CN115572254A - 2, 6-diaryl pyridine HDAC/Tubulin bifunctional inhibitor, preparation method and application - Google Patents

2, 6-diaryl pyridine HDAC/Tubulin bifunctional inhibitor, preparation method and application Download PDF

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CN115572254A
CN115572254A CN202110685918.4A CN202110685918A CN115572254A CN 115572254 A CN115572254 A CN 115572254A CN 202110685918 A CN202110685918 A CN 202110685918A CN 115572254 A CN115572254 A CN 115572254A
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carcinoma
cancer
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tubulin
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王洋
唐海荣
梁玉茹
蔡劭文
范鸿瑞
丁奎岭
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Shanghai Institute of Organic Chemistry of CAS
Fudan University
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Abstract

The invention belongs to the technical field of synthetic pharmaceutical chemistry, and relates to a novel 2, 6-diaryl pyridine HDAC/Tubulin bifunctional inhibitor with a general formula structure and obvious anti-tumor activity and application thereof in research and development of anti-tumor drugs. The invention also discloses the application of the compound, the pharmaceutical salt thereof and the compound medicine thereof in preparing medicines for preventing or treating diseases related to tumors. The compound or the pharmaceutically acceptable salt thereof can inhibit the growth of tumor cells in vitro and in vivo by inhibiting the aggregation of histone deacetylase and tubulin and inhibiting the regulation mechanism of tumor cell proliferation, and can be further used for preparing medicines for preventing or treating tumor-related diseases including benign tumor, malignant tumor, tumor and the like,Malignant tumor and other diseases caused by tumor.

Description

2, 6-diaryl pyridine HDAC/Tubulin bifunctional inhibitor, preparation method and application
Technical Field
The invention belongs to the technical field of synthetic pharmaceutical chemistry, and relates to a2, 6-diaryl pyridine HDAC/Tubulin bifunctional inhibitor, a preparation method and application thereof, in particular to a2, 6-diaryl pyridine HDAC/Tubulin bifunctional inhibitor with obvious anti-tumor activity, a preparation method thereof, in-vivo and in-vitro anti-tumor activity thereof, and application of the compound, acceptable pharmaceutical salt thereof or a compound medicine taking the compound as one of components thereof in preparing medicines for preventing and treating tumor-related diseases.
Background
Microtubules (microtubule) are essential for mitosis of cells, and play an essential role in maintaining cell morphology, cell motility, cell division, and proliferation. The mitosis and metastasis of malignant tumor cells are extremely vigorous, so that the dynamic balance of polymerization and depolymerization of tubulin is broken by targeting microtubules, and the division and proliferation of tumor cells can be selectively inhibited (Science 2013,339, 587-590). Although there have been some major advances in the research on tubulin aggregation inhibitors acting on colchicine, especially in the structural modification of Combretastatin (Combretastatin a-4), such as the disodium phosphate ester of Combretastatin (CA-4P) and the disodium phosphate ester of BNC105 (BNC 105P) have entered phase I and phase II clinical trials, respectively, the results show that these drugs have poor clinical effects, have certain toxic side effects, such as nausea, vomiting, visual disturbances and headache, and also have deficiencies in extending the life of patients, and no such drugs have been approved for marketing until now (j.med.chem.2016, 59, 8685-8711). Therefore, the development of tubulin aggregation inhibitors with better antitumor activity, higher selectivity and less toxic side effects is a major direction for the development of such drugs in the future.
There are studies disclosing that Histone Deacetylases (HDACs), which are key enzymes for regulating cell epigenetics, are highly expressed in a number of tumor cell lines, are highly correlated with growth, proliferation and invasion of tumor cells, and are considered as one of the most promising targets for tumor therapy (nat. Rev. Drug Discovery 2012, 11, 384-400). pan-HDAC inhibitors are mainly used for the treatment of hematological tumors and have poor therapeutic effect on solid tumors, so that HDAC inhibitors are often combined with other antitumor drugs, and although the combination mode can produce synergistic antitumor effect, complicated and unpredictable pharmacokinetics, poor patient compliance and even drug-drug interaction are caused. The medicine mode of 'one medicine and multiple targets' can effectively overcome the defects, and is an ideal alternative treatment mode of traditional 'single target and single medicine' and combined medicine treatment (J.Med.chem.2005, 48, 6523-6543). A large number of research reports have proved that the design of the HDAC based dual-target medicine is reasonable and feasible, and is also obvious for improving the tumor treatment effect.
Preclinical studies have shown that a tubulin aggregation inhibitor (vincristine) and an HDAC inhibitor SAHA can produce a synergistic antitumor effect when used in combination for treating leukemia. In a MOLT-4 nude mouse transplantation tumor model, the tumor inhibition rate of the vincristine and SAHA combined administration group is obviously higher than that of two single drug groups, and the combined administration group prolongs the survival period of mice (J.Hematol.Oncol.2017, 8, 82). In addition, it is also shown by physical research that tubulin and HDAC are associated and cooperated with each other in the process of generating and developing tumors. In early studies, HDACs catalyzed primarily deacetylation of lysine residues of histones located on the nuclear chromosome, but in fact, catalytic substrates of HDACs were also found extensively in the cytoplasm, such as α -tubulin and HSP90. The over-expressed HDAC in tumor cells can over-deacetylate α -tubulin in cytoplasm, thereby accelerating the aggregation and disaggregation of microtubules and promoting the migration and invasion of tumor cells. The microtubules themselves also have the kinetic property of aggregation and disaggregation, and the synergistic interaction process of microtubules and HDAC is very obvious in malignant tumor cells with vigorous division (J.Med.chem.2020, 63, 23-39). The data from these mechanistic studies, as well as preclinical studies, have provided a rational basis for the design of HDAC/Tubulin dual-target inhibitors.
Based on the basis and the current situation of the prior art, the inventor of the application intends to provide a2, 6-diaryl pyridine HDAC/Tubulin bifunctional inhibitor, a preparation method and a pharmaceutical application.
Disclosure of Invention
The invention aims to provide a novel 2, 6-diaryl pyridine HDAC/Tubulin bifunctional inhibitor, a preparation method thereof and application of the compound and pharmaceutical salts thereof or compound medicines taking the compound as a component in preparing medicines for preventing and treating tumor-related diseases based on the basis and the current situation of the prior art.
Based on the structural characteristics of the Tubulin aggregation inhibitor and the HDAC inhibitor, the invention adopts drug design of fused pharmacophores to construct a2, 6-diaryl pyridine HDAC/Tubulin dual-target molecular compound library, and a lead compound with good activity is obtained by screening through anti-tumor activity tests at a molecular level and a cell level, so that a candidate compound with a novel structure and potential drug development prospects is finally obtained.
Specifically, the invention provides a2, 6-diaryl pyridine HDAC/Tubulin bifunctional inhibitor with the following general structure or a pharmaceutical salt thereof,
Figure BDA0003124653950000031
wherein R is 1 And R 2 Is selected from hydrogen atom, alkyl, substituted alkyl, alkoxy, halogen atom, amino, hydroxyl, acyloxy, methoxy formyl, allyloxy, propargyloxy, sulfonyloxy, alkylamino, acylamino, sulfonylamino or combination of 2-3 of the same or different groups; x is selected from carbon, nitrogen, oxygen, ester group, amide group; l is taken from
Figure BDA0003124653950000032
Wherein n is selected from 0, 1, 2, 3,4,5, 6, 7; l can also be taken from
Figure BDA0003124653950000033
Figure BDA0003124653950000034
Figure BDA0003124653950000035
Alicyclic and aromatic heterocycles; r 3 Is taken from
Figure BDA0003124653950000036
Figure BDA0003124653950000037
Preferred compounds of the invention are:
Figure BDA0003124653950000038
Figure BDA0003124653950000041
the "pharmaceutically acceptable salt" of the present invention includes salts with organic acids such as malic acid, lactic acid, camphorsulfonic acid, citric acid, fumaric acid, and oxalic acid, and inorganic acids such as phosphoric acid, hydrohalic acid, sulfuric acid, and nitric acid.
The invention also aims to provide application of the compounds or the pharmaceutically acceptable salts of the compounds and compositions containing the compounds or the salts of the compounds in preparing medicines for preventing or treating diseases related to tumors.
Examples of the tumor-related diseases include, but are not limited to, thyroid cancer, lymphoma, prostate cancer, kidney cancer, bladder cancer, brain glioma, nasopharyngeal carcinoma, neuroendocrine cancer, head and neck squamous cell carcinoma, cervical cancer, ovarian cancer, breast cancer, colorectal cancer, pancreatic cancer, esophageal cancer, osteosarcoma, interstitial sarcoma, choriocarcinoma, malignant hydatidiform mole, malignant teratoma, gastric cancer, lung cancer, liver cancer, melanoma, undifferentiated carcinoma, and benign tumor.
