CN113461612B - Quinolone tankyrase 2 inhibitor and preparation method and application thereof - Google Patents
Quinolone tankyrase 2 inhibitor and preparation method and application thereof Download PDFInfo
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- CN113461612B CN113461612B CN202110821935.6A CN202110821935A CN113461612B CN 113461612 B CN113461612 B CN 113461612B CN 202110821935 A CN202110821935 A CN 202110821935A CN 113461612 B CN113461612 B CN 113461612B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
Abstract
The invention relates to a quinolone terminal anchor polymerase 2 inhibitor and a preparation method and application thereof, wherein the inhibitor has a structure shown in a formula I:
the method adopts 4-oxo-1,4-dihydroquinoline-3-carboxylic acid and aniline derivatives or benzoyl hydrazine derivatives as starting materials, uses uronium salts as condensing agents, and carries out condensation reaction in an organic solvent under the condition of adding alkali to obtain the quinolone terminal-anchor polymerase 2 inhibitor. Compared with the prior art, the preparation method is simple, and the synthesized compound has a novel structure and has better activity and selectivity for inhibiting tankyrase 2.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a quinolone tankyrase 2 inhibitor, and a preparation method and application thereof.
Background
Tankyrase (TNKS) belongs to the family of polyadenylic diphosphribose polymerases and has an ASM domain ankyrin repeat. TNKS is involved in the regulation of a variety of cellular functions, including telomere homeostasis, wnt signaling pathways, glucose metabolism, and spindle formation during mitosis. The catalytic domain of TNKS is a potential drug target and becomes the focus of targeted drug research. More and more researches on the medicines developed by TNKS show the huge development prospect of the antitumor medicines. Quinolones (quinolones) are artificially synthesized antibacterial drugs containing 4-quinolones basic structure and having selective inhibition effect on bacterial DNA helicase. The development of quinolone drugs in recent years is on the rise, and the molecular skeleton of the quinolone drugs is found to have various biological activities, and besides the broad-spectrum antibacterial property, quinolone compounds have been proved to inhibit tankyrase 2 to play an anti-tumor role. Most of the reported quinolone compounds tankyrase 2 inhibitors act only on the nicotinamide binding site of tankyrase 2.
Disclosure of Invention
In order to find a new tankyrase 2 inhibitor, the invention aims to provide a novel quinolone tankyrase 2 inhibitor, a preparation method and an application thereof.
The inhibitor which acts on the binding site of nicotinamide and adenosine has better inhibitory activity and selectivity. The newly designed and synthesized quinolone compound has longer branched chains and can simultaneously occupy the nicotinamide and adenosine binding sites of tankyrase 2, thereby improving the inhibitory activity and selectivity of the compound.
In the invention, a plurality of tankyrase 2 inhibitors with novel structures are designed and synthesized aiming at the structure of tankyrase 2 by a computer-aided drug design method, and finally the tankyrase 2 inhibitors are tested for the inhibitory activity of the tankyrase 2 and the reported inhibitory activity of the tankyrase 2 inhibitor GK-007 (IC of GK-007) 50 =0.035 uM), and six compounds of the synthesized multiple tankyrase 2 inhibitors were found to have better tankyrase 2 inhibitory activity. Especially the IC of six compounds preferred therein 50 0.26uM, 2.85uM, 1.78uM, 0.97uM, 0.022, and 0.17uM, respectively.
The purpose of the invention can be realized by the following technical scheme:
in a first aspect, the present invention provides a quinolone tankyrase 2 inhibitor having a structure represented by formula I:
wherein R is selected from:
Preferably, said R is selected from:
The third aspect of the present invention provides a method for preparing the quinolone terminal-anchored polymerase 2 inhibitor, which comprises using 4-oxo-1,4-dihydroquinoline-3-carboxylic acid and aniline derivative or benzoyl hydrazine derivative as starting materials, using uronium salt as a condensing agent, and performing a condensation reaction in an organic solvent under the condition of adding alkali to obtain the quinolone terminal-anchored polymerase 2 inhibitor;
the aniline derivative is
Or
The benzoyl hydrazine derivative is
In the formula R 1 Selected from H, CH 3 、OCH 3 、Cl、Br、3,4,5-tri-OCH 3 Or COOCH 3 ；
In the formula R 2 Selected from H, CH 3 、OCH 3 Cl or Br.
The reaction equations are shown in the following three processes a, b and c respectively:
preferably, the uronium salt is selected from HATU, HBTU, HCTU, TBTU, TSTU or TNTU.
Preferably, the molar ratio of the 4-oxo-1,4-dihydroquinoline-3-carboxylic acid to the condensing agent is 1:1-1:5.
