CN112062760B - NO donor type quinoline derivative and preparation method and application thereof - Google Patents
NO donor type quinoline derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of biological medicines and discloses an NO donor type quinoline derivative shown as a formula I, wherein R is1、R2Each independently selected from H, F, 3,4, 5-trialkoxyphenyl and 3,4, 5-trialkoxyphenylamino, and n is a positive integer of 1-5; the alkoxy is C1-C3 alkoxy. The preparation method of the compound has mild reaction conditions, low toxicity of used reagents, easily obtained raw materials, convenient post-treatment and higher yield. The invention also discloses application of the NO donor type quinoline derivative in preparing antitumor drugs, wherein the NO donor type quinoline derivative has excellent antitumor activity which is improved or equivalent to that of a quinoline parent nucleus.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry and pharmacotherapeutics, and relates to an NO donor type quinoline derivative, a preparation method thereof and application of the NO donor type quinoline derivative in preparation of an anti-cancer medicament.
Technical Field
In recent years, malignant tumor (cancer) has become one of the major diseases affecting human life health and socioeconomic performance. Cancer has the biological characteristics of abnormal cell proliferation and differentiation, uncontrolled growth, easy metastasis and the like, and the occurrence process of the cancer involves multiple factors and multiple steps and is very complex, and the etiology of the cancer is not completely understood. There are many types of cancer, which are closely related to the diseased tissue and disease stage, and thus, the treatment regimens are very different. Chemotherapy is currently one of the most effective means of treating cancer. Most of clinically used anti-tumor chemotherapeutic drugs can generate toxic and side effects of different degrees, and the drugs can damage normal tissue cells, especially blood, lymphocytes and the like while killing tumor cells. However, the white blood cells in lymphocytes and blood cells are important components of the immune defense system of human body, and once damaged, the immune system of human body is destroyed, and cancer may rapidly develop, causing serious consequences.
Nitric Oxide (NO) is a gaseous signaling molecule with multiple biological functions, produced by Nitric Oxide Synthase (NOs). Tumor biology studies show that, with different concentrations, NO has dual regulatory effects on tumor development and progression: on one hand, low-concentration NO can play an anti-apoptosis role by promoting tumor angiogenesis, cell invasion and metastasis so as to promote tumor growth; on the other hand, high concentrations of NO can be achieved by: (1) inducing apoptosis, inhibiting proliferation of endothelial cells and vascular smooth muscle cells, and further inhibiting tumor growth and metastasis; (2) the sGC-cGMP pathway prevents platelet aggregation and adhesion and prevents tumor metastasis; (3) up-regulating p53 gene to induce apoptosis; (4) down-regulating anti-apoptotic protease molecules; (5) increasing cytochrome C release; (6) affecting the expression of p53 gene by forming peroxynitrite ion; (7) the anti-tumor effect of the compound can be exerted by mechanisms of influencing the tumor cell cycle arrest and tumor cell necrosis, inhibiting the generation of tumor environment micro-vessels, inhibiting tumor cell toxicity and the like.
NO donors are compounds that release NO in vivo by enzymatic or non-enzymatic action. At present, common NO donors comprise organic nitrates, metal-NO complexes, furazan nitrogen oxide NO donors, azodializinium salt donors, novel NO donor nanoparticles and the like. Furazan nitrogen oxides are sulfhydryl-dependent heterocyclic NO donors, and natural products of a plurality of furazan nitrogen oxide fragments show outstanding anti-tumor activity for decades. For example, novel furazan compound 1-oxo-oridonin derivative (1) has proliferation inhibitory activity IC on Bel-7402 cell50The value can reach 0.74 mu M, which is superior to the positive control drug paclitaxel (IC)501.89 ± 0.09 μ M); the nitric oxide donor type CDDO analogue (2) has obvious proliferation inhibition activity (IC) on 4 tumor cells500.8-1.4 μ M), and adding CDDO methyl ester (IC) as positive control drug501.315 μ M).
The small molecular nitrogen-containing heterocycle is a very important structure and has wide application in the design of potential active medicaments. Among them, quinoline skeleton is of particular interest as a class of compounds with various biological activities. Quinoline rings are often used as a mother nucleus for designing a large number of molecules with diverse structures and good pharmacological effects. Therefore, the search for novel antitumor drugs with high efficiency, low toxicity, strong targeting property and high bioavailability is very slow.
Disclosure of Invention
The invention aims to provide an NO donor quinoline derivative, and pharmacological experiments show that the NO donor quinoline derivative has excellent antitumor activity, the activity is improved or equivalent to that of a quinoline parent nucleus, and simultaneously, the stability is improved, so that the NO donor quinoline derivative can be applied as an antitumor drug.
One of the objects of the present invention is to provide a NO donor type quinoline derivative represented by formula I:
wherein R is1、R2Each independently selected from H, F, 3,4, 5-trialkoxyphenyl and 3,4, 5-trialkoxyphenylamino, and n is a positive integer of 1-5; the alkoxy is C1-C3 alkoxy.
Preferably, R1、R2Each independently selected from H and 3,4, 5-trialkoxy phenyl, and n is a positive integer of 1-5.
Further preferably, R1Independently selected from H, 3,4, 5-trimethoxyphenyl, R2Is selected from H, and n is a positive integer from 1 to 5.
