1320 thousands of people will die from cancer in the world by 2030, with 1/4 in china.
Of the deaths caused by cancer, approximately 90% are caused by metastasis of tumors off the primary site, metastatic tumors often being refractory to existing therapies and therefore incurable. Tumor metastasis, which is one of the important biological characteristics of malignant tumors, is both the main cause of death of patients and a major challenge in research, tumor cell invasion is a key link of tumor metastasis, invasiveness and metastatic capacity are the most basic characteristics of tumor cells from normal cells, and are the pathological bases of eventual death of patients due to tumor recurrence and disease deterioration, and tumor metastasis is a complex, multi-step and multi-gene regulation process. Metastasis of malignant cells is currently generally considered to involve several steps: 1) tumor cells detach from the primary foci and adhere to the basement membrane; 2) tumor cells secrete and induce tumor interstitial cells to secrete protease to degrade a basement membrane, and then penetrate through extracellular matrix to infiltrate into surrounding tissues and adhere to vascular endothelial cells at the part; 3) penetrate through the vascular wall to enter the circulatory system, migrate with the blood flow and stay at a new position, and adhere to the vascular endothelial cells at the position; 4) after passing through the vessel wall and extracellular matrix, tumor cells locally proliferate and induce vascular proliferation, and finally form metastases in specific tissues or organs. Therefore, the process of the tumor cells infiltrating to the surrounding tissues and transferring to the distant sites is understood, and effective blocking measures are taken, so that the method has important significance for anti-tumor treatment.
In view of the fact that most of the deaths caused by malignant tumors are due to the severe condition that tumors have metastasized, molecular targeted therapy, particularly the search for molecular targeted therapy of tumor metastasis, is the most active field of tumor therapy research in recent years. The tumor molecule targeted therapeutic drug is a small molecule targeted therapeutic drug, can directly hit cancer cells, does not damage normal cells as far as possible, and has attracted attention due to high efficiency and safety. The exploration and development of molecular targeting compounds based on the inhibition of tumor cell metastasis can bring new opportunities for tumor treatment.
The research result of the invention clearly influences the in vitro migration of the PC3 cell, provides help for the development and research of the anti-tumor metastasis medicament, provides a theoretical basis for the design of the anti-tumor metastasis medicament, and lays a foundation for the development of future biological treatment.
Disclosure of Invention
The invention aims to provide a compound for inhibiting PCa cell transfer and application thereof, aiming at the defects of the prior art. The invention uses PCa cell strain, and after adding the compound, the invention observes whether the compound can inhibit the migration of PCa cells through a tumor cell migration experiment.
The purpose of the invention is realized by the following technical scheme:
in a first aspect, the present invention is directed to a class of compounds having the structural formula:
wherein X is NH or S; r1Selected from the group consisting of lower branched alkyl, R2Selected from lower alkyl or H, R3Selected from lower alkyl or H, R4Is selected from lower alkyl or-NRyRw, Ry and Rw are respectively selected from lower alkyl, or Ry and Rw form 4-8 rings, and the rings contain 0-3 substituents selected from O, N, S, Cl and F.
As an embodiment of the present invention, the lower branched alkyl group is a 3-8 carbon alkyl group, and the lower alkyl group is a 1-8 carbon alkyl group.
As a specific embodiment of the present invention, the structural formula of the compound includes:
in a second aspect, the invention relates to the use of a class of compounds of the invention in the preparation of a medicament for inhibiting prostate cancer cell migration.
As one embodiment of the invention, in the medicament for inhibiting the migration of prostate cancer cells, the effective concentration of the compound is 0.5 to 2.5. mu.M.
In a third aspect, the present invention relates to a pharmaceutical composition for inhibiting prostate cancer cell migration, which comprises the compound of the present invention as an active ingredient.
As one embodiment of the present invention, the total effective concentration of the compounds in the pharmaceutical composition is 0.5. mu.M-2.5. mu.M.
As an embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.
As one embodiment of the present invention, said compounds of the present invention include LD-55, LD-75 and LD-79.
Compared with the prior art, the invention has the following beneficial effects:
1) the invention provides a compound
The compounds have a core structure:
the compound can be used for inhibiting migration of prostate cancer cells;
2) the invention provides a pharmaceutical composition for inhibiting prostate cancer cell migration, which takes the compound as an active ingredient.