The invention provides and proves that the 2, 6-diaryl pyridine HDAC/Tubulin bifunctional inhibitor with obvious anti-tumor activity or the pharmaceutically acceptable salt thereof can inhibit the regulation mechanism of tumor cell growth by inhibiting the aggregation of HDAC and Tubulin and has obvious proliferation inhibition and angiogenesis inhibition on tumor cells in-vitro and in-vivo anti-tumor experiments.
Drawings
FIG. 1. Compound 7a inhibits microtubule self-assembly assay in vitro-absorbance-time curves.
Figure 2. Effect of compound 7a on HDAC related protein expression.
Figure 3. Effect of compound 7a on tumor cell cycle.
FIG. 4. Effect of Compound 7a on tumor cell cycle-associated protein expression.
Figure 5. Compound 7a induces apoptosis assay.
FIG. 6. Effect of Compound 7a on apoptosis-related protein expression.
FIG. 7 inhibition of colony formation by Compound 7a on tumor cells.
Detailed Description
The present invention is further illustrated by the following examples. These examples are intended only to further illustrate the invention and do not alter the scope of protection of the invention. The process for the preparation of the object compounds of the present invention can be further embodied by the following representative compound preparation processes:
EXAMPLE 1 Synthesis of intermediate (1 a-1 b)
Figure BDA0003124653950000051
The synthetic method is reported in a reference document, and the specific operation is as follows: aryl boric acid (5.0 mmol), 2, 6-dibromopyridine (1.30g, 5.5 mmol), and [1, 1-bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (36mg, 0.05mmol) and sodium carbonate (1.59g, 15mmol) are sequentially added into a 50mL Schlenk tube, nitrogen is pumped out, toluene (8 mL) and ethanol (2 mL) are injected, and the mixture is heated and refluxed for reaction for 12 hours under the protection of nitrogen. After the reaction was completed, cooling was performed, water was added, extraction was performed three times with ethyl acetate, and the organic phases were combined, washed once with saturated brine, and dried over anhydrous sodium sulfate. And (4) carrying out rotary evaporation and concentration, then carrying out silica gel column chromatography separation (PE/EA 8.
1.1 Synthesis of 6- (3, 4, 5-trimethoxyphenyl) -2-bromopyridine (1 a)
White solid (1 a), yield 66%. 1 H NMR(400MHz,CDCl 3 ):δ8.60(d,J＝2.5Hz, 1H),7.85(dd,J＝2.5,8.4Hz,1H),7.58(d,J＝8.4Hz,1H),7.11(s,2H),3.95(s,6H), 3.90(s,3H).ESI-MS(m/z):325.3(M+H + ).
1.2 Synthesis of 6- (2, 4-dimethoxyphenyl) -2-bromopyridine (1 b)
Pale yellow solid (1 b), yield 68%. 1 H NMR(400MHz,CDCl 3 ):δ8.11(m,1H), 7.76-7.72(m,3H),6.63(dd,J＝2.4,8.7Hz,1H),6.52(d,J＝2.4Hz,1H),3.85(s, 3H),3.82(s,3H).ESI-MS(m/z):295.3(M+H + ).。
EXAMPLE 2 Synthesis of intermediate (2 a-2 b)
Figure BDA0003124653950000061
3-hydroxy-4-methoxyphenylboronic acid pinacol ester (0.75g, 2.4 mmol), tetrakis (triphenylphosphine) palladium (0.21g, 0.18mmol), potassium carbonate (0.51g, 3.7mmol) and raw material 1 (1.85 mmol) were sequentially added to a 50mL Schlenk tube, and after purging nitrogen, tetrahydrofuran (10 mL) and water (5 mL) were injected and the mixture was refluxed for 12 hours under nitrogen protection. After the reaction is completed, cooling, adding water, extracting with ethyl acetate for three times, combining organic phases, washing with saturated salt water once, and drying with anhydrous sodium sulfate. Concentrating by rotary evaporation, separating by silica gel column chromatography (PE/EA 3.
2.1 Synthesis of 2-methoxy-5- (6- (3, 4, 5-trimethoxyphenyl) -2-pyridyl) phenol (2 a)
Yellow solid (2 a), yield 68%. 1 H NMR(400MHz,CDCl 3 ):δ7.86(m,2H),7.76 (m,1H),7.71(m,1H),7.60(d,J＝8.4Hz,1H),7.48(s,2H),7.03(d,J＝8.4Hz,1H), 5.16(s,1H),3.92(s,6H),3.82(s,3H),3.74(s,3H).ESI-MS(m/z):368.5(M+H + ).
2.1 Synthesis of 2-methoxy-5- (6- (2, 4-dimethoxyphenyl) -2-pyridyl) phenol (2 b)
Pale yellow solid (2 b), yield 58%. 1 H NMR(400MHz,CDCl 3 ):δ8.04-8.02(m,1H), 7.77(d,J＝7.9Hz,1H),7.71(m,2H),7.64(d,J＝8.4Hz,1H),7.54(d,J＝8.5Hz, 1H),6.94(d,J＝8.5Hz,1H),6.66(d,J＝8.5Hz,1H),6.57(s,1H),5.67(s,1H),3.95 (s,3H),3.88(s,6H).ESI-MS(m/z):338.5(M+H + ).。
EXAMPLE 3 Synthesis of intermediate Compound (3 a-3 h)
Figure BDA0003124653950000071
The synthetic method is reported in a reference document, and the specific operation is as follows: a25 mL eggplant-shaped flask was charged with raw material 2 (0.27 mmol), potassium carbonate (75mg, 0.54mmol), bromoalkyl ester (0.54 mmol) and acetonitrile (2 mL), and reacted under reflux overnight. After the reaction, the mixture was cooled, water was added, the mixture was extracted with ethyl acetate three times, and the organic phases were combined, washed with saturated brine once, and dried over anhydrous sodium sulfate. Concentrating by rotary evaporation, separating by silica gel column chromatography (PE/EA 3.
3.1 Synthesis of ethyl 2- [ 2-methoxy-5- (6- (3, 4, 5-trimethoxyphenyl) -2-pyridyl) ] phenoxyacetate (3 a)
Yellow solid (3 a), yield 76%. mp 130-122 ℃. 1 H NMR(400MHz,CDCl 3 ):δ7.82 (s,1H),7.77-7.72(m,2H),7.62-7.59(m,2H),7.38(s,2H),7.02(d,J＝6.1Hz,1H), 4.79(s,2H),4.16(q,J＝7.1Hz,2H),4.00(s,6H),3.96(s,3H),3.92(s,3H),1.27(t, J＝7.1Hz,3H). 13 C NMR(150MHz,CDCl 3 ):δ168.9,156.3,155.8,153.4,150.6, 147.4,139.1,137.5,135.1,132.2,121.0,118.0,117.9,113.1,111.8,104.2,66.6,61.3, 60.9,56.3,56.0,14.2.ESI-MS(m/z):454.2(M+H + ).ESI-HRMS(m/z):calcd for C 25 H 28 NO 7 [M+H + ],454.1860；found,454.1865.
3.2 Synthesis of ethyl 4- [ 2-methoxy-5- (6- (3, 4, 5-trimethoxyphenyl) -2-pyridyl) ] phenoxybutyrate (3 b)
Yellow solid (3 b), yield 77%. mp 86-88 ℃. 1 H NMR(400MHz,CDCl 3 ):δ7.82 (s,1H),7.79-7.76(m,1H),7.67(d,J＝8.9Hz,1H),7.64-7.58(m,2H),7.39(s,2H), 6.99(d,J＝8.5Hz,1H),4.21(t,J＝6.9Hz,2H),4.14(q,J＝6.9Hz,2H),3.99(s, 6H),3.93(s,6H),2.57(t,J＝7.4Hz,2H),2.25-2.20(m,2H),1.25(t,J＝6.9Hz,3H). 13 C NMR(150MHz,CDCl 3 ):δ173.2,156.2,153.4,150.6,148.4,139.1,137.4,135.2, 132.3,119.8,117.9,112.1,111.6,104.2,67.9,60.9,60.4,56.2,56.0,30.8,24.6,14.2. ESI-MS(m/z):482.2(M+H + ).ESI-HRMS(m/z):calcd for C 27 H 32 NO 7 [M+H + ], 482.2173；found,482.2181.