It is still further preferred that the first and second substrates,
is a substituent at the 4-position, R1＝R2H, n is 1, 2, 3,5, or R1Selected from 3,4, 5-trimethoxyphenyl, R2Selected from H, n ═ 1, 2, 3,4, 5;
Specifically, the NO donor quinoline derivative is selected from the following compounds:
the invention also aims to provide a preparation method of the NO donor quinoline derivative shown in the formula I, and the reaction route is as follows:
the method comprises the following steps: and (3) forming ester by the quinoline carboxylic acid compound shown in the formula IV and the furazan nitrogen oxide compound shown in the formula III under the action of catalysts EDCI and DMAP to obtain the target compound.
The molar ratio of the quinoline carboxylic acid compounds to the furazan nitrogen oxide compounds is 1.5: 1.
The molar ratio of the quinoline carboxylic acid compound to EDCI and DMAP is 3.75:4.5: 1.
The reaction solvent is one or more selected from DMF, acetone, acetonitrile, toluene, benzene, 1, 4-dioxane, ethyl acetate, dichloromethane, chloroform, tetrahydrofuran or diethyl ether.
The reaction temperature is 0-30 ℃.
The preparation method of the NO donor type quinoline derivative has the advantages of mild reaction conditions, low toxicity of the used reagent, easily obtained raw materials, convenient post-treatment and higher yield. After the reaction is finished, concentrating the reaction solution under reduced pressure, and purifying by silica gel column chromatography to obtain a target compound; the eluent is PE, EA is 3: 1-5: 1V/V.
The synthesis method of the furazan nitrogen oxide compound comprises the following reaction route:
pharmacological experiments show that the NO donor quinoline derivative has excellent antitumor activity, activity higher than or equal to that of a quinoline parent nucleus and high stability, so that the invention also aims to provide the application of the NO donor quinoline derivative in preparing antitumor medicaments.
Another object of the present invention is to provide an antitumor agent comprising the NO donor-type quinoline derivative of the present invention as an active ingredient or a main active ingredient, which can be used alone or in combination with clinically used antitumor agents such as antimetabolite, alkylating agent, antitumor antibiotic, antitumor botanical drug, hormone, and in addition, can be used in combination with radiotherapy.
The tumor of the invention is lung cancer, breast cancer and colon cancer.
Detailed Description
To further illustrate the invention, a series of examples are set forth below. These examples are illustrative and should not be construed as limiting the invention.
Example 12- (3,4, 5-trimethoxyphenyl) -4-quinolinecarboxylic acid (Compound IV)1) Synthesis of (2)
Dissolving isatin (0.1mmol, 1.0eq) and 3,4, 5-trimethoxyacetophenone (0.12mmol, 1.2eq) in 15mL of ethanol aqueous solution (ethanol: water ═ 2:1V/V), adding KOH aqueous solution (33% by mass), heating and refluxing at 70 ℃ for 5h, monitoring by TLC until the raw materials are completely reacted, cooling the reaction solution to room temperature, adding 1M hydrochloric acid to adjust the pH to 6.0, precipitating solids, standing, and performing suction filtration to obtain a compound IV1The yield is about 65%.
MS：[M-H]-338.11.
Example 22- (3,4, 5-trimethoxyaniline) -3-quinoline-6-fluoro-carboxylic acid (Compound IV)2) Synthesis of (2)
Phosphorus oxychloride (0.7mmol, 7eq) was dissolved in an appropriate amount of anhydrous DCM and placed in a two-necked flask, to which anhydrous DMF (0.25mmol, 2.5eq) was added dropwise with stirring under ice-bath conditions. Under the ice-bath condition, 4-methylacetophenone (0.05mmol, 1eq) is added into a two-necked flask, the temperature is raised to 80 ℃, the mixture is heated and refluxed, TLC monitoring is carried out, and after 24 hours, the raw materials are completely reacted. Adding ice water into the reaction solution, stirring for 1h, standing, precipitating, filtering, and washing with water to obtain 2-chloro-3-formyl-6-fluoroquinoline.
5mL of an aqueous solution of NaOH (0.84mmol, 4eq) was added to 5mL of an aqueous solution of silver nitrate (0.42mmol, 2eq), and 2-chloro-3-formyl-6-fluoroquinoline (0.21mmol, 1eq) was added to the above mixed solution under ice-bath conditions, and the mixture was reacted at 0 ℃ for 3 hours while maintaining the ice-bath. The reaction solution was filtered by suction, 1M hydrochloric acid was added to adjust the pH of the filtrate to 6.0, and a solid precipitated, filtered by suction, dried, and further purified by silica gel column chromatography (DCM: MeOH ═ 7:1V/V) to give 2-chloro-6-fluoro-3-quinolinecarboxylic acid.
