CN110590804B - Dihydroartemisinin carboxyl-containing phenol/esterphenol/amido phenol conjugate, synthetic method and application - Google Patents

Dihydroartemisinin carboxyl-containing phenol/esterphenol/amido phenol conjugate, synthetic method and application Download PDF

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CN110590804B
CN110590804B CN201910804369.0A CN201910804369A CN110590804B CN 110590804 B CN110590804 B CN 110590804B CN 201910804369 A CN201910804369 A CN 201910804369A CN 110590804 B CN110590804 B CN 110590804B
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杨大成
潘建芳
范莉
刘建
唐雪梅
周福委
杨龙
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Abstract

The invention discloses a dihydroartemisinin carboxyl-containing phenol/ester-based phenol/amido phenol conjugate, wherein the conjugate or racemate, stereoisomer and tautomer thereof and pharmaceutically acceptable salt thereof have a structural general formula shown in a formula I:
Figure DDA0002183202360000011
n is 2 or 3, X is alkoxy, hydroxy, amino or-O (CH)2)b-DHA, Y is-H or alkoxy, Z is alkenyl, alkyl or nothing, b ═ 2 or 3, DHA represents dihydroartemisinin. The invention also discloses a synthetic method of the conjugate and application of the conjugate in anti-tuberculosis, anti-diabetes, lipid-lowering and interleukin-17 inhibition drugs.

