CN115028612A - Flavonoid compounds, preparation and application in preparation of antidiabetic drugs - Google Patents
Flavonoid compounds, preparation and application in preparation of antidiabetic drugs Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention belongs to the technical field of biological medicines, and discloses a flavonoid compound, a preparation method thereof and application thereof in preparing antidiabetic medicines. The structural formula of the flavonoid compound is shown as the following formula (I):
wherein R is substituted I/unsubstituted C1-C10 linear/branched/cyclic alkyl, substituted I/unsubstituted phenyl, substituted I/unsubstituted benzyl or substituted I/unsubstituted ethylcarboxyl. On the basis of not causing side effects caused by PPAR gamma complete agonists such as adipocyte differentiation, weight gain, hepatotoxicity and the like, the flavonoid compound can obviously improve the blood sugar level, does not cause side effects similar to thiazolidinedione drugs, and can be applied to the preparation of antidiabetic drugs or lead compounds thereof; and can be used as PPAR gamma selective regulationThe agent exerts an anti-type II diabetes effect; can also be used for preparing medicaments for treating and/or preventing diseases modulated by PPAR gamma nuclear receptors.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to flavonoid compounds, a preparation method thereof and application thereof in preparing antidiabetic medicines.
Background
Diabetes is a chronic disease, and the number of chronic patients such as diabetes is increasing with the aging population and the change of living habits. According to the IDF data, the number of adult patients with diabetes mellitus is up to 5.37 hundred million worldwide in 2021, which accounts for about 10.5% of the global population. Of diabetic patients, type II diabetes accounts for about 90% of the total population, and its main pathological feature is insulin resistance in the liver and peripheral tissues, and thus, improvement of insulin resistance is the key to the treatment of type II diabetes.
Peroxisome proliferator activated receptor gamma (PPAR γ) is an important cell differentiation transcription factor, and is expressed in adipose tissue, vascular smooth muscle tissue and cardiac muscle tissue of mammals. At present, medicaments such as thiazolidinedione PPAR gamma complete agonists, such as Rosiglitazone (Rosiglitazone), Pioglitazone (Pioglitazone) and the like are utilized, and the insulin sensitivity is improved through a locking mechanism participated by AF-2(Activation Function 2), so that the aim of efficiently reducing the blood sugar is fulfilled; however, these agonists cause complete PPAR γ agonism, and cause side effects such as obesity and cardiac hypertrophy, thereby greatly limiting the clinical application of these drugs. Therefore, there is a need to develop a novel compound for preparing antidiabetic drugs, which has the dual characteristics of high efficiency for lowering blood sugar and low side effect.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention mainly aims to provide a flavonoid compound.
The invention also aims to provide a preparation method of the flavonoid compound.
The invention also aims to provide the application of the flavonoid compound in preparing antidiabetic drugs or lead compounds thereof.
The flavonoid compound has the effect of remarkably reducing blood sugar, does not cause weight increase and side effects similar to thiazolidinedione drugs, and can be applied to the preparation of antidiabetic drugs.
The flavonoid compound can be used as a PPAR gamma selective regulator to play a role in resisting type II diabetes, can obviously improve the blood sugar level on the basis of not causing side effects caused by PPAR gamma complete agonists such as adipocyte differentiation, weight gain, hepatotoxicity and the like, and is a potential drug lead compound with an efficient and safe blood sugar reduction function.
The invention further aims to provide application of the flavonoid compound in preparing a medicament for treating and/or preventing diseases regulated by a PPAR gamma nuclear receptor.
The flavonoid compound has stronger binding capacity with PPAR gamma and IC thereof 50 And k i The content of the flavonoid compounds is respectively as low as 1.72 mu M and 0.62 mu M, and the flavonoid compounds only weakly activate PPAR gamma and induce adipocyte differentiation, so that the flavonoid compounds are expected to be developed into PPAR gamma selective regulators serving as PPAR gamma small molecule regulators.
The purpose of the invention is realized by the following scheme:
a flavonoid compound has a structural formula shown as the following formula (I):
wherein R is substituted I/unsubstituted C1-C10 linear/branched/cyclic alkyl, substituted I/unsubstituted phenyl, substituted I/unsubstituted benzyl or substituted I/unsubstituted ethylcarboxyl.
Furthermore, the structural formula of the flavonoid compound is shown in formula (I), wherein R is methyl, ethyl, substituted I/unsubstituted C3-C10 linear chain/branched chain/cyclic alkyl, substituted I/unsubstituted phenyl, substituted I/unsubstituted benzyl or substituted I/unsubstituted ethylcarboxyl.
In some embodiments of the present invention, the substituent I is the same or different and each indicates that one or more hydrogen atoms in the group can be substituted by halogen atom, C1-C10 linear/branched/cyclic alkyl group, C1-C10 haloalkyl group, substituted II/unsubstituted C2-C10 alkenyl group, substituted II/unsubstituted C2-C10 alkynyl group, substituted II/unsubstituted C1-C10 alkoxy group, hydroxyl group, substituted II/unsubstituted C1-C10 alkylhydroxyl group, carboxyl group, cyano group, nitro group, amino group, substituted II/unsubstituted C3-C20 heteroalkyl group containing one or more of N, O and S, and the like.
Furthermore, the same or different substituents I mean that one or more hydrogen atoms in the groups can be substituted by-F, -Cl, -Br, -I, methyl, ethyl, C3-C10 linear/branched/cyclic alkyl, halogenated methyl, methoxy, hydroxyl, cyano, substituted II/unsubstituted hydroxymethyl, substituted II/unsubstituted C3-C20 heteroalkyl containing one or more of N, O and S, etc.;
the substituted II/unsubstituted C3-C20 heteroalkyl containing one or more of N, O and S may include- (CH) 2 ) 2 SCH 3 、-(CH 2 ) 4 NH(CO)OCH 2 C 6 H 5 And the like.
Further, the substituents I are the same or different and mean that one or more hydrogen atoms in the groups may be replaced by-F, -Cl, -Br, -I, methyl, ethyl, C3-C10 linear/branched/cyclic alkyl, halomethyl, methoxy, hydroxy, cyano, -CH 2 OH、-CH(CH 3 )OH、-(CH 2 ) 2 SCH 3 、-(CH 2 ) 4 NH(CO)OCH 2 C 6 H 5 And the like.
The substituent II is the same or different, and one or more hydrogen atoms in the groups can be substituted by-F, -Cl, -Br, -I, oxygen atoms, methyl, ethyl, propyl, butyl, alkenyl, alkynyl, phenyl, aryl, hydroxyl, amino, carbonyl, carboxyl, ester, methoxyl, cyano, nitro and the like.
The invention also provides a preparation method of the flavonoid compound (YGT), and the flavonoid compound is obtained by reacting 7-O-carboxyalkylated chrysin derivative with amine or amino acid derivative.
The amino acid derivative can be amino acid methyl ester hydrochloride; and hydrolyzing to obtain the target product after reaction.
The structural formula of the 7-O-carboxyalkylated chrysin derivative is shown as follows:
in some embodiments of the invention, the reaction may be carried out under an EDCI/DMAP catalytic system.
The specific reaction equation is as follows:
the invention also provides application of the flavonoid compound in preparation of antidiabetic drugs or lead compounds thereof. The flavonoid compound has the effect of remarkably reducing blood sugar, does not cause weight increase and side effects similar to thiazolidinedione drugs, and can be applied to the preparation of antidiabetic drugs.
The flavonoid compound can be used as a PPAR gamma selective regulator to play a role in resisting type II diabetes, can obviously improve the blood sugar level on the basis of not causing side effects caused by PPAR gamma complete agonists such as adipocyte differentiation, weight gain, hepatotoxicity and the like, and is a potential medicinal lead compound with high-efficiency and safe hypoglycemic effects.