Drawings
Other features, objects and advantages of the invention will become more apparent upon reading of the detailed description of non-limiting embodiments with reference to the following drawings:
FIG. 1 is a schematic representation of the effect of LD-55, LD-75, and LD-79 on cell viability;
FIG. 2(a) is a graph showing the effect of LD-55 on tumor cell migration, and (b) is a statistical graph showing the effect of LD-55 on tumor cell migration;
FIG. 3(a) is a graph showing the effect of LD-75 on tumor cell migration, and (b) is a statistical graph showing the effect of LD-75 on tumor cell migration;
FIG. 4(a) is a graph showing the effect of LD-79 on tumor cell migration, and (b) is a statistical graph showing the effect of LD-79 on tumor cell migration.
Detailed Description
The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that it would be obvious to those skilled in the art that various changes and modifications can be made without departing from the spirit of the invention. All falling within the scope of the present invention.
Example 1 Synthesis of Compound LD-55
The synthetic route of the compound LD-55 is shown as the following formula: -
Experimental procedure and results for Compound LD-55:
the first step is as follows: synthesis 2
Compound 1(1g,4.08mmol,1.0eq) was dissolved in acetonitrile (15mL), to which triethylamine (824mg,8.16mmol,2eq) was added, cooled to 0 ℃ with an ice-water bath, and then a solution of tetrahydropyrrole (319mg,4.49mmol,1.1eq) in acetonitrile (3mL) was added dropwise to the solution, and reacted at room temperature overnight. The reaction was concentrated and redissolved in ethyl acetate (60 mL). Then washed with 1N diluted hydrochloric acid (20mL), saturated sodium bicarbonate solution (20mL) and saturated brine (20mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate-20/1) to give the title compound 2(1g, 81%, yellow solid).
LCMS:(M+H)+:280.1.
The second step is that: synthesis 3
Compound 2(1g, 3.58mmol, 1.0eq) was dissolved in dioxane (15mL), to which was added 4-isopropylaniline (532mg, 3.94mmol, 1.1eq), palladium acetate (40mg, 0.18mmol, 0.05eq), BINAP (224mg, 0.36mmol, 0.1eq) and cesium carbonate (2.33g, 7.16mmol, 2 eq). After the addition, nitrogen gas was purged three times and reacted at 100 ℃ overnight. The reaction mixture was concentrated, diluted with water (25mL) and ethyl acetate (30mL), the insoluble matter was removed by filtration, the mixture was separated, and the aqueous phase was extracted with ethyl acetate (30 mL). The combined organic phases were washed with 1N dilute hydrochloric acid (20mL), saturated aqueous NaHCO3 (20mL), and saturated brine (20mL), respectively, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 30/1-20/1) to give the title compound 3(700mg, 51%, white solid).
LCMS:(M+H)+:379.1.
The third step: synthesis 4
Compound 3(700mg, 1.85mmol, 1.0eq) was dissolved in ethanol (12mL), to which was added an aqueous solution (4mL) of potassium hydroxide (3.12g, 55.6mmol, 30eq), and the mixture was refluxed at 75 ℃ overnight. The ethanol was removed by rotary evaporation, diluted with water (30mL) and the aqueous phase was extracted with ethyl acetate (25mL × 2). The pH of the aqueous phase is then adjusted to 2-3 with 6N dilute hydrochloric acid. The precipitated solid was filtered, then washed with a small amount of water and dried to give crude compound 4(400mg, 58%, yellow solid).
LCMS:(M+H)+:370.2.
The fourth step: synthesis 5
Compound 4(0.55g, 1.49mmol,1.0eq) and DMF (one drop) were dissolved in dry dichloromethane (25mL), placed in an ice-water bath under nitrogen protection, oxalyl chloride (0.5mL,5.96mmol,4eq) was added dropwise to the solution, allowed to warm to room temperature and stirred for 1 hour, and the solvent and excess oxalyl chloride were removed by spin-drying to give the crude aroyl chloride intermediate. The aroyl chloride intermediate was redissolved in dry dichloromethane (25mL), placed in an ice-water bath under nitrogen, to which aluminum trichloride (1.19g,8.94mmol,10eq) was added in portions and allowed to react overnight at room temperature. Anhydrous ethanol (5mL) was added to the reaction mixture, and the mixture was reacted at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane and 2N diluted hydrochloric acid (20mL), separated, and the aqueous phase (20mL) was extracted with dichloromethane. The combined organic phases were washed with saturated aqueous Na2CO3 (20mL) and saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate-4/1) to give the title compound 5(400mg, 70%, yellow solid).