2-chloro-6-fluoro-3-quinolinecarboxylic acid (3mmol, 1eq) and 3,4, 5-trimethoxyaniline (4.5mmol, 1.5eq) were dissolved in 15mL of a boiled aqueous ethanol solution (ethanol: water ═ 2:1V/V), adjusted to pH 6 by adding concentrated hydrochloric acid, and heated under reflux overnight (TLC detection). Spin-drying the solvent, pouring into ice water, neutralizing with 1N NaOH aqueous solution, suction-filtering to obtain a filter cake, and purifying by silica gel column chromatography (DCM: MeOH ═ 10:1V/V) to obtain compound IV2。
MS：[M-H]-371.11
EXAMPLE 3 intermediate Furazan oxynitrides (Compound III)0) Synthesis of (2)
Dissolving phenylthioacetic acid (0.1mol, 16.8g) in 75mL of glacial acetic acid, slowly dropwise adding 20.3mL of 30% hydrogen peroxide in a fume hood, and stirring at room temperature for 4 h; slowly adding 40mL fuming nitric acid dropwise, keeping the internal temperature not more than 40 ℃, after dropwise adding is finished within 1h, heating to 100 ℃, generating a large amount of reddish brown gas, absorbing tail gas with alkali liquor, and gradually changing the solution from colorless and transparent to yellowBrown, reacting for 4h, cooling to room temperature, precipitating white needle crystal, filtering, and drying to obtain compound III0(13.3g, yield 44%) M.p.153-155 ℃.
MS：[M-H]-365.00.
EXAMPLE 4 Compound III1Synthesis of (2)
Compound III0(0.5mmol, 1eq) was dissolved in 10mL tetrahydrofuran, stirred at low temperature (below-15 deg.C), ethylene glycol (0.6mol, 1.2eq) was added, the reaction temperature was kept below-15 deg.C by ice salt bath, 80. mu.L of 1mol/L aqueous NaOH solution was added, and the mixture was warmed to room temperature for reaction for 3 hours. After completion of the reaction, 20mL of water was added to the reaction mixture, followed by extraction with ethyl acetate (20 mL. times.3), and the organic layers were combined, washed with saturated brine and anhydrous Na2SO4Drying overnight, suction filtering, concentrating, and purifying by silica gel column chromatography (PE: EA ═ 7:1V/V) to give a white solid (Compound III)1) The yield is about 50.5%.
MS：285.02[M-H]-.
EXAMPLE 5 Compound III2Synthesis of (2)
1, 3-propanediol (0.6mol, 1.2eq) was substituted for ethylene glycol in example 4, and the other conditions were not changed to give compound III2White solid, yield about 52.3%.
MS：299.12[M-H]-.
EXAMPLE 6 Compound III3Synthesis of (2)
The ethylene glycol of example 4 was replaced with 1, 4-butanediol (0.6mol, 1.2eq), and the reaction was changed without changing the other conditionsCompound III3White solid, yield about 54.6%.
MS：313.08[M-H]-.
Example 7 Compound III4Synthesis of (2)
1, 5-pentanediol (0.6mol, 1.2eq) was substituted for the ethylene glycol of example 4, and the other conditions were not changed to obtain Compound III4White solid, yield about 51.2%.
MS：327.20[M-H]-.
Example 8 Compound III5Synthesis of (2)
1, 6-hexanediol (0.6mol, 1.2eq) was used in place of the ethylene glycol of example 4, and the other conditions were unchanged to give compound III5White solid, yield about 51.7%.
MS：341.02[M-H]-.
EXAMPLE 9 Compound I1Synthesis of (2)
Dissolving 4-quinolinecarboxylic acid (0.15mmol, 1.5eq) in 10mL DCM, adding EDCI (0.18mmol, 1.8eq) and DMAP (0.04mmol, 0.4eq) in that order, stirring at 0 deg.C for 30min, adding Compound III1(0.1mmol, 1eq), heating to room temperature, and continuing the reaction for 6-8 h. After the reaction is finished, concentrating the reaction solution under reduced pressure, and purifying by silica gel column chromatography (PE: EA is 3: 1-5: 1V/V) to obtain the target compound I1White solid, yield 51%.
ESI-MS：[M+H]+442.1.
1H NMR(300MHz,DMSO-d6,ppm)δ9.10(d,J＝4.1Hz,1H),8.65(d,J＝8.3Hz,1H),8.16(d,J＝8.3Hz,1H),7.95(m,2H),7.88(m,2H),7.74(t,J＝6.9Hz,2H),7.55(t,J＝7.4Hz,2H),4.83(s,4H).
13C NMR(150MHz,DMSO-d6)δ166.03,159.26,150.79,148.85,137.55,136.50,134.92,130.57,130.30(C×2),130.16,128.86,128.69(C×2),125.79,124.46,122.78,111.04,69.67,63.46.
EXAMPLE 10 Compound I2Synthesis of (2)
With compounds III2Compound III of alternative example 91Other conditions are not changed to obtain the target compound I2White solid, yield 46%.
ESI-MS：[M+H]+456.1.
1H NMR(300MHz,DMSO-d6,ppm)δ9.07(d,J＝4.2Hz,1H),8.63(d,J＝8.4Hz,1H),8.14(d,J＝8.4Hz,1H),8.00(m,3H),7.87(m,2H),7.73(m,3H),4.60(dd,J＝10.6,4.9Hz,2H),4.54(d,J＝4.9,10.6Hz,2H),2.23(m,2H).
13C NMR(150MHz,DMSO-d6)δ166.15,159.33,150.85,148.83,137.58,136.63,135.01,130.48(C×3),130.17,128.79(C×2),128.75,125.66,124.57,122.73,111.03,68.86,62.58,27.78.
EXAMPLE 11 Compound I3Synthesis of (2)
With compounds III3Alternative example 9 Compound III1Other conditions are not changed to obtain the target compound I3White solid, yield 53%.