3.3 Synthesis of ethyl 5- [ 2-methoxy-5- (6- (3, 4, 5-trimethoxyphenyl) -2-pyridyl) ] phenoxypentanoate (3 c)
Yellow solid (3 c), yield 80%. mp 61-63 ℃. 1 H NMR(400MHz,CDCl 3 ):δ7.81 (s,1H),7.77(d,J＝7.6Hz,1H),7.63-7.67(m,2H),7.60(d,J＝6.7Hz,1H),7.40(s, 2H),6.99(d,J＝6.7Hz,1H),4.17-4.10(m,4H),3.98(s,6H),3.92(s,6H),2.33(m, 2H),1.92(m,2H),1.77-1.71(m,2H),1.56-1.51(m,2H),1.26(t,J＝6.8Hz,3H). 13 C NMR(150MHz,CDCl 3 ):δ173.6,156.3,153.4,150.5,148.6,139.1,137.4,135.2, 132.2,119.6,117.9,111.7,111.5,104.2,68.7,60.9,60.3,56.2,34.2,28.9,25.6,24.8, 14.2.ESI-MS(m/z):496.2(M+H + ).ESI-HRMS(m/z):calcd for C 28 H 34 NO 7 [M+H + ], 496.2330；found,496.2330.
3.4 Synthesis of ethyl 6- [ 2-methoxy-5- (6- (3, 4, 5-trimethoxyphenyl) -2-pyridyl) ] phenoxyhexanoate (3 d)
Yellow solid (3 d), yield 76%. mp 84-86 ℃. 1 H NMR(400MHz,CDCl 3 ):δ7.81 (s,1H),7.79-7.76(m,1H),7.69-7.67(m,2H),7.61(d,J＝8.5Hz,1H),7.40(s,2H), 6.99(d,J＝8.8Hz,1H),4.20-4.13(m,4H),3.99(s,6H),3.93(s,6H),2.45-2.39(m, 2H),1.98-1.94(m,2H),1.88-1.82(m,2H),1.28-1.25(m,5H). 13 C NMR(150MHz, CDCl 3 ):δ173.4,156.3,153.4,150.5,148.5,139.1,137.5,135.2,132.2,128.6,119.7, 117.9,111.8,111.5,104.2,68.5,60.9,60.3,56.2,56.1,33.9,28.7,21.6,14.3.ESI-MS (m/z):510.2(M+H + ).ESI-HRMS(m/z):calcd for C 29 H 36 NO 7 [M+H + ],510.2486； found,510.2490.
3.5 Synthesis of ethyl 2- [ 2-methoxy-5- (6- (2, 4-dimethoxyphenyl) -2-pyridyl) phenoxyacetate (3 e)
Yellow solid (3 e), yield 72%. mp 101-103 ℃. 1 H NMR(400MHz,CDCl 3 ):δ7.99 (d,J＝8.5Hz,1H),7.78(d,J＝7.9Hz,1H),7.73-7.67(m,3H),7.53(d,J＝7.7Hz, 1H),6.99(d,J＝8.3Hz,1H),6.67(d,J＝9.5Hz,1H),6.58(s,1H),4.81(s,2H),3.94 (s,3H),3.88(s,6H),3.82(s,3H). 13 C NMR(150MHz,CDCl 3 ):δ169.5,161.3,158.4, 155.7,155.0,150.3,147.3,136.3,132.9,132.2,122.6,122.2,121.0,117.1,113.0, 111.8,105.2,98.9,66.6,56.0,55.6,55.5,52.3.ESI-MS(m/z):410.2(M+H + ). ESI-HRMS(m/z):calcd for C 23 H 24 NO 6 [M+H + ],410.1598；found,410.1605.
3.6 Synthesis of ethyl 4- [ 2-methoxy-5- (6- (2, 4-dimethoxyphenyl) -2-pyridyl) phenoxybutyrate (3 f)
Pale yellow solid (3 f), yield 70%. mp 68-70 ℃. 1 H NMR(400MHz,CDCl 3 ):δ7.99 (d,J＝9.2Hz,1H),7.77-7.70(m,3H),7.63(d,J＝8.3Hz,1H),7.55(d,J＝7.6Hz, 1H),6.96(d,J＝8.3Hz,1H),6.67(d,J＝8.6Hz,1H),6.58(s,1H),4.17(m,4H), 3.91(s,3H),3.88(s,6H),2.57(m,2H),2.22-2.19(m,2H),1.25(m,3H). 13 C NMR (150MHz,CDCl 3 ):δ173.3,161.3,158.4,156.2,155.0,150.3,148.4,136.2,132.9, 132.3,122.5,122.3,119.8,117.2,112.3,111.6,105.1,98.9,68.0,60.4,56.0,55.5, 30.9,24.7,14.2.ESI-MS(m/z):452.5(M+H + ).ESI-HRMS(m/z):calcd for C 26 H 30 NO 6 [M+H + ],452.2068；found,452.2069.
3.7 Synthesis of ethyl 5- [ 2-methoxy-5- (6- (2, 4-dimethoxyphenyl) -2-pyridyl) phenoxypentanoate (3 g)
White solid (3 g), yield 67%. mp 56-58 ℃. 1 H NMR(400MHz,CDCl 3 ):δ7.99 (d,J＝9.2Hz,1H),7.77-7.70(m,3H),7.63(d,J＝8.3Hz,1H),7.55(d,J＝7.6Hz, 1H),6.96(d,J＝8.3Hz,1H),6.67(d,J＝8.6Hz,1H),6.58(s,1H),4.17(m,4H), 3.91(s,3H),3.88(s,6H),2.57(m,2H),2.22-2.19(m,2H),1.25(m,3H). 13 C NMR (150MHz,CDCl 3 ):δ173.7,161.3,158.4,156.3,155.0,150.2,148.6,136.2,132.9, 132.2,122.5,122.3,119.6,117.2,111.9,111.5,105.1,98.9,68.8,60.2,56.1,55.6, 55.5,34.3,29.0,25.7,24.8,14.3.ESI-MS(m/z):466.5(M+H + ).ESI-HRMS(m/z): calcd for C 27 H 32 NO 6 [M+H + ],466.2224；found,466.2229.
3.8 Synthesis of ethyl 6- [ 2-methoxy-5- (6- (2, 4-dimethoxyphenyl) -2-pyridyl) phenoxyhexanoate (3 h)
Yellow solid (3 h), yield 56%. mp 61-63 ℃. 1 H NMR(400MHz,CDCl 3 ):δ8.00 (d,J＝8.5Hz,1H),7.78-7.68(m,3H),7.62(d,J＝8.2Hz,1H),7.55(d,J＝7.6Hz, 1H),6.96(d,J＝8.3Hz,1H),6.68(d,J＝8.5Hz,1H),6.58(s,1H),4.46-4.41(m, 4H),3.92(s,3H),3.88(s,6H),2.41(t,J＝6.6Hz,2H),1.93(m,2H),1.91(m,2H), 1.25(t,J＝7.1Hz,3H). 13 C NMR(150MHz,CDCl 3 ):δ173.5,161.3,158.4,156.2, 155.0,150.2,148.5,136.2,132.9,132.2,122.5,119.6,117.2,112.0,111.5,105.1,98.9, 68.6,60.3,56.1,55.6,55.5,34.0,28.7,21.6,14.3.ESI-MS(m/z):480.5(M+H + ). ESI-HRMS(m/z):calcd for C 28 H 34 NO 6 [M+H + ],480.2381；found,480.2388.。
EXAMPLE 4 Synthesis of the object Compound (4 a-4 h)
Figure BDA0003124653950000101
A25 mL eggplant-shaped bottle was charged with the starting material 3 (0.1 mmol), sodium hydroxide (40mg, 1.0 mmol) and an aqueous hydroxylamine solution (0.15 mL), and the mixture was dissolved in methylene chloride (0.5 mL) and methanol (1.0 mL). Reacting in ice bath, adding water after the raw materials completely disappear, adjusting pH to 6 with acetic acid, and extracting with ethyl acetateThe organic phases were combined and washed once with saturated brine and dried over anhydrous sodium sulfate. Filtering, concentrating by rotary evaporation, separating by silica gel column Chromatography (CH) 2 Cl 2 /MeOH 30:1)。
4.1 Synthesis of 2- [ 2-methoxy-5- (6- (3, 4, 5-trimethoxyphenyl) -2-pyridyl) ] phenoxy-N-hydroxyacetamide (4 a)
White solid (4 a), yield 53%. mp 68-70 ℃. 1 H NMR(400MHz,CDCl 3 ):δ 7.76-7.74(m,3H),7.57(d,J＝7.5Hz,2H),7.32(s,2H),7.00(d,J＝7.6Hz,1H), 4.73(s,2H),3.97(s,6H),3.94(s,3H),3.91(s,3H). 13 C NMR(150MHz,CDCl 3 ):δ 165.7,156.5,155.5,153.5,150.6,147.2,139.2,137.5,135.0,132.9,122.0,118.3, 117.9,114.6,112.0,104.3,61.0,56.3,56.0.ESI-MS(m/z):441.2(M+H + ). ESI-HRMS(m/z):calcd for C 23 H 25 N 2 O 7 [M+H + ],441.1656；found,441.1667.