The invention also provides application of the flavonoid compound in preparing a medicament for treating and/or preventing diseases regulated by PPAR gamma nuclear receptors. The flavonoid compound has strong binding capacity with PPAR gamma and IC thereof 50 And k i The content of the flavonoid compounds is respectively as low as 1.72 mu M and 0.62 mu M, and the flavonoid compounds only weakly activate PPAR gamma and induce adipocyte differentiation, so that the flavonoid compounds are expected to be developed into a novel PPAR gamma selective regulator serving as a PPAR gamma small molecular regulator to play the roles of reducing blood sugar and the like, and can not cause the side effect similar to thiazolidinediones.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
Fig. 1 is a competitive binding curve of flavonoids according to the present invention with PPAR γ.
FIG. 2 is a graph showing the luciferase activity of the flavonoid compound of the present invention.
FIG. 3 is a graph showing the oil red O staining pattern of the flavonoid compounds of the present invention.
FIG. 4 shows the expression patterns of the activated lipogenic gene and the insulin sensitivity-related gene of the flavonoid compounds of the present invention.
FIG. 5 is a graph showing the effect of a mouse hypoglycemic experiment.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto. The materials referred to in the following examples are commercially available without specific reference. The method is a conventional method unless otherwise specified.
Example 1: preparation of flavonoid compounds
A flavonoid compound (YGT) has a structural formula shown as the following formula (I):
wherein R is substituted I/unsubstituted C1-C10 linear/branched/cyclic alkyl, substituted I/unsubstituted phenyl, substituted I/unsubstituted benzyl or substituted I/unsubstituted ethylcarboxyl.
The preparation method is specifically to react 7-O-carboxyalkylated chrysin derivatives with amine or amino acid derivatives. The amino acid derivative can be amino acid methyl ester hydrochloride, and a target product is obtained by hydrolysis after reaction.
The structural formula of the 7-O-carboxyalkylated chrysin derivative is shown as follows:
the specific reaction equation is as follows:
the 7-O-carboxyalkylated chrysin derivative can be prepared by referring to [ J ] synthetic chemistry 2015, (2) 93-97, and comprises the following specific steps:
(1) mixing a molar equivalent of 1: 1.1, stirring and reacting chrysin and ethyl bromoacetate at room temperature under the alkaline condition of potassium carbonate and the environment of N, N-Dimethylformamide (DMF) solvent to obtain corresponding ether compounds. The completion of the reaction can be monitored by thin layer chromatography, PE/EA 3/1. After the reaction is finished, water is added to separate out the product, and the solid product is obtained after separation, washing and drying.
1 H NMR(400MHz,DMSO-d 6 )δ8.08(d,J＝7.2Hz,2H),7.65-7.52(m,3H),7.03(s,1H),6.83(s,1H),6.42(s,1H),4.94(s,2H),4.20(s,2H),1.23(t,J＝7.0Hz,3H).
(2) Adding the ether compound prepared in the step (1) into a mixed solvent of water and methanol (1:1, v/v), stirring and reacting at room temperature under an alkaline condition (such as NaOH), and hydrolyzing to obtain the 7-O-carboxyalkylated chrysin derivative. The completion of the reaction can be monitored by thin layer chromatography, PE/EA 3/1. After the reaction is finished, acid (such as 2M hydrochloric acid solution) can be added to adjust the pH value of the system to 5, so that the product is separated out, separated, washed by water and dried to obtain a solid product.
1 H NMR(400MHz,DMSO-d 6 )δ8.11(d,J＝7.2Hz,2H),7.60-7.53(m,3H),7.07(s,1H),6.84(s,1H),6.41(s,1H),4.86(s,2H). 13 C NMR(100MHz,DMSO-d 6 )δ182.1,169.4,163.8,163.6,161.1,157.2,132.2,130.5,129.1,126.5,105.4,105.2,98.6,93.5,64.9.HRMS(ESI)m/z:[M-H] + :311.0561；Found:311.0560.
Preparation of (di) flavonoid YGT-1
Adding 1.2 molar equivalents of aniline into DMF solvent containing 4-dimethylaminopyridine (DMAP, 1.5eq)/1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI, 1.5eq) catalytic system, stirring uniformly, adding 1 molar equivalent of 7-O-carboxyalkylated chrysin derivative, and reacting at room temperature for 12-24h to obtain the compound YGT-1.
Completion of the reaction can be monitored by thin layer chromatography. After the reaction is finished, the pH value of the system can be adjusted to 5 by adding acid (such as 0.5M hydrochloric acid solution), ethyl acetate is used for extraction, and the target product is obtained by washing and drying the organic phase and purifying the organic phase by thin layer chromatography.
(III) preparation methods of other flavonoids YGT-2 to YGT-49 are the same as above, and different amine or amino acid derivatives are used to react with 7-O-carboxyalkylated chrysin derivatives, and specific reagents are shown in Table 1.
Wherein, when the amino acid derivative is adopted to react with the 7-O-carboxyalkylated chrysin derivative to prepare the compounds YGT-18 to YGT-25, a crude product can be obtained after the reaction is finished; adding the crude product into a mixed solvent of water containing alkali (such as sodium hydroxide) and methanol (1:1, v/v), reacting at room temperature, and hydrolyzing to obtain a target product; after the hydrolysis reaction is finished, acid (such as 0.5M hydrochloric acid solution) can be added to adjust the pH of the system to 5, so that the product is separated out, separated, washed by water and dried to obtain a solid product.
TABLE 1
The structural formulae and the characterization data of the compounds YGT-1 to YGT-49 are as follows:
YGT-1： 1 H NMR(400MHz,DMSO-d 6 )δ10.09(s,1H),8.09(d,J＝6.9Hz,2H),7.67-7.56(m,5H),7.33(t,J＝7.4Hz,2H),7.09(t,J＝6.9Hz,1H),7.03(s,1H),6.88(s,1H),6.51(s,1H),4.87(s,2H). 13 CNMR(100MHz,DMSO-d 6 )δ181.9,165.5,163.8,163.6,161.1,157.1,138.2,132.0,130.5,129.0,128.6,126.4,123.7,119.6,105.4,105.2,98.6,93.6,67.3.HRMS(ESI)m/z:[M+H] + :388.1179；Found:388.1177.
YGT-2： 1 H NMR(400MHz,DMSO-d 6 )δ10.02(s,1H),8.08(d,J＝7.7Hz,2H),7.66-7.52(m,5H),7.34(d,J＝8.5Hz,2H),7.03(s,1H),6.86(s,1H),6.50(s,1H),4.85(s,2H),1.26(s,9H). 13 C NMR(100MHz,DMSO-d 6 )δ181.9,165.3,163.8,163.6,161.1,157.1,146.1,135.6,132.0,130.5,129.0,126.4,125.2,119.4,105.4,105.2,98.6,93.6,67.3,33.9,31.1.HRMS(ESI)m/z:[M+H] + :444.1805；Found:444.1802.
YGT-3： 1 H NMR(400MHz,DMSO-d 6 )δ10.06(s,1H),8.10(d,J＝7.7Hz,2H),7.65-7.57(m,3H),7.54(d,J＝8.1Hz,2H),7.15(d,J＝8.0Hz,2H),7.05(s,1H),6.89(s,1H),6.52(s,1H),4.87(s,2H),2.28(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ182.0,165.3,163.8,163.6,161.2,157.2,135.7,132.7,132.1,130.5,129.1,126.4,119.7,105.4,105.2,98.7,93.6,67.3,59.6,20.4.HRMS(ESI)m/z:[M+H] + :402.1336；Found:402.1337.
YGT-4： 1 H NMR(400MHz,DMSO-d 6 )δ10.02(s,1H),8.09(d,J＝7.5Hz,2H),7.67-7.58(m,3H),7.55(d,J＝8.7Hz,2H),7.03(s,1H),6.90(d,J＝8.9Hz,2H),6.88(s,1H),6.50(s,1H),4.84(s,2H),3.73(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ182.0,165.1,163.8,163.5,161.2,157.2,155.6,132.1,131.3,130.5,129.1,126.4,121.3,113.8,105.4,105.3,98.7,93.6,67.3,55.1.HRMS(ESI)m/z:[M+H] + :418.1285；Found:418.1280.