1HNMR(400MHz,CD3OD)9.04(s,1H),8.04(d,J＝2.1Hz,1H),7.58(dd,J＝8.6,2.1Hz,1H),7.42(d,J＝8.6Hz,1H),4.27(q,J＝7.1Hz,2H),3.00–2.87(m,1H),2.76(s,3H),1.31(t,J＝7.1Hz,3H),1.20(d,J＝6.9Hz,6H).
LCMS:(M+H)+:380.2.
The fifth step: synthesis 6
Compound 5(400mg,1.05mmol,1eq) was dissolved in methanol (10mL) and tetrahydrofuran (10mL), to which was added dropwise an aqueous solution (10mL) of sodium hydroxide (211mg,5.27mmol,5 eq). After the addition, the reaction was carried out at 60 ℃ for 40 hours. The reaction mixture was concentrated to remove the organic solvent, which was then diluted with water (40mL) and extracted with ethyl acetate (30 mL). The aqueous phase is then adjusted to pH 2-3 with 6N hydrochloric acid. The precipitated solid was collected by filtration and dried to give crude compound 6(385mg, yellow solid).
LCMS:(M+H)+:352.2.
And a sixth step: synthesis 7
Compound 6(385mg,1.1mmol,1eq) was dissolved in DMF (6mL), to which was added HATU (501mg,1.32mmol,1.2eq), DIEA (426mg,3.3mmol,3eq) and aminoacetone hydrochloride (144mg,1.32mmol,1.2 eq). The reaction was carried out at room temperature for 2 hours. The reaction was diluted with water (25mL) and extracted with ethyl acetate (25 mL. times.2). The combined organic phases were washed with water (25mL x 3) and saturated brine (25mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol ═ 50/1) to give the title compound 7(240mg, 53%, yellow solid).
LCMS:(M+H)+:407.2.
The seventh step: synthesis of LD-55
Compound 7(240mg,0.59mmol) was dissolved in acetic anhydride (2mL), and trifluoroacetic acid (0.2mL) was added dropwise thereto, after which reaction was carried out at 80 ℃ for 2 hours. The reaction was diluted with water (15mL) and extracted with ethyl acetate (20 mL. times.2). The combined organic phases were washed with saturated aqueous sodium bicarbonate (20mL) and saturated brine (20mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol-100/1) and then purified by silica gel plate (dichloromethane/methanol-30/1) to give the desired compound LD-55(24.8mg, 11%, yellow solid).
1H NMR(400MHz,CDCl3)8.69(s,1H),8.54(br s,1H),8.24(d,J＝1.6Hz,1H),7.49(dd,J＝8.4,1.9Hz,1H),7.20(d,J＝8.4Hz,1H),6.85(d,J＝0.8Hz,1H),3.46–3.26(m,4H),3.09–2.96(m,1H),2.40(s,3H),1.94–1.79(m,4H),1.30(d,J＝6.9Hz,6H).
LCMS:(M+H)+:389.2.
HPLC:95.3％
Example 2 Synthesis of Compound LD-75
The synthetic route of the compound LD-75 is shown as the following formula:
experimental procedure and results for Compound LD-75:
the first step is as follows: synthesis 3
Under the protection of nitrogen, compound 1(0.5g,1.98mmol,1eq), compound 2(0.29g,1.98mmol,1eq), pd (oac)2(22mg,0.10mmol,0.05eq), BINAP (0.12g,0.20mmol,0.1eq) and cesium carbonate (1.29g,3.95mmol,2eq) were added to dioxane (10mL), oil bath heated at 100 ℃ overnight for reaction, LC-MS detection reaction was complete, cooled to room temperature, diluted with ethyl acetate, water, filtered through celite, washed with organic phase brine, washed with sodium bicarbonate, washed with brine, dried and concentrated column chromatography (3% EtOAc in PE) to purify compound 3(0.52g, 72%).
1H NMR(400MHz,CDCl3):8.13(s,1H),7.57–7.49(m,2H),7.41–7.30(m,2H),6.98(br s,1H),4.30(q,J＝7.4Hz,2H),3.08(s,6H),1.36(t,J＝7.2Hz,3H),1.33(s,9H).