4.2 Synthesis of 4- [ 2-methoxy-5- (6- (3, 4, 5-trimethoxyphenyl) -2-pyridyl) ] phenoxy-N-hydroxybutyramide (4 b)
Red solid (4 b), yield 33%. mp 96-98 ℃. 1 H NMR(400MHz,CDCl 3 ):δ 7.78-7.71(m,2H),7.65(d,J＝7.5Hz,1H),7.57(m,2H),7.33(s,2H),6.95(d,J＝ 7.0Hz,1H),4.15-4.11(m,2H),3.95(s,6H),3.90(s,6H),2.44(m,2H),2.15(m,2H). 13 C NMR(151MHz,CDCl 3 ):δ170.8,156.3,156.0,153.4,150.1,147.9,139.1,137.5, 135.2,132.5,120.1,118.0,118.0,111.7,111.4,104.3,68.1,61.0,56.2,56.0,24.8. ESI-MS(m/z):469.2(M+H + ).ESI-HRMS(m/z):calcd for C 25 H 29 N 2 O 7 [M+H + ], 469.1969；found,469.1975.
4.3 Synthesis of 5- [ 2-methoxy-5- (6- (3, 4, 5-trimethoxyphenyl) -2-pyridyl) ] phenoxy-N-hydroxypentanamide (4 c)
Red solid (4 c), yield 37%. mp 90-92 ℃. 1 H NMR(400MHz,CDCl 3 ):δ 7.78-7.75(m,2H),7.66-7.61(m,3H),7.37(s,2H),7.00(d,J＝6.6Hz,1H), 4.21-4.16(m,2H),3.98(s,9H),3.92(s,3H),2.49-2.38(m,2H),1.98-1.89(m,4H). 13 C NMR(150MHz,CDCl 3 ):δ169.9,155.7,155.5,152.8,148.8,147.6,138.6,136.8, 134.6,132.1,118.9,117.3,110.4,109.8,103.8,69.0,60.3,55.6,55.3,25.9,24.1. ESI-MS(m/z):483.2(M+H + ).ESI-HRMS(m/z):calcd for C 26 H 31 N 2 O 7 [M+H + ], 483.2126；found,483.2133.
4.4 Synthesis of 6- [ 2-methoxy-5- (6- (3, 4, 5-trimethoxyphenyl) -2-pyridyl) ] phenoxy-N-hydroxyhexanamide (4 d)
Yellow solid (4 d), yield 40%. mp 76-78 ℃. 1 H NMR(400MHz,CDCl 3 ):δ 7.77-7.70(m,2H),7.61(d,J＝8.6Hz,1H),7.59-7.53(m,2H),7.35(s,2H),6.94(d, J＝8.2Hz,1H),4.12-4.04(m,2H),3.95(s,6H),3.90(s,6H),2.13-2.12(m,2H), 1.86-1.82(m,2H),1.68-1.65(m,2H),1.47-1.45(m,2H). 13 C NMR(150MHz, CDCl 3 ):δ171.1,156.2,153.4,150.2,148.5,139.0,137.4,135.2,132.3,119.6,117.9, 111.5,104.3,68.7,60.9,56.2,56.0,32.6,28.7,25.6,25.1.ESI-MS(m/z):497.2 (M+H + ).ESI-HRMS(m/z):calcd for C 27 H 33 N 2 O 7 [M+H + ],497.2282；found, 497.2288.
4.5 Synthesis of 2- [ 2-methoxy-5- (6- (2, 4-dimethoxyphenyl) -2-pyridyl) ] phenoxy-N-hydroxyacetamide (4 e)
Yellow solid (4 e), yield 45%. mp 98-100 ℃. 1 H NMR(400MHz,CDCl 3 ):δ9.80 (s,1H),7.92(d,J＝6.1Hz,1H),7.71(m,3H),7.64(d,J＝7.1Hz,1H),7.50(s,1H), 6.94(d,J＝7.2Hz,1H),6.68(m,1H),6.55(s,1H),5.29(s,1H),4.69(s,1H),3.88(s, 3H),3.85(s,6H). 13 C NMR(150MHz,CDCl 3 ):δ166.0,161.4,158.3,155.4,155.3, 150.3,147.2,136.5,133.2,132.2,122.9,121.9,121.8,117.3,114.7,111.8,105.2,98.9, 69.0,55.9,55.6,55.5.ESI-MS(m/z):411.2(M+H + ).ESI-HRMS(m/z):calcd for C 22 H 23 N 2 O 6 [M+H + ],411.1551；found,411.1554.
4.6 Synthesis of 4- [ 2-methoxy-5- (6- (2, 4-dimethoxyphenyl) -2-pyridyl) ] phenoxy-N-hydroxybutyramide (4 f)
Red solid (4 f), yield 35%. mp 86-88 deg.C. 1 H NMR(400MHz,CDCl 3 ):δ7.94 (dd,J＝6.0,2.4Hz,1H),7.73-7.69(m,3H),7.59-7.52(m,2H),6.94(d,J＝7.4Hz, 1H),6.66(d,J＝8.8Hz,1H),6.57(s,1H),4.20-4.11(m,2H),3.94(s,3H),3.86(s, 6H),2.13(m,4H). 13 C NMR(150MHz,CDCl 3 ):δ170.9,161.4,158.3,156.1,155.2, 149.8,147.9,136.4,133.0,132.2,122.8,122.1,120.1,117.4,111.9,111.3,105.1,98.9, 68.2,56.1,55.6,29.3,24.8.ESI-MS(m/z):439.2(M+H + ).ESI-HRMS(m/z):calcd for C 24 H 27 N 2 O 6 [M+H + ],439.1864；found,439.1869.
4.7 Synthesis of 5- [ 2-methoxy-5- (6- (2, 4-dimethoxyphenyl) -2-pyridyl) ] phenoxy-N-hydroxypentanamide (4 g)
White solid (4 g), yield 37%. mp 96-98 ℃. 1 H NMR(400MHz,CDCl 3 ):δ7.95 (d,J＝6.8Hz,1H),7.74-7.68(m,3H),7.58-7.56(m,2H),6.94(d,J＝5.8Hz,1H), 6.66(d,J＝6.8Hz,1H),6.57(s,1H),4.16(s,2H),3.97(s,3H),3.86(s,6H), 2.44-2.34(m,2H),1.90(m,4H). 13 C NMR(150MHz,CDCl 3 ):δ161.4,158.4,156.1, 155.2,149.1,148.1,136.3,132.2,122.7,122.6,119.8,119.4,117.3,112.2,111.6, 105.2,98.9,68.7,56.1,55.6,55.5,29.7,29.3,28.5.ESI-MS(m/z):453.2(M+H + ). ESI-HRMS(m/z):calcd for C 25 H 29 N 2 O 6 [M+H + ],453.2020；found,453.2025.
4.8 Synthesis of 6- [ 2-methoxy-5- (6- (2, 4-dimethoxyphenyl) -2-pyridyl) ] phenoxy-N-hydroxyhexanamide (4 h)
Red solid (4 h), yield 32%. mp 68-71 ℃. 1 H NMR(400MHz,CDCl 3 ):δ7.93 (m,1H),7.1(m,3H),7.55(d,J＝6.8Hz,2H),6.93(m,1H),6.65(d,J＝7.8Hz,1H), 6.56(s,1H),4.08(s,2H),3.85(s,9H),2.09-2.02(m,2H),1.83-1.77(m,2H), 1.65-1.56(m,2H),1.47-1.40(m,2H). 13 C NMR(150MHz,CDCl 3 ):δ171.4,161.3, 158.3,156.3,155.2,149.9,148.5,136.4,132.9,132.2,122.7,122.1,119.6,117.5, 111.8,111.5,105.1,98.9,68.7,56.0,55.6,55.5,29.7,28.6,25.5,25.0.ESI-MS(m/z): 467.2(M+H + ).ESI-HRMS(m/z):calcd for C 26 H 31 N 2 O 6 [M+H + ],467.2177；found, 467.2185.。
EXAMPLE 5 Synthesis of intermediate Compounds (5 a-5 d)
Figure BDA0003124653950000131
The synthesis method is similar to the synthesis of the intermediate (2 a-2 b).