ESI-MS：[M+Na]+492.5.
1H NMR(300MHz,CDCl3,ppm)δ9.06(d,J＝4.4Hz,1H),8.80(d,J＝8.5Hz,1H),8.23(d,J＝8.5Hz,1H),8.09(s,1H),8.07(s,1H),7.95(d,J＝4.4Hz,1H),7.82(m,1H),7.73(dt,J＝11.5,7.3Hz,2H),7.61(m,2H),4.58(dt,J＝11.3,5.8Hz,4H),2.11(m,4H).
13C NMR(150MHz,DMSO-d6)δ166.20,159.34,150.81,148.84,137.67,136.58,135.35,130.46(C×3),130.17,128.78(C×2),128.74,125.67,124.57,122.50,110.97,71.57,65.69,25.22,24.94.
EXAMPLE 12 Compound I4Synthesis of (2)
With compounds III4Compound III of alternative example 91Other conditions are not changed to obtain the target compound I4White solid, yield 49%.
ESI-MS：[M+H]+484.2.
1H NMR(300MHz,DMSO-d6,ppm)δ9.04(d,J＝4.3Hz,1H),8.62(d,J＝8.4Hz,1H),8.13(d,J＝8.4Hz,1H),7.97(m,3H),7.85(m,2H),7.72(m,3H),4.44(m,4H),1.86(m,4H),1.56(m,2H).
13C NMR(150MHz,DMSO-d6)δ166.24,159.34,150.80,148.85,137.65,136.53,135.31,130.42(C×3),130.16,128.71(C×2),125.66,124.57,122.50,110.92,71.81,65.95,28.00,27.95,22.22.
EXAMPLE 13 Compound I5Synthesis of (2)
With compounds III5Compound III of alternative example 91Other conditions are not changed to obtain the target compound I5White solid, yield 54%.
ESI-MS：[M+Na]+520.2.
1H NMR(300MHz,DMSO-d6,ppm)δ9.07(d,J＝4.4Hz,1H),8.61(d,J＝8.4Hz,1H),8.14(d,J＝8.4Hz,1H),8.02(s,1H),7.99(d,J＝1.5Hz,1H),7.95(d,J＝4.4Hz,1H),7.87(m,2H),7.76(d,J＝1.5Hz,1H),7.71(m,2H),4.45(m,4H),1.81(m,4H),1.47(m,4H).
13C NMR(150MHz,DMSO-d6)δ166.30,159.35,150.87,148.85,137.68,136.59,135.41,130.48(C×2),130.18,128.73(C×2),125.65,124.55,122.49,110.91,71.86,66.07,28.38,28.18,25.40,25.14.
EXAMPLE 14 Compound I6Synthesis of (2)
With a compound IV1Replacing the 4-quinolinecarboxylic acid in example 9 with the other conditions to give the title compound I6White solid, yield 42%.
ESI-MS：[M+H]+607.1
1H NMR(300MHz,DMSO-d6,ppm)δ8.53(d,J＝8.4Hz,1H),8.50(s,1H),8.20(d,J＝8.4Hz,1H),7.94(d,J＝7.9Hz,2H),7.87(m,1H),7.69(t,J＝7.4Hz,2H),7.56(s,2H),7.50(t,J＝7.4Hz,2H),4.89(m,4H),3.91(s,6H),3.75(s,3H).
13C NMR(150MHz,DMSO-d6)δ166.41,159.29,156.04,153.79(C×2),148.61,139.92,137.47,136.93,136.46,133.78,131.00(C×3),130.27(C×2),128.63,128.47,125.63,123.31,119.95,111.04,105.23(C×2),69.69,63.56,60.65,56.54(C×2).
EXAMPLE 15 Compound I7Synthesis of (2)
With a compound IV1Alternative 4-quinolinecarboxylic acid of example 9 to Compound III2Alternative example 9 Compound III1Other conditions are not changed to obtain the target compound I7White solid, yield 38%.
ESI-MS：[M+H]+622.1.
1H NMR(300MHz,DMSO-d6,ppm)δ8.51(d,J＝8.4Hz,1H),8.48(s,1H),8.18(d,J＝8.4Hz,1H),8.01(d,J＝7.7Hz,2H),7.86(m,2H),7.72(d,J＝7.7Hz,2H),7.66(m,2H),7.57(s,2H),4.62(m,4H),3.93(s,6H),3.76(s,3H),2.37(m,2H).
13C NMR(150MHz,DMSO-d6)δ166.45,159.37,156.00,153.79(C×2),148.59,139.90,137.60,136.97,136.62,133.79,130.89,130.48(C×2),130.26,128.78(C×2),128.34,125.45,123.42,119.93,111.03,105.23(C×2),68.81,62.64,60.66,56.57(C×2),27.79.
EXAMPLE 16 Compound I8Synthesis of (2)
With a compound IV1Alternative 4-quinolinecarboxylic acid of example 9 to Compound III3Compound III of alternative example 91Other conditions are not changed to obtain the target compound I8White solid, yield 41%.
ESI-MS[M+H]+636.3.