LCMS:(M+H)+:367.2
The second step is that: synthesis 4
Compound 3(0.52g,1.42mmol,1.0eq) was dissolved in ethanol (10mL), to which was added an aqueous solution (5mL) of potassium hydroxide (2.39g,42.60mmol,30 eq). The reaction was refluxed for 2 days. Ethyl acetate (50mL) and water (50mL) were added to the reaction mixture, and after separating the layers, the aqueous layer was extracted with ethyl acetate (50mL) and the organic layers from both extractions were discarded. The aqueous phase was adjusted to pH 2-3 with 6N hydrochloric acid, and the precipitated solid was collected by suction filtration and dried to give crude title compound 4(0.38g) as a white solid.
LCMS:(M+H)+:358.2
The third step: synthesis 5
Compound 4(0.38g,1.06mmol,1.0eq) was dissolved in dry dichloromethane (10mL), to which one drop of DMF was added dropwise followed by oxalyl chloride (0.81g,6.39mmol,6.0eq) dropwise and reacted at room temperature for 1 hour. And concentrating the reaction solution to obtain an acyl chloride intermediate. The acid chloride intermediate was redissolved in dry dichloromethane (10mL), cooled in an ice water bath, and aluminum trichloride (0.85g,6.39mmol,6eq) was added portionwise and allowed to react at room temperature overnight. Anhydrous ethanol (5mL) was added to the reaction system, and the reaction was carried out at room temperature for 2 hours. The reaction was diluted with dichloromethane (30mL) and 2N dilute hydrochloric acid (10 mL). After separation, the aqueous phase was extracted with dichloromethane (2 × 30 mL). The combined organic phases were washed with saturated brine (20mL), dried over anhydrous sodium sulfate and spin-dried to give the crude compound. The crude compound was purified on a silica gel column (DCM/MeOH ═ 100/1) to give compound 5(94mg, 24%) as a white solid.
1H NMR(400MHz,CDCl3):8.92(s,1H),8.38(d,J＝2.2Hz,1H),7.69(dd,J＝8.6,2.3Hz,1H),7.20(d,J＝8.6Hz,1H),4.37(q,J＝7.1Hz,2H),3.12(s,6H),1.48–1.33(m,12H).
LCMS:(M+H)+:368.2
HPLC:98.6％
The fourth step: synthesis 6
Compound 5(1.5g, 4.08mmol,1.0eq) was dissolved in methanol (5mL) and tetrahydrofuran (5mL), to which was added an aqueous solution (1mL) of sodium hydroxide (0.49g,12.26mmol,3.0eq), and reacted at 60 ℃ overnight. After the reaction was complete, the organic phase was spun off, the aqueous phase was extracted with ethyl acetate (2 × 20mL), the pH of the aqueous phase was adjusted to 2-3, the precipitated solid was collected by filtration and dried to give compound 6(1.1g, 79%, light yellow solid).
1H NMR(400MHz,DMSO)12.95(br s,1H),11.68(br s,1H),8.62(s,1H),8.09(d,J＝2.0Hz,1H),7.79(dd,J＝8.7,2.2Hz,1H),7.56(d,J＝8.7Hz,1H),3.11(s,6H),1.34(s,9H).
HPLC:99.79％
The fifth step: synthesis 7
Compound 6(2.6g,7.67mmol,1.0eq) was dissolved in acetonitrile (15mL) and tert-butanol (15mL), triethylamine (1.55g,15.1mmol,2.0eq) was added, with nitrogen protection, and DPPA (3.16g,11.5mmol,1.5eq) was added dropwise thereto. After the addition, the reaction was carried out at 100 ℃ for 4 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate 3/1-1/1) to obtain compound 7(400mg, 9.6%, yellow solid).
1H NMR(400MHz,DMSO-d6)ppm 11.54(brs,1H),8.67(brs,1H),8.08(d,J＝2.3Hz,1H),7.92(s,1H),7.76(dd,J＝8.7,2.4Hz,1H),7.56(d,J＝8.7Hz,1H),3.18(s,6H),1.45(s,9H),1.34(s,9H).