5.1 Synthesis of 2- (3-bromo-4-methoxyphenyl) -6- (3, 4, 5-trimethoxyphenyl) pyridine (5 a)
White solid (5 a), yield 72%. mp 140-142 ℃. 1 H NMR(400MHz,CDCl 3 ):δ8.36 (s,1H),8.07(dd,J＝8.6,2.2Hz,1H),7.79(t,J＝8.8Hz,1H),7.61(d,J＝7.9Hz, 2H),7.36(s,2H),7.02(d,J＝8.7Hz,1H),4.00(s,6H),3.97(s,3H),3.92(s,3H). 13 C NMR(150MHz,CDCl 3 ):δ156.6,154.9,153.5,139.1,137.6,135.1,133.3,131.9, 127.0,118.4,117.9,112.1,111.8,104.4,60.9,56.4,56.3.ESI-MS(m/z):430.2 (M+H + ).ESI-HRMS(m/z):calcd for C 21 H 21 BrNO 4 [M+H + ],430.0648；found, 430.0655.
5.2 Synthesis of 2- (3-bromo-4-methoxyphenyl) -6- (2, 4-dimethoxyphenyl) pyridine (5 b)
Yellow solid (5 b), yield 76%. mp 63-65 ℃. 1 H NMR(400MHz,CDCl 3 ):δ8.34 (s,1H),8.01(t,J＝9.8Hz,2H),7.79(d,J＝7.9Hz,1H),7.71(t,J＝7.6Hz,1H), 7.54(d,J＝7.7Hz,1H),6.98(d,J＝8.6Hz,1H),6.68(d,J＝10.4Hz,1H),6.58(s, 1H),3.95(s,3H),3.88(s,6H). 13 C NMR(150MHz,CDCl 3 ):δ161.4,158.4,156.3, 155.3,154.8,136.4,132.3,131.8,126.9,122.9,117.0,111.7,105.2,98.9,56.4,55.6, 55.5.ESI-MS(m/z):400.5(M+H + ).ESI-HRMS(m/z):calcd for C 20 H 19 BrNO 3 [M+H + ],400.0543；found,400.0546.
5.3 Synthesis of 2- (3-bromophenyl) -6- (3, 4, 5-trimethoxyphenyl) pyridine (5 c)
Yellow oily liquid (5 c) in 86% yield. 1 H NMR(400MHz,CDCl 3 ):δ8.30(s,1H), 8.04(d,J＝7.8Hz,1H),7.85-7.80(m,1H),7.67(m,2H),7.57-7.55(m,1H),7.37(s, 3H),4.00(s,6H),3.93(s,3H). 13 C NMR(150MHz,CDCl 3 ):δ156.1,154.5,152.9, 140.8,138.6,137.1,134.3,131.3,129.6,129.5,124.8,122.4,118.5,118.0,103.7, 60.4,55.7.ESI-MS(m/z):401.3(M+H + ).ESI-HRMS(m/z):calcd for C 20 H 19 BrNO 3 [M+H + ],401.0312；found,401.0315.
5.3 Synthesis of 2- (4-bromophenyl) -6- (3, 4, 5-trimethoxyphenyl) pyridine (5 d)
Yellow oily liquid (5 d), yield 76%. 1 H NMR(400MHz,CDCl 3 ):δ8.01-7.98(m, 2H),7.80(t,J＝7.0Hz,1H),7.64-7.60(m,4H),7.35(s,2H),3.97(s,6H),3.90(s, 3H). 13 C NMR(150MHz,CDCl 3 ):δ156.09,154.97,152.87,138.60,137.65,137.01, 134.37,131.22,127.89,122.85,118.26,117.72,103.69,60.36,55.66.ESI-MS(m/z): 401.2(M+H + ).ESI-HRMS(m/z):calcd for C 20 H 19 BrNO 3 [M+H + ],401.0316；found, 401.0319.。
EXAMPLE 6 Synthesis of intermediate Compound (6 a-6 f)
Figure BDA0003124653950000141
The synthetic method is reported in a reference document, and the specific operation is as follows: a15 mL stoppered tube was charged with the starting material (1.5 mmol), ethyl acrylate or methyl 1-butenoate (11.7 mmol), triethylamine (2.0 mL,14.6 mmol) and N-methylpyrrolidone (8 mL), purged with nitrogen to remove oxygen sufficiently, added with palladium acetate (49mg, 0.22 mmol) and tris (o-methylphenyl) phosphine (133mg, 0.44mmol), and strictly sealed and heated at 128 ℃ for 12 hours. After the reaction, the reaction mixture was cooled, ethyl acetate was added thereto, and the mixture was washed with water three times, and the organic phase was washed once with saturated brine and dried over anhydrous sodium sulfate. Concentrating by rotary evaporation, separating by silica gel column chromatography (PE/EA 5.
6.1 Synthesis of ethyl (E) -3- [ 2-methoxy-5- (6- (3, 4, 5-trimethoxyphenyl) -2-pyridyl) ] phenylacrylate (6 a)
White solid (6 a), yield 42%. mp 118-120 ℃. 1 H NMR(400MHz,CDCl 3 ):δ8.36 (s,1H),8.14(d,J＝6.6Hz,1H),8.07(d,J＝16.1Hz,1H),7.80(t,J＝8.1Hz,1H), 7.63(t,J＝8.5Hz,2H),7.39(s,2H),7.05(d,J＝6.8Hz,1H),6.65(d,J＝16.1Hz, 1H),4.28(q,J＝6.9Hz,2H),4.00(s,6H),3.97(s,3H),3.92(s,3H),1.35(t,J＝7.0 Hz,3H). 13 C NMR(150MHz,CDCl 3 ):δ167.4,159.1,156.4,155.6,153.5,139.9, 139.2,137.5,135.1,131.9,129.8,127.5,123.5,119.2,118.1,117.7,111.3,104.3,60.9, 60.4,56.3,55.7,14.4.ESI-MS(m/z):450.5(M+H + ).ESI-HRMS(m/z):calcd for C 26 H 28 NO 6 [M+H + ],450.1911；found,450.1920.
6.2 Synthesis of methyl (E) -4- [ 2-methoxy-5- (6- (3, 4, 5-trimethoxyphenyl) -2-pyridyl) ] phenyl-3-butenoate (6 b)
Yellow oily liquid (6 b) in 52% yield. 1 H NMR(400MHz,CDCl 3 ):δ8.27(s,1H), 8.03(d,J＝7.2Hz,1H),7.78(d,J＝6.8Hz,1H),7.66(d,J＝8.1Hz,1H),7.60(d,J ＝7.6Hz,1H),7.40(s,2H),6.99(d,J＝8.8Hz,1H),6.89(d,J＝16.0Hz,1H),6.48- 6.41(m,1H),4.00(s,6H),3.92(s,6H),3.73(s,3H),3.32(d,J＝6.8Hz,2H). 13 C NMR(150MHz,CDCl 3 ):δ172.1,157.4,156.2,153.4,139.0,137.4,135.3,131.8, 128.2,127.3,125.9,125.5,122.7,117.8,110.9,104.2,60.9,56.3,55.6,51.9,38.7. ESI-MS(m/z):450.3(M+H + ).ESI-HRMS(m/z):calcd for C 26 H 28 NO 6 [M+H + ], 450.1911；found,450.1920.
6.3 Synthesis of ethyl (E) -3- [ 2-methoxy-5- (6- (2, 4-dimethoxyphenyl) -2-pyridyl) ] phenylacrylate (6 c)
Pale yellow solid (6 c), yield 46%. mp 86-88 ℃. 1 H NMR(400MHz,CDCl 3 ):δ8.25 (s,1H),8.12-8.07(m,1H),8.03-7.98(m,1H),7.78(d,J＝8.1Hz,1H),7.72(t,J＝ 7.8Hz,1H),7.56(d,J＝8.1Hz,1H),7.01(d,J＝8.8Hz,1H),6.65(d,J＝16.3Hz, 1H),6.58(s,1H),4.28(q,J＝6.8Hz,2H),3.95(s,3H),3.88(s,6H),1.35(t,J＝6.8 Hz,3H). 13 C NMR(150MHz,CDCl 3 ):δ166.9,160.7,158.3,157.8,154.9,154.6, 139.6,135.7,131.9,131.7,129.4,127.1,122.8,122.1,121.6,118.6,116.4,110.6, 104.6,98.3,59.8,55.1,54.9,13.8.ESI-MS(m/z):420.3(M+H + ).ESI-HRMS(m/z): calcd for C 25 H 26 NO 5 [M+H + ],420.1805；found,420.1813.