1H NMR(300MHz,DMSO-d6,ppm)δ8.48(d,J＝8.4Hz,1H),8.46(s,1H),8.18(d,J＝8.4Hz,1H),8.01(s,1H),7.98(s,1H),7.84(m,2H),7.69(m,3H),7.57(s,2H),5.75(s,1H),4.56(m,2H),4.50(m,2H),3.93(s,6H),3.76(s,3H),1.99(m,4H).
13C NMR(150MHz,DMSO-d6)δ166.60,159.32,156.04,153.79(C×2),148.59,139.88,137.63,137.40,136.55,133.81,130.90,130.44(C×2),130.28,128.74(C×2),128.34,125.44,123.38,119.68,110.93,105.22(C×2),71.61,65.90,60.65,56.57(C×2),25.29,24.96.
EXAMPLE 17 Compound I9Synthesis of (2)
With a compound IV1Alternative 4-quinolinecarboxylic acid of example 9 to Compound III4Alternative example 9 Compound III1Other conditions are not changed to obtain the target compound I9White solid, yield 43%.
ESI-MS[M+K]+688.3.
1H NMR(300MHz,DMSO-d6,ppm)δ8.48(d,J＝8.4Hz,1H),8.46(1H,s),8.17(d,J＝8.4Hz,1H),7.97(s,1H),7.95(s,1H),7.84(m,2H),7.70(m,3H),7.56(s,2H),4.51(t,J＝6.5Hz,2H),4.43(t,J＝6.5Hz,2H),3.93(s,6H),3.76(s,3H),1.88(m,4H),1.57(m,2H).
13C NMR(150MHz,DMSO-d6)δ166.70,159.34,156.03,153.78(C×2),148.56,139.87,137.61,137.50,136.52,133.81,130.90,130.42(C×2),130.26,128.68(C×2),128.35,125.45,123.37,119.65,110.91,105.22(C×2),71.87,66.19,60.65,56.58(C×2),28.01,27.96,22.28.
EXAMPLE 18 Compound I10Synthesis of (2)
With a compound IV1Alternative 4-quinolinecarboxylic acid of example 9 to Compound III5Compound III of alternative example 91Other conditions are not changed to obtain the target compound I10White solid, yield 39%.
ESI-MS：[M+K]+702.4
1H NMR(300MHz,DMSO-d6,ppm)δ8.46(1H,s),8.45(d,J＝8.3Hz,1H),8.18(d,J＝8.3Hz,1H),8.00(s,1H),7.98(s,1H),7.86(m,2H),7.71(m,3H),7.58(s,2H),4.49(t,J＝6.2Hz,2H),4.40(t,J＝6.2Hz,2H),3.94(s,6H),3.76(s,3H),1.82(m,4H),1.50(m,4H).
13C NMR(150MHz,DMSO-d6)δ166.67,159.32,155.99,153.80(C×2),148.57,139.90,137.66,137.51,136.57,133.80,130.88,130.46(C×2),130.26,128.72(C×2),125.42,123.37,119.62,110.90,105.20(C×2),71.86,66.26,60.65,56.57(C×2),33.05,28.37,28.21,25.48,25.15.
EXAMPLE 19 Compound I11Synthesis of (2)
The 3-quinoline carboxylic acid is used for replacing the 4-quinoline carboxylic acid in the example 9, and other conditions are not changed to obtain the target compound I11White solid, yield 48%.
ESI-MS：[M+H]+442.1.
1H NMR(300MHz,DMSO-d6,ppm)δ9.32(s,1H),8.98(s,1H),8.15(m,2H),7.95(m,3H),7.74(m,2H),7.59(m,2H),4.82(t,J＝3Hz,2H),4.77(t,J＝3Hz,2H).
13C NMR(150MHz,DMSO-d6)δ165.05,162.72,149.76(C×2),139.29(C×2),132.98(C×2),130.09(C×2),129.29(C×2),128.34(C×2),126.91,125.95,122.82,110.24,69.25,63.11.
EXAMPLE 20 Compound I12Synthesis of (2)
Replacement of the 4-quinolinecarboxylic acid in example 9 by 3-quinolinecarboxylic acid, preparation of Compound III2Compound III of alternative example 91Other conditions are not changed to obtain the target compound I12White solid, yield 51%.
ESI-MS[M+H]+456.1.
1H NMR(300MHz,DMSO-d6,ppm)δ9.34(d,J＝2.1Hz,1H),9.04(d,J＝1.6Hz,1H),8.20(d,J＝8.4Hz,1H),8.11(d,J＝8.4Hz,1H),8.02(s,1H),7.99(d,J＝1.3Hz,1H),7.92(m,2H),7.74(m,1H),7.71(s,1H),7.69(d,J＝6.6Hz,1H),4.62(t,J＝6.0Hz,2H),4.50(t,J＝6.0Hz,2H),2.30(m,2H).
13C NMR(150MHz,DMSO-d6)δ165.23,159.33,149.87,149.52,139.22,137.58,136.63,132.81,130.48(C×2),130.09,129.19,128.79(C×2),128.18,126.95,123.09,111.03,68.94,62.09,27.91.
EXAMPLE 21 Compound I13Synthesis of (2)
Replacement of the 4-quinolinecarboxylic acid in example 9 by 3-quinolinecarboxylic acid, preparation of Compound III3Compound III of alternative example 91Other conditions are not changed to obtain the target compound I13White solid, yield 53%.