Preferably, the molar ratio of the 4-oxo-1,4-dihydroquinoline-3-carboxylic acid to the aniline derivative or the benzoyl hydrazine derivative is 1:1 to 1:3.
Preferably, the molar ratio of the 4-oxo-1,4-dihydroquinoline-3-carboxylic acid to the base is 1:1 to 1:5.
Preferably, the base is selected from DIPEA or triethylamine.
Preferably, the organic solvent is selected from DMSO, DMF or NMP.
Preferably, the reaction temperature of the condensation reaction is from 0 ℃ to 70 ℃.
The third aspect of the invention provides the application of the quinolone tankyrase 2 inhibitor in preparing a medicament for inhibiting tankyrase 2.
Compared with the prior art, the invention has the beneficial effects that:
(1) The preparation method is simple, low in cost and mild in reaction condition.
(2) The compound synthesized by the invention has a novel structure, and is reported for the first time.
(3) The quinolone tankyrase 2 inhibitor synthesized by the invention has good effect, wherein the IC of the compound 5 (see example 5) 50 The value is better than that of GK-007, which shows that the compound 5 has better inhibitory activity and selectivity than that of GK-007.
Drawings
FIG. 1 shows a hydrogen spectrum of the product obtained in example 1: ( 1 H NMR(DMSO))。
FIG. 2 is a carbon spectrum of the product obtained in example 1: ( 13 C NMR(DMSO))。
FIG. 3 is a hydrogen spectrum of the product obtained in example 2 (f) 1 H NMR(DMSO))。
FIG. 4 is a carbon spectrum of the product obtained in example 2 (C:) 13 C NMR(DMSO))。
FIG. 5 is a hydrogen spectrum of the product obtained in example 3 (see 1 H NMR(DMSO))。
FIG. 6 is a carbon spectrum of the product obtained in example 3 (C:) 13 C NMR(DMSO))。
FIG. 7 is a hydrogen spectrum (C) of the product obtained in example 4 1 H NMR(DMSO))。
FIG. 8 is a carbon spectrum of the product obtained in example 4 (C:) 13 C NMR(DMSO))。
FIG. 9 is a hydrogen spectrum (C) of the product obtained in example 5 1 H NMR(DMSO))。
FIG. 10 is a carbon spectrum (C) of the product obtained in example 5 13 C NMR(DMSO))。
FIG. 11 is a hydrogen spectrum (C) of the product obtained in example 6 1 H NMR(DMSO))。
FIG. 12 is a carbon spectrum (C) of the product obtained in example 6 13 C NMR(DMSO))。
Detailed Description
A quinolone tankyrase 2 inhibitor having the structure of formula I:
wherein R is selected from:
Preferably R is selected from:
The preparation method of the quinolone terminal-anchored polymerase 2 inhibitor adopts 4-oxo-1,4-dihydroquinoline-3-carboxylic acid and aniline derivatives or benzoyl hydrazine derivatives as starting materials, uses uronium salts as a condensing agent, and carries out condensation reaction in an organic solvent under the condition of adding alkali to obtain the quinolone terminal-anchored polymerase 2 inhibitor;
the aniline derivative is
Or
The benzoyl hydrazine derivative is
In the formula R 1 Selected from H, CH 3 、OCH 3 、Cl、Br、3,4,5-tri-OCH 3 Or COOCH 3 ；
In the formula R 2 Selected from H, CH 3 、OCH 3 Cl or Br.
The uronium salts are preferably selected from HATU, HBTU, HCTU, TBTU, TSTU or TNTU. The molar ratio of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid to the condensing agent is preferably 1:1 to 1:5. The molar ratio of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid to aniline derivative or benzoyl hydrazine derivative is preferably 1:1 to 1:3. The molar ratio of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid to base is preferably 1:1 to 1:5. The base is preferably DIPEA or triethylamine. The organic solvent is preferably selected from DMSO, DMF or NMP. The reaction temperature of the condensation reaction is preferably 0 ℃ to 70 ℃.
The quinolone tankyrase 2 inhibitor can be applied to the preparation of drugs for inhibiting tankyrase 2.
The invention is described in detail below with reference to the figures and specific embodiments.