YGT-5： 1 H NMR(400MHz,DMSO-d 6 )δ10.03(s,1H),8.09(d,J＝7.7Hz,2H),7.64-7.51(m,5H),7.19(d,J＝8.1Hz,2H),7.03(s,1H),6.87(s,1H),6.50(s,1H),4.85(s,2H),2.91-2.79(m,1H),1.18(s,3H),1.17(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ182.0,165.3,163.8,163.6,161.1,157.2,143.8,135.9,132.0,130.5,129.1,126.4,126.3,119.7,105.4,105.2,98.7,93.6,67.3,32.7,23.8.HRMS(ESI)m/z:[M+H] + :430.1649；Found:430.1645.
YGT-6： 1 H NMR(400MHz,DMSO-d 6 )δ10.49(s,1H),8.09(d,J＝7.4Hz,2H),7.67-7.56(m,3H),7.40(d,J＝8.7Hz,2H),7.04(s,1H),6.94(t,J＝9.1Hz,1H),6.89(s,1H),6.51(s,1H),4.91(s,2H). 13 C NMR(100MHz,DMSO-d 6 )δ182.0,166.4,163.6,163.6,161.1,157.2,132.1,130.5,129.1,126.4,105.4,105.3,102.6,102.3,98.8,98.7,93.6,67.2,59.6. 19 F NMR(376MHz,DMSO-d 6 )δ-109.00.HRMS(ESI)m/z:[M+H] + :424.0991；Found:424.0985.
YGT-7： 1 H NMR(400MHz,DMSO-d6)δ10.69(s,1H),8.14(s,1H),8.08(d,J＝7.2Hz,2H),7.90(d,J＝7.7Hz,1H),7.64-7.53(m,4H),7.43(d,J＝7.6Hz,1H),7.04(s,1H),6.89(s,1H),6.50(s,1H),4.94(s,2H). 13 C NMR(100MHz,DMSO-d6)δ182.1,166.4,163.8,163.6,161.3,157.3,139.2,132.2,130.6,130.1,129.2,126.5,123.2,120.1,115.7,105.5,98.8,93.6,67.1. 19 F NMR(376MHz,DMSO-d 6 )δ-61.26.HRMS(ESI)m/z:[M+H] + :524.0927；Found:524.0921.
YGT-8： 1 H NMR(400MHz,DMSO-d6)δ9.59(s,1H),8.16–8.01(m,2H),7.67-7.50(m,3H),7.38(d,J＝6.6Hz,1H),7.25-7.05(m,3H),7.03(s,1H),6.86(s,1H),6.48(s,1H),4.88(s,2H),2.18(s,3H). 13 C NMR(100MHz,DMSO-d6)δ182.2,165.8,163.8,163.6,161.3,157.3,135.5,132.3,130.6,130.4,129.3,126.5,126.1,125.8,125.4,105.5,105.4,98.9,93.7,67.3,17.8.HRMS(ESI)m/z:[M+H] + :402.1336；Found:402.1331.
YGT-9： 1 H NMR(400MHz,DMSO-d 6 )δ10.10(s,1H),8.07(d,J＝7.5Hz,2H),7.62-7.52(m,3H),7.34(s,1H),7.29-7.16(m,2H),7.02(s,1H),6.86(s,1H),6.67(d,J＝6.6Hz,1H),6.49(s,1H),4.86(s,2H),3.73(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ182.0,165.6,163.8,163.5,161.1,159.5,157.1,139.4,132.1,130.5,129.5,129.1,126.4,126.1,111.9,109.2,105.4,105.2,98.7,93.6,67.3,54.9.HRMS(ESI)m/z:[M+H] + :418.1285；Found:418.1281.
YGT-10： 1 H NMR(400MHz,DMSO-d 6 )δ10.10(s,1H),8.07(d,J＝7.7Hz,2H),7.67-7.52(m,4H),7.03(s,1H),6.90(d,J＝3.2Hz,2H),6.88-6.84(m,1H),6.47(s,1H),6.24(s,1H),4.85(s,2H),3.70(s,6H). 13 C NMR(100MHz,DMSO-d 6 )δ182.2,165.8,163.9,163.6,161.2,160.5,157.3,140.0,132.3,130.6,129.2,126.5,105.5,105.3,98.8,97.9,95.7,93.7,67.2,55.2,39.5.HRMS(ESI)m/z:[M+H] + :448.1391；Found:448.1385.
YGT-11： 1 H NMR(400MHz,DMSO-d 6 )δ10.58(s,1H),8.13(s,1H),8.09(d,J＝7.6Hz,2H),7.90(d,J＝8.0Hz,1H),7.58(t,J＝7.5Hz,4H),7.44(d,J＝7.7Hz,1H),7.03(s,1H),6.89(s,1H),6.51(s,1H),4.93(s,2H). 13 C NMR(100MHz,DMSO-d 6 )δ181.9,166.2,163.7,163.5,162.2,161.2,157.2,139.1,132.1,130.5,129.9,129.6,129.3,129.1,126.4,123.2,120.0,115.7,105.4,98.7,93.5,67.1. 19 F NMR(376MHz,DMSO-d 6 )δ-61.24.HRMS(ESI)m/z:[M+H] + :456.1503；Found:456.1502.
YGT-12： 1 H NMR(400MHz,DMSO-d 6 )δ10.59(s,1H),8.09(d,J＝7.8Hz,2H),7.87(d,J＝8.3Hz,2H),7.70(d,J＝8.4Hz,2H),7.59(t,J＝9.2Hz,3H),7.04(s,1H),6.89(s,1H),6.51(s,1H),4.94(s,2H). 13 C NMR(100MHz,DMSO-d 6 )δ182.0,166.3,163.7,163.6,161.1,157.2,141.9,132.1,130.5,129.1,126.4,126.0,125.9,125.6,119.5,105.4,105.3,98.7,93.6,67.2. 19 F NMR(376MHz,DMSO-d 6 )δ-60.29.HRMS(ESI)m/z:[M+H] + :456.1503；Found:456.1502.
YGT-13： 1 H NMR(400MHz,DMSO-d 6 )δ10.05(s,1H),8.09(d,J＝7.8Hz,2H),7.64–7.57(m,3H),7.49(s,1H),7.43(d,J＝8.0Hz,1H),7.21(t,J＝7.8Hz,1H),7.04(s,1H),6.92(d,J＝7.4Hz,1H),6.88(s,1H),6.51(s,1H),4.87(s,2H),2.29(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ182.0,165.5,163.8,163.6,161.1,157.2,138.2,137.9,132.1,130.5,129.1,128.5,126.4,124.4,120.1,116.8,105.4,105.2,98.7,93.6,67.3,21.1.HRMS(ESI)m/z:[M+H] + :402.1336；Found:402.1332.
YGT-14： 1 H NMR(400MHz,DMSO-d 6 )δ10.02(s,1H),8.03(d,J＝7.2Hz,2H),7.61-7.51(m,3H),7.32(s,1H),7.16(d,J＝8.5Hz,1H),6.97(s,1H),6.89(d,J＝8.6Hz,1H),6.83(s,1H),6.47(s,1H),4.81(s,2H),3.70(s,6H). 13 C NMR(100MHz,DMSO-d 6 )δ182.2,165.4,163.9,163.7,161.3,157.3,148.6,145.4,132.3,131.9,130.6,129.3,126.6,112.0,111.9,105.5,105.4,104.9,98.9,93.8,67.4,55.8,55.5.HRMS(ESI)m/z:[M+H] + :448.1391；Found:448.1387.