6.4 Synthesis of methyl (E) -3- [ 2-methoxy-5- (6- (2, 4-dimethoxyphenyl) -2-pyridyl) ] phenyl-3-butenoate (6 d)
Yellow oily liquid (6 d) in 56% yield. 1 H NMR(400MHz,CDCl 3 ):δ8.13(s,1H), 8.02-7.97(m,2H),7.77-7.71(m,3H),7.57(d,J＝7.9Hz,1H),6.95(d,J＝8.3Hz, 1H),6.85-6.82(m,1H),6.67(d,J＝7.9Hz,1H),6.57(d,J＝8.2Hz,1H),6.46-6.41 (m,1H),3.88(s,9H),3.73(s,3H),3.31(d,J＝7.2Hz,2H). 13 C NMR(150MHz, CDCl 3 ):δ171.6,160.7,157.8,156.6,155.6,154.5,135.6,131.8,131.7,127.8,126.8, 125.2,124.9,121.9,121.9,121.7,116.6,110.2,104.5,98.3,54.9,54.9,51.3,38.2. ESI-MS(m/z):420.7(M+H + ).ESI-HRMS(m/z):calcd for C 25 H 26 NO 5 [M+H + ], 420.1805；found,420.1810.
6.5 Synthesis of ethyl (E) -3- [3- (6- (3, 4, 5-trimethoxyphenyl) -2-pyridyl) ] phenylacrylate (6E)
Yellow oily liquid (6 e), yield 78%. 1 H NMR(400MHz,CDCl 3 ):δ8.34(s,1H), 8.14(s,1H),7.81(d,J＝16.1Hz,2H),7.68(m,2H),7.60(m,1H),7.53(m,1H),7.40 (s,2H),6.56(d,J＝15.8Hz,1H),4.28(m,2H),4.01(s,6H),3.93(s,3H),1.36(m, 3H). 13 C NMR(150MHz,CDCl 3 ):δ166.4,156.1,155.2,152.9,143.9,139.4,138.6, 137.0,134.4,134.3,128.7,128.1,127.9,126.0,121.8,118.3,118.1,117.9,103.7, 60.4,59.9,55.7,13.7.ESI-MS(m/z):420.3(M+H + ).ESI-HRMS(m/z):calcd for C 25 H 26 NO 5 [M+H + ],420.3005；found,420.3010.
6.6 Synthesis of ethyl (E) -3- [4- (6- (3, 4, 5-trimethoxyphenyl) -2-pyridyl) ] phenylacrylate (6 f)
Yellow oily liquid (6 f), yield 62%. 1 H NMR(400MHz,CDCl 3 ):δ8.16(m,2H), 7.83-7.75(m,2H),7.72-7.66(m,4H),7.38(s,2H),6.52(d,J＝16.3Hz,1H),4.29(m, 2H),4.00(s,6H),3.92(s,3H),1.36(m,3H). 13 C NMR(150MHz,CDCl 3 ):δ166.4, 156.1,155.1,152.9,143.4,140.4,138.6,136.9,134.4,127.8,126.7,118.4,118.0, 103.7,60.4,59.9,55.7,13.7.ESI-MS(m/z):420.4(M+H + ).ESI-HRMS(m/z):calcd C 25 H 26 NO 5 [M+H + ],420.4106；found,420.4108.。
EXAMPLE 7 Synthesis of the object Compound (7 a-7 f)
Figure BDA0003124653950000161
Synthetic methods refer to the synthesis of 4 a-d.
7.1 Synthesis of (E) -3- [ 2-methoxy-5- (6- (3, 4, 5-trimethoxyphenyl) -2-pyridyl) ] phenyl-N-hydroxyacrylamide (7 a)
White solid (7 a), yield 52%. mp 140-142 ℃. 1 H NMR(400MHz,DMSO-d 6 ): δ10.82(s,1H),9.09(s,1H),8.39(s,1H),8.22(m,1H),7.93(s,3H),7.76(d,J＝16.2 Hz,1H),7.50(s,2H),7.23(m,1H),6.66(d,J＝16.3Hz,1H),3.92(s,9H),3.73(s, 3H). 13 C NMR(150MHz,DMSO-d 6 ):δ158.1,155.1,154.6,152.9,138.4,137.9, 134.2,131.0,128.8,125.8,123.3,118.3,117.8,111.9,103.8,59.9,55.8,55.7. ESI-MS(m/z):437.7(M+H + ).ESI-HRMS(m/z):calcd for C 24 H 25 N 2 O 6 [M+H + ], 437.1707；found,437.1716.
7.2 Synthesis of (E) -4- [ 2-methoxy-5- (6- (3, 4, 5-trimethoxyphenyl) -2-pyridyl) ] phenyl-N-hydroxy-3-butenamide (7 b)
Red solid (7 b), yield 42%. mp 108-110 ℃. 1 H NMR(400MHz,DMSO-d 6 ): δ10.55(s,1H),8.83(s,1H),8.37(s,1H),8.11(dd,J＝8.3,2.0Hz,1H),7.92(s,3H), 7.52(s,2H),7.15(d,J＝7.2Hz,1H),6.79(d,J＝16.2Hz,1H),6.46(m,1H),3.92(s, 6H),3.89(s,3H),3.73(s,3H),2.98(d,J＝5.5Hz,2H). 13 C NMR(150MHz, DMSO-d 6 ):δ166.8,156.8,154.8,154.7,152.9,138.3,137.9,134.1,130.7,126.7, 126.4,125.2,124.8,124.1,117.9,117.6,111.4,103.7,59.9,55.8,55.5,37.2.ESI-MS (m/z):451.7(M+H + ).ESI-HRMS(m/z):calcd for C 25 H 27 N 2 O 6 [M+H + ],451.1864； found,451.1873.
7.3 Synthesis of (E) -3- [ 2-methoxy-5- (6- (2, 4-dimethoxyphenyl) -2-pyridyl) ] phenyl-N-hydroxyacrylamide (7 c)
Red solid (7 c), yield 66%. mp 144-146 ℃. 1 H NMR(400MHz,DMSO-d 6 ): δ10.78(s,1H),9.06(s,1H),8.30(s,1H),8.13(s,1H),7.89(d,J＝7.7Hz,1H),7.81 (s,1H),7.74(d,J＝8.0Hz,2H),7.19(d,J＝6.9Hz,1H),6.70(s,2H),6.65(s,1H), 5.75(s,1H),3.92(s,3H),3.85(s,3H),3.83(s,3H). 13 C NMR(150MHz,DMSO-d 6 ): δ160.9,158.0,154.6,154.4,136.7,131.5,131.4,128.8,125.8,123.2,122.3,120.9, 119.7,116.9,111.8,105.6,98.6,55.7,55.2,54.7.ESI-MS(m/z):407.7(M+H + ). ESI-HRMS(m/z):calcd for C 23 H 23 N 2 O 5 [M+H + ],407.1601；found,407.1612.
7.4 Synthesis of (E) -4- [ 2-methoxy-5- (6- (2, 4-dimethoxyphenyl) -2-pyridyl) ] phenyl-N-hydroxy-3-butenamide (7 d)
Yellow solid (7 d), yield 56%. mp 124-126 ℃. 1 H NMR(400MHz,DMSO-d 6 ): δ8.20(s,1H),8.04(d,J＝8.2Hz,1H),7.89(d,J＝8.4Hz,1H),7.82-7.79(m,2H), 7.71-7.74(m,1H),7.12(d,J＝8.4Hz,1H),6.76(d,J＝16.3Hz,1H),6.71(m,2H), 6.43(dt,J＝16.3,7.8Hz,1H),3.86(s,3H),3.84(s,3H),3.82(s,3H),3.22(d,J＝7.8 Hz,2H). 13 C NMR(150MHz,DMSO-d 6 ):δ172.6,160.9,157.9,156.7,154.9,154.3, 136.7,131.4,131.3,126.8,125.2,124.4,122.1,121.1,116.9,111.3,105.5,98.6,55.6, 55.5,55.2,38.3.ESI-MS(m/z):421.7(M+H + ).ESI-HRMS(m/z):calcd for C 24 H 25 N 2 O 5 [M+H + ],421.1758；found,421.1762.