LCMS:411.2([M+H]+
And a sixth step: synthesis 8
Compound 7(400mg,0.97mmol,1.0eq) was dissolved in dichloromethane (8mL), to which trifluoroacetic acid (3mL) was added dropwise, and reacted at room temperature for 2 hours. The reaction was concentrated and extracted with aqueous sodium bicarbonate (50mL) and dichloromethane (50mL x 2). The combined organic phases were washed with saturated brine (25mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol-100/1-50/1) to give compound 8(150mg, 49.6%, yellow solid).
1H NMR(400MHz,DMSO-d6)ppm 11.48(brs,1H),8.09(d,J＝2.3Hz,1H),7.71(dd,J＝8.8,2.4Hz,1H),7.64(s,1H),7.56(d,J＝8.8Hz,1H),4.80(brs,2H),3.02(s,6H),1.34(s,9H).
LCMS:311.2([M+H]+).
The seventh step: synthesis 9
Compound 8(150mg,0.484mmol,1.0eq) was dissolved in acetonitrile (5mL), cuprous iodide (110mg,0.58mmol,1.2eq) was added, nitrogen blanketed, and tert-butyl nitrite (199mg,1.93mmol,4.0eq) was added. After the addition, the reaction was carried out at 60 ℃ for 2 hours. The reaction was concentrated and extracted with ammonia (10mL) and dichloromethane (50 mL. times.2). The combined organic phases were washed with saturated brine (25mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate-10/1) to give compound 9(20mg, 9.8%, yellow solid).
1H NMR(400MHz,CDCl3)ppm 8.90(s,1H),8.32(d,J＝2.2Hz,1H),7.63(dd,J＝8.6,2.3Hz,1H),7.16(d,J＝8.6Hz,1H),3.10(s,6H),1.32(s,9H).
LCMS:422.1([M+H]+).
Eighth step: synthesis of Compound LD-75
Compound 9(20mg,0.047mmol,1.0eq) was dissolved in acetonitrile (5mL), and Compound 4A (71mg,0.19mmol,4.0eq), PdCl, was added2(PPh3)2(4mg,0.0047mmol,0.1eq), under nitrogen, at 80 ℃ overnight. The reaction was concentrated and extracted with water (10mL) and ethyl acetate (25 mL. times.2). The combined organic phases were washed with saturated brine (25mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol-100/1) to give crude product. The crude product was run on a plate with dichloromethane/methanol-20/1 to give the desired compound LD-75(4.8mg, 27%, yellow solid).
1H NMR(400MHz,CDCl3)8.81(s,1H),8.38(d,J＝2.2Hz,1H),7.70(dd,J＝8.6,2.3Hz,1H),7.46(d,J＝1.2Hz,1H),7.24(s,1H),3.01(s,6H),2.26(s,3H),1.39(s,9H).
LCMS:377.2([M+H]+).
HPLC：93.02％
Example 3 Synthesis of Compound LD-79
The synthetic route of the compound LD-79 is shown as the following formula:
experimental procedure and results for Compound LD-79:
the first step is as follows: synthesis 2
Sodium hydride (128mg,3.2mmol,1.2eq) was dispersed in anhydrous tetrahydrofuran (15mL), under nitrogen protection, cooled in an ice-water bath, and a solution of compound 1A (445mg,2.67mmol,1.0eq) in tetrahydrofuran (2mL) was added dropwise thereto, followed by reaction at 0 ℃ for 20 minutes. Then, a solution of Compound 1(723mg,2.67mmol,1.0eq) in tetrahydrofuran (3mL) was added dropwise to the reaction mixture, followed by reaction at 0 ℃ for 40 minutes. The reaction was quenched with water and extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and spun to give the crude product. The crude product was purified by column on silica gel (petroleum ether/ethyl acetate-15/1) to give the title compound 2(800mg, 74%, white solid).
1H NMR(400MHz,CDCl3)8.69(s,1H),7.45(q,J＝8.4Hz,4H),4.45(q,J＝7.1Hz,2H),4.36(q,J＝7.1Hz,2H),2.56(s,3H),1.45(t,J＝7.1Hz,3H),1.39(t,J＝7.2Hz,3H),1.36(s,9H).
LCMS:(M+H)+:402.2.