YGT-15： 1 H NMR(400MHz,DMSO-d 6 )δ9.81(s,1H),8.10(d,J＝6.8Hz,2H),7.76-7.70(m,1H),7.66-7.57(m,4H),7.54(d,J＝8.7Hz,1H),7.29-7.22(m,1H),7.06(s,1H),6.90(s,1H),6.52(s,1H),4.94(s,2H). 13 C NMR(100MHz,DMSO-d 6 )δ182.2,169.6,163.9,163.6,161.2,157.3,132.3,130.6,129.2,126.5,115.80,115.76,115.7,115.6,114.8,114.6,105.4,105.2,98.6,93.5,65.1. 19 F NMR(376MHz,DMSO-d 6 )δ-127.84.HRMS(ESI)m/z:[M+H] + :440.0696；Found:440.0695.
YGT-16： 1 H NMR(400MHz,DMSO-d 6 )δ8.08(d,J＝6.8Hz,2H),7.68–7.51(m,4H),7.03(s,1H),6.80(s,1H),6.43(d,J＝11.3Hz,1H),6.39(s,1H),6.16(s,1H),4.83(s,2H). 19 F NMR(376MHz,DMSO-d 6 )δ-57.38～-59.15,-116.36.HRMS(ESI)m/z:[M+H] + :474.0959；Found:474.0961.
YGT-17： 1 H NMR(400MHz,DMSO-d 6 )δ10.18(s,1H),8.12(d,J＝16.6Hz,2H),7.78–7.55(m,5H),7.29–7.13(m,2H),7.05(s,1H),6.89(s,1H),6.52(s,1H),4.88(s,2H). 13 C NMR(100MHz,DMSO-d 6 )δ182.2,165.6,163.9,163.7,161.2,159.5,157.3,157.1,134.7,132.3,130.6,129.2,126.5,121.6,121.5,115.5,115.3,112.9,105.5,105.3,98.8,93.7,67.2,39.5. 19 F NMR(376MHz,DMSO-d 6 )δ-118.60.HRMS(ESI)m/z:[M+H] + :406.1085；Found:406.1080.
YGT-18： 1 H NMR(400MHz,DMSO-d 6 )δ8.52(d,J＝6.3Hz,1H),7.97(d,J＝6.2Hz,2H),7.61–7.45(m,3H),6.90(s,1H),6.70(s,1H),6.36(s,1H),4.66(s,2H),4.41–4.26(m,1H),1.35(d,J＝6.5Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ182.1,174.0,166.9,163.7,163.5,161.2,157.2,132.2,130.6,129.2,126.4,105.4,105.3,98.8,93.6,67.0,47.6,17.2.HRMS(ESI)m/z:[M+H] + :384.1078；Found:384.1078.
YGT-19： 1 H NMR(400MHz,DMSO-d 6 )δ8.47(d,J＝7.9Hz,1H),8.07(d,J＝7.2Hz,2H),7.65–7.54(m,4H),7.02(s,1H),6.77(s,1H),6.43(s,1H),4.73(s,2H),4.47–4.37(m,1H),2.48–2.39(m,1H),2.08–2.03(m,1H),2.01(s,3H),1.26–1.17(m,2H). 13 C NMR(100MHz,DMSO-d 6 )δ182.1,173.0,167.1,163.7,163.6,161.1,157.2,132.2,130.6,129.2,126.4,105.4,105.3,98.9,93.6,67.0,50.7,30.4,29.8,14.5.HRMS(ESI)m/z:[M+H] + :444.1111；Found:444.1111.
YGT-20： 1 H NMR(400MHz,DMSO-d 6 )δ8.49(d,J＝8.2Hz,1H),8.06(d,J＝7.5Hz,2H),7.64–7.53(m,3H),7.01(s,1H),6.75(s,1H),6.40(s,1H),4.77(s,2H),4.31–4.24(m,1H),2.17–2.07(m,1H),0.91(d,J＝7.2Hz,6H). 13 C NMR(100MHz,DMSO-d 6 )δ182.1,171.8,167.3,163.9,163.5,161.2,157.1,132.2,130.6,129.1,126.4,105.4,105.2,98.6,93.6,66.7,57.2,29.9,19.0.HRMS(ESI)m/z:[M+H] + :412.3191；Found:412.3191.
YGT-21： 1 H NMR(400MHz,DMSO-d 6 )δ8.29(d,J＝8.3Hz,1H),8.00(d,J＝7.1Hz,2H),7.60–7.48(m,3H),6.95(s,1H),6.71(s,1H),6.37(s,1H),4.75(s,2H),4.32–4.25(m,1H),1.87(s,1H),1.50–1.39(m,1H),1.29–1.13(m,1H),0.89(d,J＝6.7Hz,3H),0.85(t,J＝7.3Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ182.0,172.8,167.0,163.8,163.5,161.2,157.1,132.1,130.5,129.1,126.4,105.4,105.2,98.7,93.5,66.9,56.2,36.5,24.8,15.6,11.3.HRMS(ESI)m/z:[M+H] + :426.1547；Found:426.1542.
YGT-22： 1 H NMR(400MHz,DMSO-d 6 )δ8.18(d,J＝8.6Hz,1H),7.98(d,J＝7.1Hz,2H),7.60–7.47(m,3H),6.92(s,1H),6.73(s,1H),6.37(s,1H),4.79(s,2H),4.30(d,J＝8.6Hz,1H),4.28–4.18(m,1H),1.11(d,J＝6.0Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ182.1,172.0,167.6,163.7,163.6,161.3,157.2,132.3,130.6,129.2,126.5,105.4,105.3,98.8,93.7,67.0,66.5,57.7,20.7.HRMS(ESI)m/z:[M+H] + :414.1183；Found:414.1183.
YGT-23： 1 H NMR(400MHz,DMSO-d 6 )δ8.43(d,J＝8.0Hz,1H),8.07(d,J＝7.3Hz,2H),7.63-7.53(m,3H),7.03(s,1H),6.77(s,1H),6.43(s,1H),4.71(s,2H),4.36-4.28(m,1H),1.68-1.59(m,2H),1.59-1.50(m,1H),0.87(d,J＝5.6Hz,3H),0.82(d,J＝5.7Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ182.1,173.7,167.0,163.8,162.3,161.1,157.2,132.2,130.6,129.2,126.4,105.4,105.2,98.9,93.6,66.9,50.0,24.3,22.9,21.1.HRMS(ESI)m/z:[M+H] + :426.1547；Found:426.1540.
YGT-24： 1 H NMR(400MHz,DMSO-d 6 )δ8.12(s,1H),8.08(d,J＝7.7Hz,2H),7.65-7.54(m,4H),7.02(s,1H),6.83(s,1H),6.43(s,1H),4.70(s,2H),4.13-4.07(m,1H),3.76-3.70(m,1H),3.62-3.56(m,1H). 13 C NMR(100MHz,DMSO-d 6 )δ182.1,172.3,166.4,163.6,161.2,157.2,132.2,130.5,129.2,126.5,105.4,105.3,98.7,93.7,67.1,61.8,54.8.HRMS(ESI)m/z:[M+H] + :400.1027；Found:400.1025.
YGT-25： 1 H NMR(400MHz,DMSO-d 6 )δ8.08(d,J＝7.2Hz,2H),7.61-7.55(m,3H),7.35-7.28(m,5H),7.03(s,1H),6.80(s,1H),6.42(s,1H),4.97(s,2H),4.69(s,2H),4.16-4.09(m,1H),2.95-2.90(m,2H),1.80-1.70(m,1H),1.70-1.59(m,1H),1.40-1.34(m,2H),1.28-1.19(m,4H). 13 C NMR(100MHz,DMSO-d 6 )δ182.1,173.6,166.3,163.7,163.6,161.2,157.2,156.1,137.3,132.2,130.6,129.2,128.3,127.7,127.3,126.5,105.4,105.3,98.8,93.7,67.1,65.1,52.6,31.2,29.8,29.2,22.6.HRMS(ESI)m/z:[M+H] + :575.2024；Found:575.2020.