In the present invention, IC 50 Test method of value: the inhibitory activity of the compounds on TNKS2 was determined by enzymatic reactions. Dissolving a compound to be tested in a DMSO solution to prepare an initial concentrationThe concentration is 200 mu M/L, then the mixture is diluted by 5 times according to the proportion, 7 concentration gradients are configured, and the concentration range of the solution of each compound to be tested is 0.0128 mu M/L to 200 mu M/L. The enzymatic reaction was carried out in 96-well plates (Greiner bio-one U-shaped blackboard) at room temperature. TNKS2 at 5nM was incubated with compound and 500nM NAD' in assay buffer (50mM HEPES pH 7.0, 1mM CHAPS) for 1 hour, with four parallel experimental groups being set up simultaneously per concentration gradient. Then, a detection buffer (0.1% of 50mM HEPES in BSA, 0.8M KF and 20mM EDTA) was added thereto, and the reaction was carried out at room temperature for 1 hour. And finally, adding 20mL of 20% acetophenone ethanol solution and 20mL of 2MKOH to terminate the reaction, chemically converting the unreacted NAD' into a fluorescent substance, and reading the fluorescence intensity under the conditions of an excitation wavelength of 355nm and an absorption wavelength of 450 nm. According to the formula: inhibition = (sample fluorescence intensity-blank)/(enzyme value fluorescence intensity-blank) the corresponding inhibition for each inhibitor was calculated and then fitted to the half-effective inhibitory concentration using Graph Pad Prism software.
Example 1
N- (4- (morpholine-4-carbonyl) phenyl) -4-oxo-1,4-dihydroquinoline-3-carboxamide
4-oxo-1,4-dihydroquinoline-3-carboxylic acid (95mg, 0.5 mmol) was dissolved in 25ml DMF and HATU (228mg, 0.6 mmol) and DIPEA (129mg, 1mmol) were added to a DMF solution containing 4-oxo-1,4-dihydroquinoline-3-carboxylic acid with stirring under ice bath conditions, slowly warmed to room temperature, and after 15 min (4-aminophenyl) (4-morpholinyl) methanone (124mg, 0.6 mmol) was added. Stirring was continued at room temperature for 6h until the 4-oxo-1,4-dihydroquinoline-3-carboxylic acid reaction was complete. After completion of the reaction, the reaction solution was poured into ice water. Precipitating solid, collecting solid, adding water, and adding Na 2 CO 3 Saline and ethanol ultrasonic washing. Purification of the solid by flash silica gel chromatography (petroleum ether/ethyl acetate = 6:1) afforded the product.
IC 50 The value was 0.26uM.
1 H NMR(400MHz,DMSO)δ＝12.64(s,1H),8.88(s,1H),8.32(d,J＝7.7Hz,1H),7.77(dd,J＝18.9,8.4Hz,4H),7.53(t,J＝7.5Hz,1H),7.43(d,J＝8.6Hz,2H),3.60(s,4H),3.50(s,4H). 13 C NMR(101MHz,DMSO)δ176.43,168.94,163.16,144.40,140.10,139.19,133.14,130.13,128.50,125.98,125.54,125.45,119.31,119.16,110.43,66.20,48.62.
The hydrogen and carbon spectra are shown in fig. 1 and 2.
Example 2
N' -benzoyl-4-oxo-1,4-dihydroquinoline-3-carbohydrazide
4-oxo-1,4-dihydroquinoline-3-carboxylic acid (95mg, 0.5 mmol) was dissolved in 25ml DMF and HATU (228mg, 0.6 mmol) and DIPEA (129mg, 1mmol) were added to a DMF solution containing 4-oxo-1,4-dihydroquinoline-3-carboxylic acid with stirring under ice bath conditions, slowly warmed to room temperature and benzoyl hydrazine (82mg, 0.6 mmol) was added after 15 min. Stirring was continued at room temperature for 6h until the 4-oxo-1,4-dihydroquinoline-3-carboxylic acid reaction was complete. After completion of the reaction, the reaction solution was poured into ice water. Precipitating solid, collecting solid, adding water, and adding Na 2 CO 3 Saline and ethanol ultrasonic washing. Purification of the solid by flash silica gel chromatography (petroleum ether/ethyl acetate = 4:1) afforded the product.
IC 50 The value was 2.85uM.
1 H NMR(400MHz,DMSO)δ＝8.82(s,1H),8.28(d,J＝8.1Hz,1H),7.93(d,J＝7.6Hz,2H),7.72-7.46(m,5H),7.36(t,J＝7.2Hz,1H). 13 C NMR(101MHz,DMSO)δ＝175.25,165.86,165.14,148.41,133.35,132.06,131.55,130.42,128.89,128.00,125.67,124.28,124.13,123.57,109.43.
The hydrogen and carbon spectra are shown in fig. 3 and 4.