7.5 Synthesis of (E) -3- [3- (6- (3, 4, 5-trimethoxyphenyl) -2-pyridyl) ] phenyl-N-hydroxyacrylamide (7E)
Red solid (7 e), yield 56%. mp 101-103 ℃. 1 H NMR(400MHz,DMSO-d 6 ): δ8.44(s,1H),8.26(d,J＝9.1Hz,1H),8.06-7.94(m,2H),7.74(d,J＝9.11Hz,1H), 7.66-7.54(m,4H),7.52(s,2H),6.70(d,J＝16.2Hz,1H),3.92(s,6H),3.73(s,3H). 13 C NMR(150MHz,CDCl 3 ):δ155.4,154.8,153.0,139.1,138.4,138.1,135.2,134.1, 129.3,127.9,127.5,125.4,119.1,118.7,103.9,59.9,55.8.ESI-MS(m/z):407.4 (M+H + ).ESI-HRMS(m/z):calcd for C 23 H 23 N 2 O 5 [M+H + ],407.4104；found, 407.1308.
7.6 Synthesis of (E) -3- [4- (6- (3, 4, 5-trimethoxyphenyl) -2-pyridyl) ] phenyl-N-hydroxyacrylamide (7 f)
Red solid (7 f), yield 46%. mp 104-106 ℃. 1 H NMR(400MHz,DMSO-d 6 ): δ12.36(s,1H),8.21(d,J＝8.4Hz,1H),7.93(s,2H),7.80(d,J＝8.8Hz,1H),7.61 (d,J＝16.7Hz,1H),7.45(s,3H),7.35(s,1H),7.21(s,1H),7.93-6.88(m,1H),6.57 (d,J＝16.8Hz,1H),3.86(s,6H),3.68(s,3H). 13 C NMR(150MHz,CDCl 3 ):δ167.4, 155.4,154.4,153.0,143.2,142.2,139.9,138.5,138.1,134.7,134.0,132.0,128.6, 126.8,125.7,119.6,119.2,118.8,103.9,59.9,55.8.ESI-MS(m/z):407.4(M+H + ). ESI-HRMS(m/z):calcd for C 23 H 23 N 2 O 5 [M+H + ],407.4302；found,407.4306.。
EXAMPLE 8 Synthesis of (E) -3- [ 2-methoxy-5- (6- (3, 4, 5-trimethoxyphenyl) -2-pyridyl) ] phenylacrylic acid (8 a)
Figure BDA0003124653950000181
A25 mL eggplant-shaped bottle was charged with the starting material (0.98 mmol), dissolved in methanol (3 mL), and then slowly dropped with an aqueous solution of sodium hydroxide (1M, 1.9mL). Heating and refluxing for reaction, adding water after the raw materials completely disappear, adjusting the pH to 6 with acetic acid, extracting with ethyl acetate for three times, combining organic phases, washing with saturated salt water for one time, and drying with anhydrous sodium sulfate. Filtration, concentration by rotary evaporation and silica gel column chromatography (PE/EA 2. Mp166-168℃. 1 H NMR(400MHz,DMSO-d 6 ): δ8.48(d,J＝2.0Hz,1H),8.28(dd,J＝8.8,2.0Hz,1H),8.00(m,1H),7.92(s,2H), 7.79(d,J＝16.0Hz,1H),7.52(s,2H),7.23(d,J＝8.8Hz,1H),6.71(d,J＝16.1Hz, 1H),3.94(s,3H),3.92(s,6H),3.74(s,3H). 13 C NMR(150MHz,DMSO-d 6 ):δ 158.03,154.87,154.45,152.97,138.35,137.92,134.13,130.92,128.90,125.64, 123.38,118.08,117.86,111.82,103.76,59.94,55.76,55.67.ESI-MS(m/z):422.4 (M+H + ).ESI-HRMS(m/z):calcd for C 24 H 23 NO 6 [M+H + ],422.1598；found, 422.1602.。
Example 9 in vitro tumor cell proliferation inhibitory Activity assay
Taking tumor cells of logarithmic growth phase, treating, inoculating into 96-well plate, and removing CO at 37 deg.C and 5% 2 Cultured under the conditions of (1) for 24 hours. Test compounds were added at 6 gradient concentrations and CA-4 was used as a positive control. And (3) continuing to culture for 48 hours under the same condition, adding MTT, culturing for 4 hours, discarding supernatant containing MTT, adding DMSO into each hole, shaking to dissolve purple crystals, measuring an OD value at 490nm or 540nm on an enzyme labeling instrument, and calculating the inhibition rate. Median Inhibitory Concentration (IC) of Compounds 50 Values) were calculated from the inhibition rates of 6 concentrations, three duplicate wells were set for each concentration gradient, and the assay was repeated three times, with the activity results shown in tables 1 and 2.
TABLE 1 inhibitory Activity of Compounds on tumor cell proliferation (IC) 50 /μM)
Figure BDA0003124653950000191
Figure BDA0003124653950000201
Figure BDA0003124653950000211
Note that: a anti-swellingTumor activity was determined by MTT method, and data were all mean values of three measurements; b BE- (2) -C is a human neuroblastoma cell strain; c a549 is a human lung cancer cell strain; d u87MG is a human glioblastoma cell strain; e HCT-116 is a human colon cancer cell line.
TABLE 2 inhibitory Activity of Compound 7a on tumor cell proliferation (IC) 50 /μM)
Figure BDA0003124653950000212
And (3) annotation: a the antitumor activity is determined by an MTT method, and the data are average values of three measurements; b HeLa is a human cervical cancer cell line; c a2780 is a human ovarian cancer cell strain; d MDA-MB-231 is a human breast cancer cell line; e HUH-7 is a human hepatoma cell line; f SKOV3 is a human ovarian cancer cell line; g MCF-7 is a human breast cancer cell line; h MDA-MB-468 is a human breast cancer cell line.
Example 10 in vitro tubulin self-Assembly experiment
Preferred compound 7a was tested for inhibition of microtubule aggregation in vitro by the nephelometry method and the test kit was purchased from cytosketon, usa. The procedure was as follows, pH =6.6 microtubule aggregation system (0.1M PIPES, 10mM MgCl) 2 1mM GTP, 1mM EGTA and 3.4M glycerol) were pre-incubated on ice in advance, different concentrations of test compound 7a were added, and the Colchicine-treated group was set as a positive control and the DMSO (4%, v/v) -treated group was set as a negative control. After tubulin (10 mM) was added to the above system, it was immediately transferred, and the aggregation reaction was carried out at 37 ℃ with keeping the temperature constant, and absorbance was measured at 340nm with a spectrophotometer (Synergy H4 Hybrid) every 1 minute for 30 minutes, and then a graph of absorbance was plotted (as shown in FIG. 1). The results show that Compound 7a is capable of significantly inhibiting microtubule aggregation, its IC 50 At 2.4. Mu.M (as shown in Table 3).
TABLE 3 Compound 7a in vitro inhibition of microtubule self-assembly assay
Figure BDA0003124653950000221
Example 11 in vitro HDAC inhibitory Activity assay
The inhibitory activity of the compounds on HDACs was tested by elisa, and all enzymatic reactions were performed at 37 ℃ for 30 min. Compounds were diluted to different concentration ranges with 5% DMSO, 5 microliters of compound solution was added to 50 microliters of pH =8.0 and contained 25mM Tris, 1mM MgCl 2 0.1mg/ml BSA, 137mM NaCl, 2.7mM KCl, HDAC and their substrates. After the enzymatic reaction has ended, the fluorescence intensity is measured at excitation at 350-360nm and emission wavelength at 450-460nm in a SpectraMax M5 microtiter plate reader. Finally, using Prism GraphPad software to perform non-linear regression calculation by fitting after normalization to obtain IC of the tested compound 50 The value is obtained. The results are shown in Table 4, where both 7a and 7c were able to significantly inhibit HDAC8 activity, its IC 50 The values were 0.117 μ M and 0.482 μ M, respectively, while both had insignificant HDAC1 and HDAC6 inhibitory activity, with preferred compound 7a selectivity to HDAC1 and HDAC6 of 50-fold and 42-fold, respectively, indicating that 7a is a selective HDAC8 inhibitor.
TABLE 4 inhibitory Activity of Compounds on HDAC1/6/8 (IC) 50 /μM)
Figure BDA0003124653950000222
Note that: a IC 50 are all averages of three measurements; b SAHA is a non-selective HDACs inhibitor; c PCI-34051 is a selective HDAC8 inhibitor; NT = not tested.