YGT-26： 1 H NMR(400MHz,DMSO-d 6 )δ8.21(s,1H),8.06(d,J＝6.6Hz,2H),7.68–7.47(m,3H),7.02(s,1H),6.78(s,1H),6.41(s,1H),4.62(s,2H),3.16–3.05(m,2H),1.58–1.37(m,2H),0.84(t,J＝7.0Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ182.1,166.6,163.7,163.5,161.3,157.2,132.2,130.6,129.2,126.4,105.4,105.3,98.8,93.5,67.2,42.5,22.4,11.4.HRMS(ESI)m/z:[M+H] + :354.1336；Found:354.1333.
YGT-27： 1 H NMR(400MHz,DMSO-d 6 )δ8.18(s,1H),8.07(d,J＝7.2Hz,2H),7.65–7.52(m,3H),7.03(s,1H),6.79(s,1H),6.42(s,1H),4.62(s,2H),3.17–3.10(m,2H),1.46–1.38(m,2H),1.30–1.23(m,2H),0.85(t,J＝7.2Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ182.1,166.6,163.7,163.5,161.1,157.2,132.2,130.6,129.2,126.4,105.4,105.3,98.9,93.6,67.2,38.0,31.2,19.5,13.7.HRMS(ESI)m/z:[M+H] + :368.1492；Found:368.1490.
YGT-28： 1 H NMR(400MHz,DMSO-d 6 )δ8.16(s,1H),8.08(d,J＝7.5Hz,2H),7.65–7.54(m,3H),7.05(s,1H),6.80(s,1H),6.43(s,1H),4.63(s,2H),3.16–3.07(m,2H),1.48–1.38(m,2H),1.21(s,4H),0.81(t,J＝6.7Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ182.1,166.6,163.7,163.6,161.1,157.2,132.2,130.6,129.2,126.5,105.4,105.3,98.9,93.6,67.3,38.3,28.8,28.6,21.9,13.9.HRMS(ESI)m/z:[M+H] + :382.1649；Found:382.1644.
YGT-29： 1 H NMR(400MHz,DMSO-d 6 )δ8.28(s,1H),8.08(d,J＝7.4Hz,2H),7.64–7.53(m,3H),7.04(s,1H),6.81(s,1H),6.44(s,1H),4.64(s,2H),3.07–3.00(m,2H),0.96(s,1H),0.40(d,J＝7.5Hz,2H),0.19(d,J＝4.2Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ182.1,166.6,163.7,163.5,161.2,157.2,132.2,130.6,129.2,126.5,105.4,105.3,98.8,93.6,67.2,42.7,10.9,3.3.HRMS(ESI)m/z:[M+H] + :366.1336；Found:366.1332.
YGT-30： 1 H NMR(400MHz,DMSO-d 6 )δ8.22(s,1H),8.09(d,J＝7.0Hz,2H),7.67–7.54(m,3H),7.05(s,1H),6.80(s,1H),6.43(s,1H),4.59(s,2H),2.77–2.64(m,1H),0.71–0.60(m,2H),0.57–0.44(m,2H). 13 C NMR(100MHz,DMSO-d 6 )δ182.2,167.9,163.8,163.6,161.1,157.2,132.3,130.6,129.2,126.5,105.5,105.3,98.8,93.6,67.2,22.2,5.6.HRMS(ESI)m/z:[M+H] + :352.1179；Found:352.1177.
YGT-31： 1 H NMR(400MHz,DMSO-d 6 )δ8.85(t,J＝5.6Hz,1H),8.09(d,J＝7.6Hz,2H),7.67–7.56(m,5H),7.49(d,J＝7.9Hz,2H),7.07(s,1H),6.84(s,1H),6.47(s,1H),4.75(s,2H),4.44(d,J＝5.6Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ182.1,167.2,163.6,161.1,157.2,144.1,132.2,130.6,129.2,127.9,126.5,125.12,125.08,125.04,105.5,105.3,99.0,93.6,67.2,41.6. 19 F NMR(376MHz,DMSO-d 6 )δ-60.74.HRMS(ESI)m/z:[M+H] + :470.1210；Found:470.1207.
YGT-32： 1 H NMR(400MHz,DMSO-d 6 )δ8.81(t,J＝4.9Hz,1H),8.12–8.05(m,2H),7.71(d,J＝7.6Hz,1H),7.61(t,J＝7.0Hz,4H),7.50(d,J＝7.8Hz,1H),7.46(t,J＝7.4Hz,1H),7.06(s,1H),6.85(s,1H),6.48(s,1H),4.80(s,2H),4.55(d,J＝4.9Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ182.1,167.3,163.7,161.1,157.2,137.2,132.6,132.2,130.6,129.2,128.4,127.4,126.5,126.3,126.0,125.80,125.75,125.69,125.64,105.5,105.3,98.9,93.6,67.1,38.5. 19 F NMR(376MHz,DMSO-d 6 )δ-58.96.HRMS(ESI)m/z:[M+H] + :470.1210；Found:470.1207.
YGT-33： 1 H NMR(400MHz,DMSO-d 6 )δ8.84(s,1H),8.07(d,J＝7.1Hz,2H),7.75(s,1H),7.68(d,J＝8.4Hz,1H),7.65–7.50(m,4H),7.03(s,1H),6.82(s,1H),6.46(s,1H),4.78(s,2H),4.51(d,J＝4.8Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ182.1,167.4,163.6,161.1,157.2,136.4,132.5,132.2,132.0,130.7,130.5,129.1,128.3,128.0,127.7,127.4,126.4,125.8,125.7,125.64,125.58,124.8,122.1,105.4,105.3,98.9,93.6,67.1,38.2. 19 F NMR(376MHz,DMSO-d 6 )δ-59.35.HRMS(ESI)m/z:[M+H] + :504.0820；Found:504.0817.
YGT-34： 1 H NMR(400MHz,DMSO-d 6 )δ8.80(t,J＝5.6Hz,1H),8.09(d,J＝7.8Hz,2H),7.67–7.56(m,3H),7.50(t,J＝8.0Hz,1H),7.25(d,J＝10.5Hz,1H),7.14(d,J＝8.2Hz,1H),7.08(s,1H),6.83(s,1H),6.47(s,1H),4.75(s,2H),4.36(d,J＝5.8Hz,2H).
YGT-35： 1 H NMR(400MHz,DMSO-d 6 )δ8.75(s,1H),8.08(d,J＝7.1Hz,2H),7.67–7.55(m,3H),7.36(t,J＝9.2Hz,2H),7.22(d,J＝8.2Hz,1H),7.05(s,1H),6.81(s,1H),6.45(s,1H),4.72(s,2H),4.37(d,J＝5.4Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ182.1,167.2,163.6,161.1,158.6,157.2,132.4,132.3,132.2,130.93,130.88,130.6,129.2,126.5,125.1,125.0,124.49,124.46,115.8,115.6,105.5,105.3,98.9,93.6,67.2,35.4. 19 F NMR(376MHz,DMSO-d 6 )δ-115.60.HRMS(ESI)m/z:[M+H] + :454.0852；Found:454.0849.
YGT-36： 1 H NMR(400MHz,DMSO-d 6 )δ8.72(s,1H),8.06(d,J＝7.0Hz,2H),7.64–7.53(m,3H),7.34(t,J＝7.9Hz,1H),7.28(t,J＝6.3Hz,1H),7.19–7.09(m,2H),7.03(s,1H),6.80(s,1H),6.44(s,1H),4.73(s,2H),4.41(d,J＝5.4Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ182.1,167.1,163.7,163.5,161.2,161.1,158.8,157.2,132.2,130.5,129.6,129.5,129.1,129.0,128.9,126.4,125.8,125.6,124.3,115.2,114.9,105.4,105.3,98.9,93.6,67.2,35.7,35.7. 19 F NMR(376MHz,DMSO-d 6 )δ-118.78.HRMS(ESI)m/z:[M+H] + :420.1237；Found:420.1238.