Example 3
N' - (4-methylbenzoyl) -4-oxo-1,4-dihydroquinoline-3-carbohydrazide
4-oxo-1,4-dihydroquinoline-3-carboxylic acid (95mg, 0.5 mmol) was dissolved in 25ml DMF and HATU (228mg, 0.6 mmol) and DIPEA (129mg, 1mmol) were added to a DMF solution containing 4-oxo-1,4-dihydroquinoline-3-carboxylic acid with stirring under ice bath conditions, slowly warmed to room temperature and after 15 min 4-methylbenzoyl hydrazine (90mg, 0.6 mmol) was added. Stirring was continued at room temperature for 6h until 4-oxo-1,4-dihydroquinoline-3-carboxylic acid was reacted to completion. After completion of the reaction, the reaction solution was poured into ice water. Precipitating solid, collecting solid, adding water, and adding Na 2 CO 3 Saline and ethanol ultrasonic washing. Purification of the solid by flash silica gel chromatography (petroleum ether/ethyl acetate = 4:1) afforded the product.
IC 50 The value was 1.78uM.
1 H NMR(400MHz,DMSO)δ＝11.78(s,1H),8.80(s,1H),8.30(d,J＝8.1Hz,1H),7.83(d,J＝7.8Hz,2H),7.79-7.71(m,2H),7.50(t,J＝7.3Hz,1H),7.30(d,J＝7.8Hz,2H),2.36(s,3H). 13 C NMR(101MHz,DMSO)δ＝175.82,164.75,163.87,144.33,141.82,139.59,132.87,129.75,129.04,127.64,126.16,125.58,125.18,119.53,109.99,21.11
The hydrogen and carbon spectra are shown in fig. 5 and 6.
Example 4
N' - (4-methoxybenzoyl) -4-oxo-1,4-dihydroquinoline-3-carbohydrazide
4-oxo-1,4-dihydroquinoline-3-carboxylic acid (95mg, 0.5 mmol) was dissolved in 25ml DMF and HATU (228mg, 0.6 mmol) and DIPEA (129mg, 1mmol) were added to a DMF solution containing 4-oxo-1,4-dihydroquinoline-3-carboxylic acid under ice bath with stirring, slowly warmed to room temperature, and after 15 minutes 4-methoxybenzoyl hydrazine (100mg, 0.6 mmol) was added. Stirring was continued at room temperature for 6h until 4-oxo-1,4-dihydroquinoline-3-carboxylic acid was reacted to completion. After completion of the reaction, the reaction solution was poured into ice water. Precipitating solid, collecting solid, adding water, and adding Na 2 CO 3 Brine andand (5) ultrasonically washing with ethanol. Purification of the solid by flash silica gel chromatography (petroleum ether/ethyl acetate = 4:1) afforded the product.
IC 50 The value was 0.97uM.
1 H NMR(400MHz,DMSO)δ＝11.71(s,1H),8.79(s,1H),8.30(d,J＝8.1Hz,1H),7.91(d,J＝8.4Hz,2H),7.83-7.70(m,2H),7.51(t,J＝7.4Hz,1H),7.03(d,J＝8.5Hz,2H),3.82(s,3H). 13 C NMR(101MHz,DMSO)δ＝175.90,164.40,163.80,162.07,144.02,139.19,133.01,129.52,126.10,125.61,125.29,124.67,119.24,113.76,110.10,55.48.
The hydrogen and carbon spectra are shown in fig. 7 and 8.
Example 5
4-oxo-N- (4- (3,4,5-trimethoxybenzoylamino) phenyl) -1,4-dihydroquinoline-3-carboxamide
4-oxo-1,4-dihydroquinoline-3-carboxylic acid (95mg, 0.5 mmol) was dissolved in 25ml DMF and HATU (228mg, 0.6 mmol) and DIPEA (129mg, 1mmol) were added to a DMF solution containing 4-oxo-1,4-dihydroquinoline-3-carboxylic acid with stirring under ice bath conditions, slowly warmed to room temperature, and N- (4-aminophenyl) -3,4,5-trimethoxybenzamide (181mg, 0.6 mmol) was added after 15 minutes. Stirring was continued at room temperature for 6h until the 4-oxo-1,4-dihydroquinoline-3-carboxylic acid reaction was complete. After completion of the reaction, the reaction solution was poured into ice water. Precipitating solid, collecting solid, adding water, and adding Na 2 CO 3 Saline and ethanol ultrasonic washing. Purification of the solid by flash silica gel chromatography (petroleum ether/ethyl acetate = 4:1) afforded the product.
IC 50 The value was 0.022uM.