The second step is that: synthesis 3
Compound 2(0.8g, 2.26mmol, 1.0eq) was dissolved in ethanol (5mL) and tetrahydrofuran (5mL), to which was added an aqueous solution (4mL) of potassium hydroxide (1.3g,22.6mmol,10eq), and refluxed at 50 ℃ for 2 hours. TLC, LCMS check reaction complete, ethanol rotary evaporation to remove, 2N dilute hydrochloric acid solution pH to 6. The precipitated solid was filtered, washed with a small amount of water, and dried to obtain the objective compound 3(0.75g, 96%, white solid).
1H NMR(400MHz,DMSO-d6)8.15(s,1H),7.42(d,J＝8.3Hz,2H),7.37(d,J＝8.3Hz,2H),2.55(s,6H),1.29(s,9H).
LCMS:(M+H)+:346.1.
The third step: synthesis 4
Compound 3(0.75g, 2.17mmol,1.0eq) and DMF (one drop) were dissolved in dry dichloromethane (15mL), placed in an ice-water bath under nitrogen protection, oxalyl chloride (0.74mL,8.7mmol,4eq) was added dropwise to the solution, warmed to room temperature and stirred for 1 hour, and the solvent and excess oxalyl chloride were removed by spin-drying to give the crude aroyl chloride intermediate. The aroyl chloride intermediate was redissolved in dry dichloromethane (15mL), placed in an ice-water bath under nitrogen, to which aluminum trichloride (1.73g,13mmol,6eq) was added in portions and allowed to react overnight at room temperature. To the reaction mixture was added absolute ethanol (2mL), the reaction was carried out at room temperature for 1 hour, and after completion of the reaction by LC-MS detection, dichloromethane (20mL) and 1N diluted hydrochloric acid (15mL) were added, followed by liquid separation, dichloromethane extraction of the aqueous phase (2 × 20mL), and the organic phases were combined, washed with brine (20mL), dried, suction-filtered, concentrated in the filtrate, and purified by column chromatography (petroleum ether/ethyl acetate ═ 15/1) to obtain compound 4(0.35g, 45%) as a pale yellow solid.
1HNMR(400MHz,CDCl3)9.31(s,1H),8.61(d,J＝2.1Hz,1H),7.77(dd,J＝8.4,2.2Hz,1H),7.60(d,J＝8.4Hz,1H),4.44(q,J＝7.1Hz,2H),2.98(s,3H),1.45(t,J＝7.1Hz,3H),1.42(s,9H).
LCMS:(M+H)+:356.1.
The fourth step: synthesis 5
Compound 4(200mg,0.56mmol,1.0eq) was dissolved in methanol (5mL) and tetrahydrofuran (5mL), and then aqueous sodium hydroxide (112mg,2.81mmol,5eq) solution (5mL) was added dropwise to the above solution and reacted at 50 ℃ overnight. The organic phase was removed by spinning, the aqueous phase was extracted with ethyl acetate (10mL), the pH of the aqueous phase was then adjusted to 3 with 2N dilute hydrochloric acid, the precipitated solid was filtered and then washed with a small amount of water and dried to give compound 5(90mg, 50%, pale yellow solid).
1HNMR(400MHz,DMSO-d6):13.58(br s,1H),8.98(s,1H),8.38(d,J＝2.0Hz,1H),7.89(dd,J＝8.5,2.1Hz,1H),7.77(d,J＝8.5Hz,1H),2.81(s,3H),1.36(s,9H).
LCMS:(M+H)+:328.1.
HPLC：99.93％
The fifth step: synthesis 6
Compound 5(10.0g,30.5mmol,1.0eq) is added to DCM (150mL), three to five drops of DMF are added dropwise, the temperature is reduced to 0 ℃, and (COCl) is added dropwise2(10mL,122.3mmol,4.0eq) was reacted at room temperature for 1 hour, and then the reaction mixture was dried, Acetone (80mL) was added, and NaN was added3(3.0g,46.1mmol,1.55eq) and then 40mL of water is added, the mixture is heated in an oil bath at 70 ℃ overnight for reaction, LC-MS detects completion of the reaction, the mixture is cooled to room temperature, excess acetone is spun off, water and DCM are used for extraction, the organic phase is spun off, and the mixture is dried and concentrated for column chromatography (50% EtOAc in petroleum ether) to obtain compound 6(3.5g, 38%).