YGT-37： 1 H NMR(400MHz,DMSO-d 6 )δ8.77(t,J＝6.8Hz,1H),8.07(d,J＝7.0Hz,2H),7.71(s,1H),7.67–7.54(m,5H),7.03(s,1H),6.80(s,1H),6.45(s,1H),4.74(s,2H),4.42(d,J＝6.1Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ182.0,167.2,163.6,163.5,161.0,157.1,139.3,133.0,132.0,131.3,130.5,129.0,128.9,126.54,126.48,126.3,126.2,105.4,105.3,98.8,93.4,67.1,40.9.HRMS(ESI)m/z:[M+H] + :504.0820；Found:504.0820.
YGT-38： 1 H NMR(400MHz,DMSO-d 6 )δ9.27(s,1H),8.60(s,1H),8.09(d,J＝6.6Hz,2H),7.68–7.55(m,3H),7.09(s,1H),7.07–7.04(m,2H),6.82(s,1H),6.68(d,J＝8.3Hz,2H),6.46(s,1H),4.69(s,2H),4.24(d,J＝5.6Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ182.1,166.7,163.7,163.6,161.2,157.3,156.4,132.2,130.6,129.3,129.2,128.7,126.5,115.0,105.5,105.3,98.9,93.6,67.2,41.6.HRMS(ESI)m/z:[M+H] + :418.1285；Found:418.1285.
YGT-39： 1 H NMR(400MHz,DMSO-d 6 )δ8.68(s,1H),8.06(d,J＝7.3Hz,2H),7.64–7.52(m,3H),7.27(d,J＝8.1Hz,2H),7.18(d,J＝8.1Hz,2H),7.02(s,1H),6.80(s,1H),6.44(s,1H),4.71(s,2H),4.32(d,J＝5.6Hz,2H),1.19(s,9H). 13 C NMR(100MHz,DMSO-d 6 )δ182.1,166.8,163.6,163.5,161.1,157.2,149.2,136.1,132.2,130.5,129.1,127.1,126.4,124.9,105.4,105.3,99.0,93.5,67.2,41.6,34.1,31.1.HRMS(ESI)m/z:[M+H] + :458.1962；Found:458.1967.
YGT-40： 1 H NMR(400MHz,DMSO-d 6 )δ8.59(s,1H),8.06(d,J＝7.4Hz,2H),7.65–7.53(m,3H),7.15(d,J＝7.8Hz,2H),7.08(d,J＝7.8Hz,2H),7.00(s,1H),6.78(s,1H),6.45(s,1H),4.70(s,2H),4.31(d,J＝5.9Hz,2H),2.22(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ181.9,166.6,163.6,163.5,161.0,157.1,136.0,135.7,132.0,130.5,129.0,128.6,127.1,126.3,105.4,105.2,98.8,93.5,67.2,41.6,20.4.HRMS(ESI)m/z:[M+H] + :416.1492；Found:416.1490.
YGT-41： 1 H NMR(400MHz,DMSO-d 6 )δ8.61(s,1H),8.05(d,J＝7.7Hz,2H),7.65–7.53(m,3H),7.20–7.12(m,1H),7.08–6.98(m,4H),6.79(s,1H),6.46(s,1H),4.72(s,2H),4.33(d,J＝5.5Hz,2H),2.23(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ181.9,166.7,163.6,163.5,161.0,157.1,138.9,137.2,132.0,130.5,129.0,128.0,127.7,127.3,126.3,124.2,105.3,105.2,98.8,93.5,67.2,41.7,20.7.HRMS(ESI)m/z:[M+H] + :416.1492；Found:416.1491.
YGT-42： 1 H NMR(400MHz,DMSO-d 6 )δ8.65(t,J＝6.6Hz,1H),8.07(d,J＝7.5Hz,2H),7.66–7.56(m,3H),7.33–7.19(m,5H),7.02(s,1H),6.81(s,1H),6.47(s,1H),4.73(s,2H),4.37(d,J＝5.5Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ181.9,166.7,163.6,163.5,161.0,157.1,139.0,132.0,130.5,129.0,128.1,127.1,126.7,126.3,105.4,105.2,98.8,93.5,67.2,41.8.HRMS(ESI)m/z:[M+H] + :402.1336；Found:402.1333.
YGT-43： 1 H NMR(400MHz,DMSO-d 6 )δ8.76(s,1H),8.04(d,J＝6.9Hz,2H),7.66–7.49(m,7H),6.99(s,1H),6.78(s,1H),6.45(s,1H),4.74(s,2H),4.46(d,J＝5.2Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ181.9,167.1,163.5,161.1,157.1,140.6,132.0,131.3,130.5,129.1,129.0,128.8,126.3,125.4,123.60,123.57,123.41,123.37,122.7,105.3,98.8,93.4,67.2,41.4. 19 F NMR(376MHz,DMSO-d 6 )δ-61.09.HRMS(ESI)m/z:[M+H] + :470.1210；Found:470.1207.
YGT-44： 1 H NMR(400MHz,DMSO-d 6 )δ8.57(s,1H),8.07(d,J＝7.0Hz,2H),7.64–7.56(m,3H),7.20(d,J＝8.4Hz,2H),7.02(s,1H),6.84(d,J＝8.5Hz,2H),6.80(s,1H),6.45(s,1H),4.70(s,2H),4.29(d,J＝5.9Hz,2H),3.68(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ181.9,166.6,163.6,163.5,161.0,158.2,157.1,132.0,131.0,130.5,129.0,128.5,126.3,113.5,105.4,105.2,98.8,93.5,67.2,54.9,41.3.HRMS(ESI)m/z:[M+H] + :432.1442；Found:432.1437.
YGT-45： 1 H NMR(400MHz,DMSO-d 6 )δ8.74(s,1H),8.12(d,J＝7.6Hz,2H),7.71–7.59(m,3H),7.43–7.33(m,1H),7.17(d,J＝7.5Hz,1H),7.13–7.03(m,3H),6.86(s,1H),6.52(s,1H),4.80(s,2H),4.43(d,J＝5.9Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ181.9,167.0,163.6,163.3,161.0,160.9,157.1,142.0,132.0,130.5,130.0,129.9,129.0,126.3,123.1,113.8,113.6,113.5,113.3,105.4,105.2,98.9,93.5,67.2,41.3. 19 F NMR(376MHz,DMSO-d 6 )δ-113.47.HRMS(ESI)m/z:[M+H] + :420.1242；Found:420.1242.
YGT-46： 1 H NMR(400MHz,DMSO-d 6 )δ8.66(s,1H),8.07(d,J＝6.6Hz,2H),7.76–7.55(m,3H),7.45–7.27(m,2H),7.21–7.05(m,2H),7.01(s,1H),6.80(s,1H),6.46(s,1H),4.71(s,2H),4.35(d,J＝7.9Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ181.9,166.8,163.6,162.4,161.0,159.9,157.1,135.3,132.0,130.5,129.2,129.0,126.3,114.9,114.7,105.4,105.2,98.8,93.5,67.2,41.1. 19 F NMR(376MHz,DMSO-d 6 )δ-115.98.HRMS(ESI)m/z:[M+H] + :420.1242；Found:420.1242.
YGT-47： 1 H NMR(400MHz,DMSO-d 6 )δ8.77(s,1H),8.13–8.00(m,2H),7.82–7.69(m,2H),7.66–7.54(m,3H),7.52–7.40(m,2H),7.01(s,1H),6.81(s,1H),6.46(s,1H),4.74(s,2H),4.44(d,J＝5.9Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ181.9,167.1,163.5,161.1,157.1,144.9,132.0,130.5,129.0,128.0,126.3,118.6,109.6,105.4,105.3,98.8,93.5,67.2,41.6.HRMS(ESI)m/z:[M+H] + :427.1288；Found:427.1288.
YGT-48： 1 H NMR(400MHz,DMSO-d 6 )δ8.62(s,1H),8.04(d,J＝7.3Hz,2H),7.64–7.53(m,3H),7.19(t,J＝7.8Hz,1H),6.99(s,1H),6.85(d,J＝7.6Hz,1H),6.82(s,1H),6.80–6.74(m,2H),6.45(s,1H),4.72(s,2H),4.35(d,J＝6.0Hz,2H),3.68(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ181.9,166.8,163.6,163.5,161.0,159.2,157.1,140.6,132.0,130.5,129.1,129.0,126.3,119.3,112.9,112.1,105.3,105.2,98.8,93.4,67.2,54.8,41.7.HRMS(ESI)m/z:[M+H] + :432.1442；Found:432.1430.