ESI-MS[M+H]+470.1.
1H NMR(300MHz,DMSO-d6,ppm)δ9.32(d,J＝1.8Hz,1H),9.01(d,J＝1.8Hz,1H),8.20(d,J＝8.4Hz,1H),8.11(d,J＝8.4Hz,1H),8.02(s,1H),7.99(s,1H),7.93(t,J＝7.5Hz,1H),7.85(t,J＝7.5Hz,1H),7.71(m,3H),4.47(m,4H),1.94(m,4H).
13C NMR(150MHz,DMSO-d6)δ165.24,159.35,149.82,149.65,138.97,137.66,136.59,132.74,130.48(C×2),130.06,129.29,128.77(C×2),128.16,126.94,123.20,110.95,71.62,65.17,25.24,25.02.
EXAMPLE 22 Compound I14Synthesis of (2)
Replacement of the 4-quinolinecarboxylic acid in example 9 with 3-quinolinecarboxylic acid, with Compound III4Compound III of alternative example 91Other conditions are not changed to obtain the target compound I14White solid, yield 49%.
ESI-MS：[M+Na]+506.2.
1H NMR(300MHz,DMSO-d6,ppm)δ9.31(d,J＝1.4Hz,1H),8.99(d,J＝1.4Hz,1H),8.18(d,J＝8.0Hz,1H),8.09(d,J＝8.3Hz,1H),7.99(s,1H),7.96(s,1H),7.89(m,2H),7.70(t,J＝7.6Hz,3H),4.41(dd,J＝13.9,6.3Hz,4H),1.85(dd,J＝6.3,7.0Hz,4H),1.57(d,J＝7.0Hz,2H).
13C NMR(150MHz,DMSO-d6)δ165.30,159.38,149.82(C×2),138.98(C×2),136.60,132.74(C×2),130.47(C×2),130.08,129.30,128.73(C×2),128.15,126.97,123.23,65.46(C×2),28.14(C×2),22.19.
EXAMPLE 23 Compound I15Synthesis of (2)
Replacement of the 4-quinolinecarboxylic acid in example 9 by 3-quinolinecarboxylic acid, preparation of Compound III5Compound III of alternative example 91Other conditions are not changed to obtain the target compound I15White solid, yield 47%.
ESI-MS[M+H]+498.2.
1H NMR(300MHz,DMSO-d6,ppm)δ9.30(d,J＝2.0Hz,1H),8.99(d,J＝2.0Hz,1H),8.20(d,J＝8.4Hz,1H),8.10(d,J＝8.4Hz,1H),8.00(s,1H),7.97(s,1H),7.90(m,2H),7.74(s,1H),7.70(m,2H),4.39(m,4H),1.79(m,4H),1.47(m,4H).
13C NMR(150MHz,DMSO-d6)δ165.30,159.35,149.80,149.62,138.97,137.67,136.59,132.73,130.48(C×2),130.10,129.26,128.72(C×2),128.15,126.96,123.26,110.90,71.89,65.56,28.50,28.19,25.39,25.19.
EXAMPLE 24 Compound I16Synthesis of (2)
With a compound IV2Replacing the 4-quinolinecarboxylic acid in example 9 with the other conditions to give the title compound I16Yellow solid, yield 35%.
ESI-MS：[M+Na]+663.2.
1H NMR(300MHz,DMSO-d6,ppm)δ9.99(s,1H),8.93(s,1H),7.97(t,J＝7.8Hz,2H),7.73(m,4H),7.55(t,J＝7.8Hz,2H),7.38(s,2H),4.85(t,J＝5.0Hz,2H),4.81(t,J＝5.0Hz,2H),3.84(m,6H),3.66(s,3H).
13C NMR(150MHz,DMSO-d6)δ166.53,159.31,157.40,153.22(C×2),151.82,146.23,137.59,136.49,136.33,133.18,130.30(C×2),128.71(C×2),125.95,123.26,123.05,122.56,122.47,112.80,112.63,111.58,111.06,97.81(C×2),63.35,60.62,56.18.
EXAMPLE 25 Compound I17Synthesis of (2)
With a compound IV2Substituting 4-quinolinecarboxylic acid in example 9 with Compound III2Compound III of alternative example 91Other conditions are not changed to obtain the target compound I17Yellow solid, yield 33%.
ESI-MS[M+Na]+677.2.
1H NMR(300MHz,DMSO-d6,ppm)δ10.09(s,1H),8.98(s,1H),8.03(s,1H),8.01(s,1H),7.87(dd,J＝10.7,4.2Hz,1H),7.79(d,J＝2.9Hz,1H),7.75(t,J＝4.4Hz,2H),7.71(d,J＝7.5Hz,1H),7.65(td,J＝8.9,2.9Hz,1H),7.38(s,2H),4.66(t,J＝6.1Hz,2H),4.55(t,J＝6.1Hz,2H),3.84(s,6H),3.66(s,3H),2.36(m,2H).
13C NMR(150MHz,DMSO-d6)δ166.92,159.39,157.31,153.26(C×2),151.89,146.16,142.48,137.56,136.64(C×2),136.42,133.13,130.49(C×2),128.81(C×2),123.08,122.88,122.59,111.72,111.09,97.70(C×2),68.99,62.73,60.63,56.20(C×2),27.84.