1H NMR(400MHz,CDCl3):8.53(s,1H),7.97(s,1H),7.63(d,J＝8.4Hz,1H),7.50(d,J＝8.5Hz,1H),3.80(brs,2H),2.49(s,3H),1.33(s,9H).
LCMS:299.1([M+H]+).
And a sixth step: synthesis 7
Compound 6(3.5g,11.7mmol,1.0eq) was dissolved in MeCN (100mL), to which CuI (2.6g,14.0mmol,1.2eq) and t-BuONO (4.8g,46.9mmol,4eq) were added, and reacted at 60 ℃ overnight. LC-MS detects the reaction is complete, after acetonitrile is spun out, brine and ammonia are mixed and added into the reaction system, DCM is added for extraction, the organic phase is spun dry, and the compound 7(2.5g, 52%) is obtained after drying, concentration and column chromatography (20% EtOAc in petroleum ether).
1H NMR(400MHz,CDCl3)9.05(s,1H),8.52(d,J＝2.2Hz,1H),7.68(dd,J＝8.5,2.2Hz,1H),7.52(d,J＝8.5Hz,1H),2.78(s,3H),1.34(s,9H).
LCMS:410.2([M+H]+).
The seventh step: synthesis of Compound 9
Adding compound 8(300g,3.1mmol,1.0eq) to THF (10mL), replacing nitrogen, cooling to-78 deg.C, adding n-BuLi (1.7mL,3.1mmol,1.0eq) dropwise, reacting at-78 deg.C for 0.5 hr, adding Bu3SnCl (1.2mL,3.1mmol,1.0eq), slowly warmed to room temperature for 1h, THF was spun off, washed with hexane, filtered, and the organic phase was spun off to give crude compound 9(1.1g, 93.5%) as a pale yellow oily liquid.
1H NMR(400MHz,CDCl3):7.79(s,1H),2.47(s,3H),1.92–1.79(m,6H),1.66–1.55(m,8H),1.49–1.43(m,4H),1.16(t,J＝7.3Hz,9H).
Eighth step: synthesis of LD-79
Compound 7(200mg,0.5mmol,1.0eq) was dissolved in MeCN (10mL), to which was added compound 9(729mg,1.9mmol,4.0eq) andPdCl2(PPh3)2(34mg,0.05mmol,0.1 eq.) and reacted at 80 ℃ for 15 hours. Upon completion of the reaction by LC-MS detection, after cooling, the acetonitrile was spun off and the crude compound was purified on a silica gel column (petroleum ether/EtOAc ═ 30:1) to afford the desired compound LD-79(49.5mg, 27.1%) as a yellow solid.
1H NMR(400MHz,CDCl3)9.33(s,1H),8.62(d,J＝2.2Hz,1H),7.76(dd,J＝8.4,2.3Hz,1H),7.60(d,J＝8.4Hz,1H),7.55(d,J＝1.2Hz,1H),3.09(s,3H),2.30(s,3H),1.42(s,9H).
LCMS:365.1([M+H]+)
HPLC：95.56％
Example 4
Experimental materials and equipment: PC3 cell line (
CRL-1435TM) CCK8(cat # CKO4, same kernel)
The experimental steps are as follows:
1. the proliferation inhibitory effect of each compound on PC3 cells was examined by the CCK8 method. Inoculating logarithmic growth phase cells into 96-well plate at density of 1000 cells/well, culturing in DMEM medium containing 10% serum at 37 deg.C and 5% CO2After further incubation for 24 hours, various compounds were added at different concentrations (0.2, 0.5 and 1 μ M), with an additional DMSO control set, with 3 duplicate wells per group. After the drug and the cells are CO-cultured for 96 hours in a complete culture medium containing 10% serum in an incubator with the culture condition of 37 ℃ and 5% CO2, the culture medium in a 96-well plate is gently thrown off, 100ul of the complete culture medium is added into each well, CCK8 is added according to the standard of 10ul of CCK8 reagent per 100ul of the culture medium, the incubation is continued in the incubator with 5% CO2 at 37 ℃ for 1 hour, and the absorbance A of each well is measured at the wavelength of 450 nm. Cell viability ═ 100% (mean of a drug group/a control group)%
As shown in FIG. 1, there was no significant killing effect on cell viability by LD-55, LD-75 and LD-79 at different concentrations.