Example 12 HDAC-related protein expression assay
Taking BE- (2) -C cells in logarithmic growth phase, treating according to 2 × 10 5 Number of cells/well was seeded in 6-well plates, at 37 ℃ C. And 5% CO 2 And culturing in an incubator with saturated humidity for 24 hours, and adding compound 7a with gradient concentration to treat tumor cells (simultaneously arrangingDMSO treated group was negative control), collected after 24 hours and lysed with lysate. Heating and denaturing a protein sample, loading the protein sample on polyacrylamide gel, carrying out SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) separation, carrying out wet membrane transfer, sealing, sequentially carrying out primary antibody reaction and secondary antibody reaction, and exposing and developing. As shown in fig. 2, the compound 7a can significantly promote the acetylation of the HDAC8 substrate protein SMC3, but has no significant effect on the acetylation of the HDAC6 substrate protein α -tubulin and the HDAC1 substrate protein histone H3, indicating that the compound 7a can selectively inhibit HDAC8.
Example 13 in vitro cell cycle arrest assay
Taking BE- (2) -C cells in logarithmic growth phase, treating according to 2X 10 5 Number of cells/well was seeded in 6-well plates, at 37 ℃ C. And 5% CO 2 And culturing for 12 hours in an incubator with saturated humidity, replacing fresh culture solution after the cells adhere to the wall, treating the cells for 24 hours by using the compound 7a with different concentrations, and setting a DMSO treatment group as negative control. Discarding supernatant, collecting adherent cells, washing with PBS twice, fixing with 75% ethanol at-20 deg.C overnight, staining with PI, and testing with flow cytometer to show that compound 7a can obviously block tumor cell cycle in G 2 the/M phase (as shown in FIG. 3).
Example 14 in vitro cell cycle-related protein assay
Taking BE- (2) -C cells in logarithmic growth phase, treating according to 2 × 10 5 Number of cells/well was seeded in 6-well plates, at 37 ℃ C. And 5% CO 2 And culturing in an incubator with saturated humidity for 24 hours, adding a compound 7a with gradient concentration to treat the tumor cells (setting a DMSO treatment group as a negative control), and collecting and lysing the cells by using a lysate after 24 hours. Heating and denaturing a protein sample, loading the protein sample on polyacrylamide gel, carrying out SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) separation, carrying out wet membrane transfer, sealing, sequentially carrying out primary antibody reaction and secondary antibody reaction, and exposing and developing. The results are shown in FIG. 4, and the compound 7a can obviously promote the expression of mitotic checkpoint protein Bubr-1, phosphorylated Histone P-Histone 3 and cyclin B1.
Example 15 in vitro apoptosis Induction assay
Taking BE- (2) -C cells in logarithmic growth phase, treating according to 2 × 10 5 Number of cells/well was inoculated in 6-well plates, at 37 ℃ and 5% 2 And incubation in an incubator at saturated humidity for 24 hours, adding a gradient of compound 7a, and setting the DMSO-treated group as a negative control. After culturing for 48 hours, collecting supernatant cells and adherent cells, carrying out double staining by PI and Annexin V, and detecting by using a flow cytometer. The results are shown in FIG. 5, where Compound 7a induces apoptosis in a concentration-dependent manner.
Example 16 detection of apoptosis-related proteins in vitro
Taking BE- (2) -C cells in logarithmic growth phase, treating according to 2 × 10 5 Number of cells/well was seeded in 6-well plates, at 37 ℃ C. And 5% CO 2 And incubation in an incubator at saturated humidity for 24 hours, adding a gradient of compound 7a, and setting the DMSO-treated group as a negative control. After 48 hours the cells were collected and lysed with lysis buffer. Loading on polyacrylamide gel, performing SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) separation, performing wet membrane transfer, sealing, sequentially performing primary antibody reaction and secondary antibody reaction, and exposing and developing color. As shown in FIG. 6, the compound 7a can significantly promote the expression of the tumor suppressor gene p53, the pro-apoptotic protein Bax and the sheared DNA repair enzyme PAPR-1.
Example 17 colony formation inhibition experiment
Taking logarithmic growth phase BE- (2) -C cells, treating, inoculating into 6-well plate, inoculating 1500 cells per well, and making 5% CO at 37 ℃% 2 And culturing for 24 hours under the condition of humidity saturation, adding the compound 7a with different concentrations to treat the cells for 48 hours after the cells adhere to the wall, and setting a DMSO treatment group as a negative control. After replacing the fresh culture medium and continuing to culture for two weeks, the supernatant was discarded, the cells were washed twice with PBS, fixed with anhydrous methanol for 30 minutes, stained with crystal violet dye for 1 hour, washed off the staining solution, and sufficiently dried, and then the number of colonies formed by more than 50 cells was counted under a microscope, showing that compound 7a was able to significantly inhibit the formation of HeLa cell colonies (as shown in fig. 7).

Claims (5)

1.2, 6-diaryl pyridine HDAC/Tubulin bifunctional inhibitors or pharmaceutically acceptable salts thereof, characterized by having the structure of formula I,
Figure FDA0003124653940000011
wherein R is 1 And R 2 Is selected from hydrogen atom, alkyl, substituted alkyl, alkoxy, halogen atom, amino, hydroxyl, acyloxy, methoxy formyl, allyloxy, propargyloxy, sulfonyloxy, alkylamino, acylamino, sulfonylamino or combination of 2-3 of the same or different groups; x is selected from carbon, nitrogen, oxygen, sulfur, ester group, amide group; l is taken from
Figure FDA0003124653940000012
Wherein n is selected from 0, 1, 2, 3,4,5, 6, 7; or, L is taken from
Figure FDA0003124653940000013
Figure FDA0003124653940000014
Figure FDA0003124653940000015
Alicyclic and aromatic (hetero) rings; r 3 Is taken from
Figure FDA0003124653940000016
Figure FDA0003124653940000017
2. The 2, 6-diaryl pyridine HDAC/Tubulin bifunctional inhibitor as claimed in claim 1, wherein said 2, 6-diaryl pyridine compound is:
Figure FDA0003124653940000018
Figure FDA0003124653940000021
3. the 2, 6-diaryl pyridine HDAC/Tubulin bifunctional inhibitor or its pharmaceutical salt as claimed in claim 1, wherein said pharmaceutical salt is "pharmaceutically acceptable salt", and is formed with malic acid, lactic acid, camphorsulfonic acid, citric acid, fumaric acid, oxalic acid organic acid, and phosphoric acid, hydrohalic acid, sulfuric acid, nitric acid inorganic acid.
4. Use of the 2, 6-diarylpyridine HDAC/Tubulin bifunctional inhibitor according to any one of claims 1-3, or a pharmaceutical salt thereof, for the preparation of a medicament for the prevention and treatment of a tumor-related disease, such as neuroblastoma, interstitial sarcoma, choriocarcinoma, malignant hydatidiform mole, thyroid carcinoma, squamous cell carcinoma of the head and neck, cervical carcinoma, prostate carcinoma, renal carcinoma, bladder carcinoma, ovarian carcinoma, breast carcinoma, colorectal carcinoma, pancreatic carcinoma, esophageal carcinoma, osteosarcoma, gastric carcinoma, lung carcinoma, liver carcinoma, melanoma, lymphoma, brain glioma, nasopharyngeal carcinoma, neuroendocrine carcinoma, undifferentiated carcinoma, malignant teratoma, and benign tumor.
5. A combination drug for the prevention and treatment of tumor-related diseases comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein the tumor-related diseases are neuroblastoma, thyroid cancer, lung cancer, liver cancer, melanoma, lymphoma, prostate cancer, head and neck squamous cell carcinoma, cervical cancer, ovarian cancer, breast cancer, colorectal cancer, pancreatic cancer, esophageal cancer, osteosarcoma, renal cancer, undifferentiated carcinoma, interstitial sarcoma, choriocarcinoma, gastric cancer, bladder cancer, brain glioma, nasopharyngeal cancer, neuroendocrine cancer, malignant hydatidiform mole, malignant teratoma, and benign tumor.
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Citations (2)

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CN104311474A (en) * 2014-09-30 2015-01-28 河南师范大学 Synthesis method of 3-alkynyl pyridine compound
US20170044103A1 (en) * 2014-03-31 2017-02-16 Guangdi Wang Anti-vasculature and anti-tubulin combretastatin analogs for treatment of cancer

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Publication number Priority date Publication date Assignee Title
US20170044103A1 (en) * 2014-03-31 2017-02-16 Guangdi Wang Anti-vasculature and anti-tubulin combretastatin analogs for treatment of cancer
CN104311474A (en) * 2014-09-30 2015-01-28 河南师范大学 Synthesis method of 3-alkynyl pyridine compound

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