1 H NMR(400MHz,DMSO)δ＝12.46(s,1H),10.10(s,1H),8.86(s,1H),8.32(d,J＝8.1Hz,1H),7.80(t,J＝7.6Hz,1H),7.74(d,J＝6.0Hz,5H),7.52(t,J＝7.5Hz,1H),7.28(s,2H),3.87(s,6H),3.73(s,3H). 13 C NMR(101MHz,DMSO)δ＝176.40,164.73,162.69,152.71,144.11,140.33,139.22,134.85,134.65,133.03,130.18,126.02,125.55,125.33,121.44,119.84,119.28,110.74,105.34,60.21,56.19.
The hydrogen and carbon spectra are shown in fig. 9 and 10.
Example 6
Methyl 4- ((4- (4-oxo-1,4-dihydroquinoline-3-carboxamido) phenyl) carbamoyl) benzoate
4-oxo-1,4-dihydroquinoline-3-carboxylic acid (95mg, 0.5 mmol) was dissolved in 25ml DMF and HATU (228mg, 0.6 mmol) and DIPEA (129mg, 1mmol) were added to a DMF solution containing 4-oxo-1,4-dihydroquinoline-3-carboxylic acid with stirring under ice bath conditions, slowly warmed to room temperature and after 15 minutes methyl 4- ((4-aminophenyl) carbamoyl) benzoate (162mg, 0.6 mmol) was added. Stirring was continued at room temperature for 6h until the 4-oxo-1,4-dihydroquinoline-3-carboxylic acid reaction was complete. After completion of the reaction, the reaction solution was poured into ice water. Precipitating solid, collecting solid, adding water, and adding Na 2 CO 3 Saline and ethanol ultrasonic washing. Purification of the solid by flash silica gel chromatography (petroleum ether/ethyl acetate = 4:1) afforded the product.
IC 50 The value was 0.17uM.
1 H NMR(400MHz,DMSO)δ＝12.46(s,1H),10.41(s,1H),8.86(s,1H),8.32(d,J＝8.1Hz,1H),8.07(s,4H),7.76(dt,J＝15.6,6.7Hz,7H),7.52(t,J＝7.5Hz,1H),3.88(s,3H). 13 C NMR(101MHz,DMSO)δ＝176.40,165.78,164.48,162.69,144.10,139.17,135.01,134.51,133.04,132.02,129.24,128.10,126.00,125.54,125.34,121.20,119.87,119.26,110.72,52.48.
The hydrogen and carbon spectra are shown in FIGS. 11 and 12.
The embodiments described above are intended to facilitate the understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.
Claims (10)
1. A quinolone tankyrase 2 inhibitor having a structure represented by formula I:
wherein R is selected from:
2. The quinolone tankyrase 2 inhibitor according to claim 1, wherein R is selected from the group consisting of:
3. the method for preparing the quinolone tankyrase 2 inhibitor according to claim 1, wherein the quinolone tankyrase 2 inhibitor is obtained by performing a condensation reaction in an organic solvent using 4-oxo-1,4-dihydroquinoline-3-carboxylic acid and an aniline derivative or a benzoyl hydrazine derivative as starting materials, using an uronium salt as a condensing agent, and adding a base;
the aniline derivative is
The benzoyl hydrazine derivative is
In the formula R 1 Selected from H, CH 3 、OCH 3 、Cl、Br、3,4,5-tri-OCH 3 Or COOCH 3 ；
In the formula R 2 Selected from Br.
4. The method of preparing a quinolone tankyrase 2 inhibitor according to claim 3, wherein the uronium salt is selected from HATU, HBTU, HCTU, TBTU, TSTU, and TNTU.
5. The method for preparing the quinolone tankyrase 2 inhibitor according to claim 3 or 4, wherein the molar ratio of the 4-oxo-1,4-dihydroquinoline-3-carboxylic acid to the condensing agent is 1:1 to 1:5.
6. The method for preparing the quinolone tankyrase 2 inhibitor according to claim 3, wherein the molar ratio of the 4-oxo-1,4-dihydroquinoline-3-carboxylic acid to the aniline derivative or the benzoyl hydrazine derivative is 1:1 to 1:3.
7. The method for preparing the quinolone tankyrase 2 inhibitor according to claim 3,
the molar ratio of the 4-oxo-1,4-dihydroquinoline-3-carboxylic acid to the alkali is 1:1-1:5;
the base is selected from DIPEA or triethylamine.
8. The method of claim 3, wherein the organic solvent is selected from DMSO, DMF or NMP.
9. The method for preparing the quinolone tankyrase 2 inhibitor according to claim 3, wherein the condensation reaction is carried out at a reaction temperature of 0 ℃ to 70 ℃.
10. Use of a quinolone tankyrase 2 inhibitor according to claim 1 or 2 for the preparation of a medicament for inhibiting tankyrase 2.
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