EXAMPLE 26 Compound I18Synthesis of (2)
With a compound IV2Alternative 4-quinolinecarboxylic acid of example 9 to Compound III3Compound III of alternative example 91Other conditions are not changed to obtain the target compound I18Yellow solid, yield 28%.
ESI-MS：[M+Na]+691.2.
1H NMR(300MHz,DMSO-d6,ppm)δ10.11(s,1H),8.92(s,1H),8.03(m,2H),7.83(m,1H),7.80–7.52(m,5H),7.36(s,2H),4.50(m,4H),3.82(s,6H),3.66(s,3H),1.99(m,4H).
13C NMR(150MHz,DMSO-d6)δ166.89,159.38,157.35,153.23(C×2),151.89,146.14,142.18,137.62,136.59(C×2),136.41,133.10,130.48(C×2),128.77(C×2),123.04,122.84,122.63,111.75,110.99,97.65(C×2),71.63,65.76,60.62,56.18(C×2),25.19,24.93.
EXAMPLE 27 Compound I19Synthesis of (2)
With a compound IV2Alternative 4-quinolinecarboxylic acid of example 9 to Compound III4Compound III of alternative example 91Other conditions are not changed to obtain the target compound I19Yellow solid, yield 31%.
ESI-MS：[M+Na]+705.2.
1H NMR(300MHz,DMSO-d6,ppm)δ10.12(s,1H),8.93(s,1H),8.00(s,1H),7.98(s,1H),7.86(m,1H),7.81–7.55(m,5H),7.37(s,2H),4.45(m,4H),3.83(s,6H),3.66(s,3H),1.88(m,4H),1.60(m,2H).
13C NMR(150MHz,DMSO-d6)δ166.92,162.86,157.39,153.26(C×2),151.90,146.14,142.72,137.76,136.61,136.40(C×2),133.21,130.46(C×2),128.69(C×2),128.11,125.96,123.05,111.86,110.05,97.81(C×2),69.95,69.25,60.64,56.24(C×2),31.63,30.31,26.26.
EXAMPLE 28 Compound I20Synthesis of (2)
With compounds IV2Alternative 4-quinolinecarboxylic acid of example 9 to Compound III5Compound III of alternative example 91Other conditions are not changed to obtain the target compound I20Yellow solid, yield 51%.
ESI-MS：[M+Na]+717.2.
1H NMR(300MHz,DMSO-d6,ppm)δ10.11(s,1H),8.92(s,1H),8.01(s,1H),7.99(s,1H),7.88(m,1H),7.83–7.60(m,5H),7.37(s,2H),4.42(t,J＝6.5Hz,4H),3.84(s,6H),3.66(s,3H),1.83(dd,J＝13.4,6.5Hz,4H),1.51(m,4H).
13C NMR (150MHz, DMSO-d6) delta 166.95,159.37,157.40,153.27 (Cx 2),151.93,146.12,145.07,139.62,136.59,136.39,133.22,130.49 (Cx 2),130.13,128.72 (Cx 2),128.10,125.96,124.50,111.91,110.92,97.83 (Cx 2),66.20,61.20,60.63,56.24 (Cx 2),33.06,31.63,30.84,25.90 pharmacological experiments with the compound of example 29
The compound of the invention is tested for anti-tumor activity by adopting a tetramethylazole blue colorimetric method (MTT method), and Doxorubicin (Doxorubicin, Dox) is taken as a positive control drug.
The instrument comprises the following steps: ultra-pure water instruments (Direct-Q with pump, Millopore), ultra-clean benches (SW-CJ-1FD, AIRTECH, Suzhou purification Co., Ltd.), flow cytometers (Accuri C6, BD), low-temperature high-speed centrifuges (3K15, SIGMA), constant-temperature CO2 incubator (3111, Thermo), inverted microscopes (IX71, OLYMPUS), microplate readers (Muskan FC, Thermo), multifunctional microplate readers (POLARTAR omega, BMG), portable pressure steam sterilization pots (YXQ. SG41.280, Shanghai Huanli medical nuclear instruments Co., Ltd.), high-speed centrifuges (TDZ4-WS, Changshan Xiang centrifuge Co., Ltd.), ultracentrifuge (SL 16, Thermo), refrigerators (FPRMA700, Thermo), inverted fluorescence microscopes (TS2R, Nikon), constant-temperature metal baths (TU-10, Shanghai science Co., Ltd.).
Reagent: DMEM incomplete medium (Kyosu Kaji Biotechnology Co., Ltd., Kaji Biotechnology for short), RPMI-1640 incomplete medium (Kaji Biotechnology), fetal bovine serum (Biological Industries), trypsin digestion solution (Kaji Biotechnology), tetramethylthiazole blue (Kaji Biotechnology), PBS (Kaji Biotechnology), DMSO (national reagent Co., Ltd.), adriamycin (Nanjing Jingjiu Ansheng Biotechnology Co., Ltd.), nitric acid reductase nitric oxide detection kit (Kaji Biotechnology), Carboxy-PTIO (Kaji Biotechnology), Annexin V-FITC/PI double-staining apoptosis detection kit (Kaji Biotechnology), 10mM PMSF (Kaji Biotechnology), ready-to-use Hoechst33342 staining solution (Kaji Biotechnology), RNase A (Kaji Biotechnology).