YGT-49： 1 H NMR(400MHz,DMSO-d 6 )δ8.82(s,1H),8.06(d,J＝7.5Hz,2H),7.94–7.87(m,3H),7.66–7.54(m,3H),7.02(s,1H),6.80(s,1H),6.45(s,1H),4.77(s,2H),4.54(d,J＝5.7Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ182.0,167.4,163.6,163.5,161.1,157.2,142.8,132.0,130.6,130.5,130.2,129.9,129.6,129.0,127.9,126.3,124.5,121.8,120.4,105.3,98.8,93.3,67.2,41.1. 19 F NMR(376MHz,DMSO-d 6 )δ-61.36.HRMS(ESI)m/z:[M+H] + :538.1084；Found:538.1084.
example 2: flavonoid Activity
(1) TR-FRET experiment is used for detecting the binding capacity of the flavonoid compound and PPAR gamma
The method comprises the following specific steps:
a. respectively diluting the flavonoid compound of the invention to 1mmol/L by DMSO; DMSO as negative control and rosiglitazone (Rosi) as positive control.
b. The diluted solution was diluted again to 200. mu. mol/L with TR-FRET buffer.
c. Fluormone TM Pan-PPAR Green solution (20nmol/L) was prepared using TR-FRET buffer as the solvent.
d. 20nmol/L of Tb anti-GST antibody and 2nmol/L of PPARL-LBD protein were prepared using TR-FRET buffer as a solvent.
e. mu.L of the solution from step b, 10. mu.L of the solution from step c and 10. mu.L of the solution from step d were mixed in a 384-well plate and shaken for 6 hours.
f. The results were read on a microplate reader and are shown in Table 2.
g. Taking compound YGT-31 as an example, the binding ability to PPAR γ was observed at different concentrations, and the results are shown in FIG. 1.
TABLE 2
| Compound (I) | 100μM | Compound (I) | 100μM | Compound (I) | 100μM |
| YGT-1 | 0.33 | YGT-18 | 0.55 | YGT-35 | 0.44 |
| YGT-2 | 0.28 | YGT-19 | 0.64 | YGT-36 | 0.31 |
| YGT-3 | 0.64 | YGT-20 | 0.51 | YGT-37 | 0.31 |
| YGT-4 | 0.34 | YGT-21 | 0.54 | YGT-38 | 0.38 |
| YGT-5 | 0.65 | YGT-22 | 0.62 | YGT-39 | 0.38 |
| YGT-6 | 0.26 | YGT-23 | 0.63 | YGT-40 | 0.55 |
| YGT-7 | 0.58 | YGT-24 | 0.55 | YGT-41 | 0.30 |
| YGT-8 | 0.58 | YGT-25 | 0.36 | YGT-42 | 0.47 |
| YGT-9 | 0.28 | YGT-26 | 0.41 | YGT-43 | 0.34 |
| YGT-10 | 0.69 | YGT-27 | 0.29 | YGT-44 | 0.29 |
| YGT-11 | 0.59 | YGT-28 | 0.27 | YGT-45 | 0.26 |
| YGT-12 | 0.38 | YGT-29 | 0.27 | YGT-46 | 0.29 |
| YGT-13 | 0.52 | YGT-30 | 0.59 | YGT-47 | 0.26 |
| YGT-14 | 0.23 | YGT-31 | 0.22 | YGT-48 | 0.28 |
| YGT-15 | 0.48 | YGT-32 | 0.21 | YGT-49 | 0.24 |
| YGT-16 | 0.56 | YGT-33 | 0.18 | DMSO | 1.02 |
| YGT-17 | 0.32 | YGT-34 | 0.30 | Rosi | 0.16 |
As can be seen from Table 2 and FIG. 1, the flavonoids of the present invention have strong binding ability to PPAR γ, wherein the IC of the compound YGT-31 and PPAR γ 50 And k i 1.72 μ M and 0.62 μ M, respectively.
(2) Luciferase activity assay to examine the ability of flavonoids of the present invention to activate PPAR γ
Cos-7 cells were purchased from ATCC (CRL-1651) and cultured in 10% FBS antibiotic-free DMEM at 37 ℃ with 5% CO 2 An incubator. Plasmid co-transfection (50ng full length hPPAR γ, 100ng PPAR γ, 5ng renilla luciferase plasmid) was performed according to the instructions of lipofectamine2000(Invitrogen) when cells were seeded into 24-well plates in logarithmic growth phase and cells were fused to about 70%. After 24 hours of cell transfection, the intervention is carried out by using 1 mu mol/L and 10 mu mol/L of the flavonoid compound of the invention respectively, wherein 1 mu mol/L and 10 mu mol/L of rosiglitazone are used as positive controls, and DMSO is used as a negative control. Luciferase activity was assayed 24h after the intervention as described in the Reporter luciferase assay kits (Promega) protocol, with 3 independent test wells per group. The results are shown in Table 3 and FIG. 2.
TABLE 3
| Compound (I) | 10μM(％) | Compound (I) | 10μM(％) |
| |
0 | YGT-28 | 22.39 |
| Rosi | 100 | YGT-29 | 17.01 |
| YGT-1 | 14.51 | YGT-31 | 21.86 |
| YGT-4 | 17.56 | YGT-32 | 17.25 |
| YGT-21 | 35.43 | YGT-41 | 25.56 |
| YGT-25 | 20.95 | YGT-43 | 38.20 |
| YGT-26 | 21.02 |
As shown in table 3 and fig. 2, unlike rosiglitazone, which fully activates PPAR γ (100%) function, the flavonoids of the present invention only weakly activated PPAR γ (as low as 14.51%).
(3) Oil red staining detection of the ability of the flavonoids to induce adipocyte differentiation
3T3-L1 preadipocytes were purchased from ATCC (CRL-1651), cultured in 10% FBS DMEM containing penicillin-streptomycin double antibody, 37 ℃, 5% CO 2 An incubator. The cells were plated and after confluency, induction solution (10% FBS DMEM containing 0.5. mu. mol/L IBMX (3-isobutyl-1-methylxanthine), 1. mu. mol/L DEX (dexamethasone), 850nmol/L insulin) was added at 2 days. After 72h, the medium was changed to DMEM medium containing 850nmol/L insulin and 10% fetal bovine serum every 2 days. 10 mu mol/L rosiglitazone is used as a positive control, DMSO is used as a negative control, and the sample group is 10 mu mol/L flavonoid compound. Oil red O staining was performed on the eighth day from the initiation of induction, photographed by a microscope (OLYMPUS), and the differentiation rate of adipocytes was calculated, and the results are shown in table 4 and fig. 3. As is clear from table 4 and fig. 3, the flavonoids of the present invention did not significantly induce differentiation of adipocytes (adipocyte differentiation rate was only 10.81%) as compared to the strong adipocyte differentiation-inducing effect of rosiglitazone (adipocyte differentiation rate 89.21%).
TABLE 4
| Compound (I) | Adipocyte differentiation rate (%) | Compound (I) | Adipocyte differentiation rate (%) |
| DMSO | 6.27 | YGT-28 | 15.39 |
| Rosi | 89.21 | YGT-29 | 19.75 |
| YGT-1 | 16.54 | YGT-31 | 10.81 |
| YGT-4 | 18.83 | YGT-32 | 20.93 |
| YGT-21 | 11.52 | YGT-41 | 16.63 |
| YGT-25 | 11.43 | YGT-43 | 10.60 |
| YGT-26 | 16.37 |
(4) Real-time fluorescent quantitative PCR determination of expression of flavonoid-induced adipogenic gene
Inducing and differentiating 3T3-L1 preadipocytes according to the detection method (3), extracting total RNA of the cells, carrying out real-time fluorescence quantitative PCR according to the scheme of a kit (takara), applying a delta-Ct method, taking beta-actin as an internal reference, and calculating the relative expression of the mRNA, wherein the results are shown in a table 5 and a figure 4. As can be seen from table 5 and fig. 4, compared to rosiglitazone, the flavonoid compound of the present invention only weakly activates the expression of PPAR γ and its downstream adipogenic genes (including aP2, CD36, C/ebpa), and the flavonoid compound of the present invention can promote the expression of insulin sensitivity-related genes such as Glut4 and adipinect.