2. Biological functional verification experiments of compounds: tumor cell migration assay
PC3 cells were plated in 6-well plates at a density of 5000 cells per well, and an experimental group and a control group were established, wherein LD-55, LD-75 and LD-79 were added to the experimental group at different concentrations (0.5, 1 and 2.5. mu.M), respectively, DMSO was added to the control group at an equal ratio, a complete medium containing 10% serum was pre-cultured for 96 hours in an incubator at 37 ℃ and 5% CO2, followed by starvation (the effect of cell growth was eliminated by 24 hours in serum-free DMEM medium, each well was digested into single cells, and the cells were resuspended at a density of 5 x 10 in serum-free DMEM medium5The single cell suspension of (1). The experimental group, which contained all the media (including serum-free media in the chamber), was supplemented with 0.5, 1 and 2.5. mu.M LD-55, LD-75 and LD-79, respectively, as well as the control group, which contained DMSO in equal proportions. Transwell wells were filled with 500ul of DMEM medium containing 10% FBS and 100ul of cell suspension per Transwell chamber. Culturing at 37 deg.C, taking out the chamber after 24 hr, discarding the culture medium in the chamber, and fixing in 4% paraformaldehyde for 15 min. PBS rinse several times, use the cotton swab to gently wipe the chamber in the layer of possible residual cells, and the chamber placed in crystal violet staining for 20 min. PBS was rinsed several times and excess crystal violet dye and PBS were gently wiped off with a cotton swab. After the chamber was air dried, the cell number was observed and recorded under a microscope.
As a result, as shown in FIGS. 2 to 4, when compounds LD-55, LD-75 and LD-79 were added, the number of cells migrating to the lower layer of the chamber decreased, and the migration ability of the cells decreased.
Wherein, represents p <0.0001, represents p <0.001, represents p <0.01, represents p <0.05, and the experimental results are expressed as the mean value ± s.e.m.
The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes or modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention. The embodiments and features of the embodiments of the present application may be combined with each other arbitrarily without conflict.
Claims (9)
1. A compound having the formula:
wherein X is NH or S; r1Selected from the group consisting of lower branched alkyl, R2Selected from lower alkyl or H, R3Selected from lower alkyl or H, R4Is selected from lower alkyl or-NRyRw, Ry and Rw are respectively selected from lower alkyl, or Ry and Rw form 4-8 rings, and the rings contain 0-3 substituents selected from O, N, S, Cl and F.
2. A compound according to claim 1, wherein the lower branched alkyl is 3-8 carbon alkyl and the lower alkyl is 1-8 carbon alkyl.
3. The compound of claim 1, wherein the structural formula of the compound comprises:
LD-55
LD-75
LD-79
4. use of a compound according to claim 1 in the manufacture of a medicament for inhibiting prostate cancer cell migration.
5. The use according to claim 4, wherein the effective concentration of the compound in the medicament for inhibiting prostate cancer cell migration is 0.5 μ M to 2.5 μ M.
6. A pharmaceutical composition for inhibiting migration of prostate cancer cells, which comprises the compound according to claim 1 as an active ingredient.
7. The pharmaceutical composition of claim 6, wherein the total effective concentration of compounds in the pharmaceutical composition is 0.5 μ M to 2.5 μ M.
8. The pharmaceutical composition of claim 6, further comprising a pharmaceutically acceptable carrier or excipient.
9. The pharmaceutical composition of claim 6, wherein said compound comprises LD-55
LD-75
LD-79
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101899051A (en) * | 2010-05-17 | 2010-12-01 | 中国人民解放军第二军医大学 | 1-azaxanthone-3-formamide compounds as well as preparation method and antitumor application thereof |
| WO2017132538A1 (en) * | 2016-01-29 | 2017-08-03 | The Regents Of The University Of Michigan | Amlexanox analogs |
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| CN101899051A (en) * | 2010-05-17 | 2010-12-01 | 中国人民解放军第二军医大学 | 1-azaxanthone-3-formamide compounds as well as preparation method and antitumor application thereof |
| WO2017132538A1 (en) * | 2016-01-29 | 2017-08-03 | The Regents Of The University Of Michigan | Amlexanox analogs |
| CN108245511A (en) * | 2018-01-04 | 2018-07-06 | 春葵生物科技（上海）有限公司 | Amlexanox inhibits the purposes in Epithelial and stromal conversion and anti-tumor metastasis |
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