Cell lines: human non-small cell lung cancer cell strain A549 (1640 culture medium containing 10% serum), human breast cancer cell strain MCF-7 (DMEM culture medium containing 10% fetal bovine serum), human colon cancer cell HCT116 (DMEM culture medium containing 10% fetal bovine serum), and human normal breast cell MCF-10A (DMEM culture medium containing 10% fetal bovine serum).
The method comprises the following steps: taking out cell strain to be recovered from liquid nitrogen, rapidly thawing in water bath at 37 deg.C, placing in prepared culture medium, and introducing into CO2Culturing at constant temperature of 37 ℃ in an incubator, and changing the culture solution after the wall is attached (more than 6 h). And (3) carrying out passage and liquid change at regular intervals, and taking cells in exponential growth phase and in good state for plating: discarding the old culture solution, adding 2mL PBS to wash for 2 times, adding 1mL 0.25% trypsin digestion solution to digest at 37 ℃ for 1-2min, tapping properly to make the cells shed, adding 1mL culture medium containing 10% fetal calf serum to stop the digestion, gently blowing to prepare cell suspension, transferring to a centrifuge tube, and centrifuging at 1500r/min for 5 min. Discarding the supernatant, adding new culture medium, gently blowing, suspending, counting cells at 5 × 104Cell suspensions were prepared at individual/mL density and seeded in 96-well plates at 100. mu.L/well, with surrounding wells sealed with PBS, and thermostatted CO2Culturing in an incubator for 24 h.
Test Compound I with Medium containing 10% fetal bovine serum1Compound I20Diluting with positive control drug and DMSO (blank control group) to required concentration, changing solution, adding drug, adding each drug in 3 multiple wells, and placing in constant temperature CO2Culturing in an incubator for 48 h. MTT reagent was added to 96-well plates 10. mu.L/well in the dark and incubation was continued for 4 h. Discard the old medium in the plate, add 100. mu.L DMSO per well, shake well to dissolve the crystals. Measuring OD (absorbance) at 570nm with microplate reader, calculating cell inhibition rate according to the following formula, preparing compound with 5 μ M concentration inhibition rate higher than 50% into gradient concentration, and calculating IC of tested drug with GraphPad Prism 5 software50Value, experiment was repeated three times.
Percent cell inhibition [ (% OD value of blank control-OD value of administered group)/OD value of blank control ]. times.100%
TABLE 1 inhibition of MCF-7 (5. mu.M) by the compounds
TABLE 2 IC of test Compounds on different tumor cell lines50(μM)
The result shows that the product compound I is modified at the C-4 position of the quinoline mother ring1Compound I10C-3 position modified product compound I with overall activity superior to quinoline parent ring11Compound I20(ii) a ② with a compound IV1Compounds I obtained as mother nucleus6Compound I10The activity of the compound I is better than that of the compound I obtained by taking 4-quinoline carboxylic acid as a mother nucleus1Compound I5(ii) a ③ with compounds IV2Compounds I obtained as mother nucleus16Compound I20The activity of the compound I is integrally inferior to that of the compound I obtained by taking 3-quinoline carboxylic acid as a mother nucleus11Compounds I15. And the NO donor quinoline derivative has activity on human breast cancer cell strain MCF-7 superior to that of human normal breast cell MCF-10A, has selectivity and embodies the medicine safety of the compound.
Claims (10)
1. An NO donor quinoline derivative represented by formula I:
wherein R is1、R2Each independently selected from H, F, 3,4, 5-trialkoxyphenyl and 3,4, 5-trialkoxyphenylamino, and n is a positive integer of 1-5; the alkoxy is C1-C3 alkoxy.
2. An NO donor quinoline derivative according to claim 1, wherein R is1、R2Each independently selected from H and 3,4, 5-trialkoxy phenyl, and n is a positive integer of 1-5.
3. An NO donor quinoline derivative according to claim 2, wherein R is1Independently selected from H, 3,4, 5-trimethoxyphenyl, R2Is selected from H, and n is a positive integer from 1 to 5.
4. The NO donor-type quinoline derivative according to claim 3, wherein
Is a substituent at the 4-position, R1=R2= H, n =1, 2, 3,5, or R1Selected from 3,4, 5-trimethoxyphenyl, R2Selected from H, n =1, 2, 3,4, 5;
5. A method for producing an NO donor type quinoline derivative according to claim 1, characterized by the following reaction scheme:
6. the method for producing an NO donor-type quinoline derivative according to claim 5, which comprises: and (3) forming ester by the quinoline carboxylic acid compound shown in the formula IV and the furazan nitrogen oxide compound shown in the formula III under the action of catalysts EDCI and DMAP to obtain the NO donor type quinoline derivative.
7. The method for producing an NO donor-type quinoline derivative according to claim 6, wherein after completion of the reaction, the reaction solution is concentrated under reduced pressure and purified by silica gel column chromatography to obtain a target compound; wherein the eluent is PE: EA =3: 1-5: 1V/V.
8. The use of the NO donor-type quinoline derivative according to claim 1 for the preparation of an antitumor agent.
9. The use according to claim 8, wherein the tumor is lung cancer, breast cancer, colon cancer.
10. An antitumor agent characterized by comprising the NO-donor-type quinoline derivative according to claim 1 as an active ingredient or a main active ingredient.
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