TABLE 5
| Compound (I) | PPARγ | aP2 | CD36 | C/EBPα | Glut4 | Adiponectin |
| DMSO | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 |
| Rosi | 6.68 | 8.59 | 3.47 | 6.30 | 5.33 | 5.97 |
| YGT-1 | 1.43 | 1.04 | 1.33 | 1.39 | 1.86 | 1.77 |
| YGT-4 | 1.52 | 1.19 | 1.12 | 1.33 | 1.96 | 2.31 |
| YGT-21 | 1.25 | 1.58 | 1.18 | 1.27 | 1.88 | 2.05 |
| YGT-25 | 1.36 | 1.24 | 1.39 | 1.26 | 2.31 | 2.05 |
| YGT-28 | 1.37 | 1.41 | 1.54 | 1.57 | 2.38 | 2.16 |
| YGT-29 | 1.56 | 1.63 | 1.59 | 1.31 | 2.66 | 2.42 |
| YGT-31 | 1.53 | 1.25 | 1.06 | 1.37 | 3.46 | 4.58 |
| YGT-41 | 1.21 | 1.16 | 1.46 | 1.29 | 1.92 | 1.90 |
(5) Detecting the hypoglycemic effect of the flavonoid compound in db/db model mice
The method comprises the following specific steps: six weeks of db/db model mice were purchased and randomly assigned. Intraperitoneal injection of solvent control group (Vehicle: mixed solvent of 1.5% DMF + 2% Tween 80+ 30% PEG300+ 66.5% phosphate buffer solution), flavonoid compound administration group (10mg/kg, 20mg/kg) of the invention, and positive control group fenticonazole nitrate (FN, 20mg/kg, CN 113209091A). Meanwhile, a group of normal wild mice (WT, wild type) was set as a control group, and a mixed solvent of 1.5% DMF + 2% tween 80+ 30% PEG300+ 66.5% phosphate buffer solution was given to the abdominal cavity. The test results show that the test mice are administered once a day and three weeks later, and the test mice test fasting blood glucose, fasting body weight and glucose tolerance level. As can be seen from FIG. 5, compared with Vehicle in the solvent control group of db mice, the flavonoids of the present invention have the effect of lowering blood sugar comparable to that of FN, and do not cause the increase of body weight of mice, and also have the effect of reducing body weight under the dosage of 20 mg/kg.
In conclusion, the flavonoid compound has strong binding force with PPAR gamma, and can improve insulin sensitivity, thereby realizing the purpose of efficiently reducing blood sugar; meanwhile, the flavonoid compound only weakly activates PPAR gamma and does not significantly induce differentiation of adipocytes and expression of a downstream adipogenic gene of PPAR gamma, so that the problems of complete activation of PPAR gamma, obesity, cardiac hypertrophy and other side effects existing in the conventional PPAR gamma agonist do not exist, and a mouse model experiment can also prove that the flavonoid compound can effectively reduce fasting plasma glucose of a mouse and does not cause weight increase.
Therefore, the flavonoid compound can be applied to the preparation of antidiabetic drugs, can obviously reduce blood sugar, does not cause weight increase, and does not cause side effects similar to thiazolidinedione drugs. Meanwhile, the flavonoid compound can be used as a PPAR gamma selective regulator to play a role in resisting type II diabetes, can obviously improve the blood sugar level on the basis of not causing side effects caused by PPAR gamma complete agonists such as adipocyte differentiation, weight gain, hepatotoxicity and the like, and is a potential drug lead compound with high-efficiency and safe hypoglycemic effect.
The flavonoid compound can also be used for preparing medicaments for treating and/or preventing diseases modulated by PPAR gamma nuclear receptors. Flavonoid compounds of the present invention andPPAR γ has strong binding ability, its IC 50 And k i Respectively reduced to 1.72 mu M and 0.62 mu M, and the flavonoid compound only weakly activates PPAR gamma and induces adipocyte differentiation, is expected to be developed into a novel PPAR gamma selective regulator which is used as a PPAR gamma small molecular regulator, thereby playing the roles of reducing blood sugar and the like and not causing the side effect similar to thiazolidinediones.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. A flavonoid compound is characterized in that the structural formula is shown as the following formula (I):
wherein R is substituted I/unsubstituted C1-C10 linear/branched/cyclic alkyl, substituted I/unsubstituted phenyl, substituted I/unsubstituted benzyl or substituted I/unsubstituted ethylcarboxyl.
2. The flavonoid compound according to claim 1, characterized in that: the substituent I is the same or different and respectively means that one or more hydrogen atoms in the groups are substituted by one or more than one of halogen atoms, straight chain/branched chain/cyclic alkyl of C1-C10, haloalkyl of C1-C10, substituted II/unsubstituted alkenyl of C2-C10, substituted II/unsubstituted alkynyl of C2-C10, substituted II/unsubstituted alkoxy of C1-C10, hydroxyl, substituted II/unsubstituted alkylhydroxyl of C1-C10, carboxyl, cyano, nitro, amino, substituted II/unsubstituted heteroalkyl containing N, O and S of C3-C20.
3. Flavonoid compound according to claim 1, characterized in that: the substituted groups I are the same or different, and one or more hydrogen atoms in the groups are substituted by one or more heteroalkyl groups of-F, -Cl, -Br, -I, methyl, ethyl, C3-C10 linear/branched/cyclic alkyl, halogenated methyl, methoxy, hydroxyl, cyano, substituted II/unsubstituted hydroxymethyl, substituted II/unsubstituted C3-C20 containing N, O and S.
4. Flavonoid compound according to claim 3, characterized in that: the substituted II/unsubstituted C3-C20 heteroalkyl containing one or more of N, O and S comprises- (CH) 2 ) 2 SCH 3 Or- (CH) 2 ) 4 NH(CO)OCH 2 C 6 H 5 。
5. Flavonoid compound according to any one of claims 2 to 3, characterized in that: the substituent II is the same or different, and one or more hydrogen atoms in the groups are substituted by-F, -Cl, -Br, -I, oxygen atoms, methyl, ethyl, propyl, butyl, alkenyl, alkynyl, phenyl, aryl, hydroxyl, amino, carbonyl, carboxyl, ester group, methoxyl, cyano and nitryl.
6. The flavonoid compound according to claim 1, characterized in that: the substituent I is the same or different, and refers to the condition that one or more hydrogen atoms in the groups are replaced by-F, -Cl, -Br, -I, methyl, ethyl, C3-C10 straight chain/branched chain/cyclic alkyl, halogenated methyl, methoxy, hydroxyl, cyano-CH 2 OH、-CH(CH 3 )OH、-(CH 2 ) 2 SCH 3 、-(CH 2 ) 4 NH(CO)OCH 2 C 6 H 5 And (4) substitution.
7. A process for the preparation of flavonoids according to any of claims 1 to 6, characterized in that they are obtained in particular by reacting 7-O-carboxyalkylated chrysin derivatives with amines or amino acid derivatives.
8. The method of claim 7, wherein:
the structural formula of the 7-O-carboxyalkylated chrysin derivative is shown as follows:
9. use of flavonoids according to any of claims 1 to 5 for the preparation of an antidiabetic agent or a lead compound thereof.
10. Use of flavonoids according to any of claims 1 to 5 for the preparation of a medicament for the treatment and/or prevention of diseases modulated by the PPAR γ nuclear receptor.
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