Description

Dihydroartemisinin carboxyl-containing phenol/esterphenol/amido phenol conjugate, synthetic method and application
Technical Field
The invention relates to the technical field of chemical medicines, in particular to a dihydroartemisinin carboxyl-containing phenol/ester group phenol/amido group phenol conjugate, a synthesis method and application.
Background
Artemisinin is a terpenoid found in the plant Artemisia annua, and is a colorless needle crystal. Dihydroartemisinin (DHA) is a first-generation derivative of artemisinin, has a unique structure, shows better pharmaceutical properties than artemisinin, and is an important clinical antimalarial drug. Based on the special structure and excellent activity of DHA, research on DHA is continuous, and at present, the research mainly focuses on the design and synthesis of novel derivatives of DHA and the exploration of new activity of old or new DHA molecules. To date, a number of novel derivatives of DHA have been synthesized, and some artemisinin derivatives have been used in clinical trials against breast cancer, colorectal cancer, non-small cell lung cancer, and the like. Researches also find that certain DHA derivatives show very good activity in diseases such as antivirus, antibacterial sensitization, anti-HIV, anti-cytomegalovirus, anti-tuberculosis and the like, show the potential of multi-target molecules, and are worthy of further research and development.
Salicylic acid is a plant willow bark extract, and is a natural anti-inflammatory drug. The common cold drug aspirin is salicylic acid derivative sodium acetylsalicylate; salicylic acid is commonly used in dermatology for the treatment of various chronic skin diseases such as acne, tinea, etc. Para-aminosalicylate is a commonly used clinical antituberculosis drug. The m-hydroxybenzoic acid is mainly used as a bactericide, a preservative, an ion exchanger, a plasticizer, a medical intermediate and the like. Para-hydroxybenzoic acid is an organic synthetic raw material with wide application, is widely used for antisepsis, mildew preventive, bactericide and the like of foods, cosmetics and medicines, and is also used as an intermediate of dyes and pesticides. P-hydroxyphenylacetic acid is an important organic synthesis intermediate and is used for synthesizing beta-receptor blocker atenolol and puerarin-4, 7-dihydroxyisoflavone serving as an effective component of daidzein. Ferulic acid is one of cinnamic acid derivatives, and its sodium salt has effects of resisting platelet aggregation, inhibiting release of platelet 5-hydroxytryptamine, inhibiting generation of platelet thromboxane A2, enhancing prostaglandin activity, relieving pain, and relieving vasospasm, and is a basic raw material for producing medicines for treating cardiovascular disease and cerebrovascular disease and leukopenia, such as XINXUEKANG, LIMAI Capsule, TAITAI oral liquid, etc., and it can be used for building body and protecting skin. Most of phenol containing carboxyl has wide biological activity, such as salicylic acid and ferulic acid which are directly used as medicines on the market for clinical application.
Carboxylic acid esters have a lower water solubility but a higher fat solubility than carboxylic acids. The carboxylic acid ester is hydrolyzed in vivo by a hydrolase. In this regard, the design of carboxylate esters as drug molecules is sometimes avoided in drug molecule design, but this point is sometimes used to design prodrugs. Carboxylic acid esters are also important intermediates in organic synthesis, and target molecules such as amides and carboxylic acids can be obtained from carboxylic acid esters.
Numerous carboxylic acid esters containing phenolic hydroxyl groups, such as methyl salicylate, methyl paraben, methyl ferulate and the like, have important application in the fields of medicine, food and chemical industry. The methyl salicylate has local stimulation effect, can promote local blood circulation, can generate stimulation reaction such as skin vasodilatation, red skin color and the like by external application or local inunction, reflectively affects skin, muscle, nerve and joints of corresponding parts, has the effects of detumescence, inflammation diminishing and pain relieving, and also has the effect of relieving itching. Methylparaben is a phenolic preservative, is effective on various molds, yeasts and bacteria, and is used as a preservative bactericide of medicaments in the pharmaceutical industry; methyl paraben is also used as preservative additive for food, spices, films and the like. The ferulic acid methyl ester has effects of resisting oxidation, whitening skin, diminishing inflammation, etc., and is mainly used in cosmetics. In addition, the ferulic acid methyl ester also has biological activities of resisting aging, regulating immunity, killing nematodes, resisting tumors and the like. Simple carboxylic ester containing phenolic hydroxyl group has wide biological activity, and the coexisting phenolic hydroxyl group can be used as a reaction site for further derivatization.
The amide compounds have wide biological activity, many polypeptide drugs with specific activity, beta-lactam antibiotics (penicillins, cephalosporins and the like), chloramphenicol antibiotics and some antituberculosis drugs all contain amide bond structures, and more drug lead molecules or candidate drugs are attempted to be introduced into the amide structures.
Although the introduction of a phenolic hydroxycarboxylic acid derivative and a carboxyl group-containing phenol structure into a DHA parent has been reported, the amount of the obtained compound is small and the system is insufficient. Therefore, the DHA phenolic hydroxyl carboxylic acid derivatives are synthesized, the biological activity and the structure-activity relationship are investigated, and the pharmaceutical significance is achieved. Based on the method, the carboxyl-containing phenol/ester-group phenol/amido phenol is connected with DHA through a simple Linker to form an aryl ether compound, namely a target molecule.
Disclosure of Invention
The invention provides a dihydroartemisinin carboxyl-containing phenol/ester-based phenol/amido phenol conjugate, a synthesis method and application.
The invention provides a conjugate of dihydroartemisinin and carboxyl-containing phenol/ester-based phenol/amido phenol, or a racemate, a stereoisomer, a tautomer and pharmaceutically acceptable salts thereof, which has a structural general formula shown in a formula I:
Figure GDA0003405286190000021
wherein n is 2 or 3, Y is H or alkoxy, Z is alkenyl, alkyl or nothing, and when X is hydroxy or-O (CH)2)b-DHA', b ═ 2 or 3, denoted by TM5, and when X is an alkoxy or amine group, denoted by TM 6; wherein DHA' is the residue of dihydroartemisinin DHA with C-12 hydroxyl hydrogen removed.
Preferably, n is 2 or 3, Y is-H or-OMe, and Z is- (CH)2)-mor-CH-, m-0, 1 or 2, X is-OH, -O (CH)2)b-DHA', -OMe or-NH2And b is 2 or 3.
The invention also provides a synthesis method of the derivative, wherein the synthesis of the TM5 is carried out according to the following reaction equation, and the synthesis method comprises the following steps:
Figure GDA0003405286190000031
wherein n is 2 or 3, Y is-H or-OMe, and Z is- (CH)2)-mor-CH ═ CH-, X is-OH or-O (CH)2)b-DHA', m ═ 0, 1 or 2, b ═ 2 or 3;
adding the raw materials of carboxyl-containing substituted phenol B1, IM1 and K2CO3And a solvent dimethylformamide, heating, stirring and dissolving, reacting for 1-15 h, and after the reaction is finished, performing post-treatment to obtain a conjugate of dihydroartemisinin containing carboxyl phenol, namely TM 5.
Preferably, the mass ratio of the raw material IM1 to the raw material carboxyl-containing substituted phenol B1 is 1: 1-2, and the reaction temperature is 40-85 ℃.
The synthesis of TM6 was performed according to the following reaction equation, including the following steps:
Figure GDA0003405286190000032
wherein n is 2 or 3, Y is-H or-OMe, and X is-OMe or-NH2Z is- (CH)2)-mor-CH ═ CH-, m ═ 0, 1, or 2;
adding the raw materials of the phenol B2, IM1 and K which contain ester group or amido group substitution2CO3And a solvent dimethylformamide, heating, stirring and dissolving, reacting for 1-10 h, and after the reaction is finished, carrying out post-treatment to obtain the dihydroartemisinin ester-containing or acylaminophenol conjugate, namely TM 6.
Preferably, the mass ratio of the raw material IM1 to the raw material containing the ester-group or amido-group substituted phenol B2 is 1: 1-2, and the reaction temperature is 40-85 ℃.
The invention also provides an application of the dihydroartemisinin carboxyl-containing phenol/ester-based phenol/amido phenol conjugate or racemate, stereoisomer, tautomer and pharmaceutically acceptable salt thereof in medicaments for resisting tuberculosis, resisting diabetes, reducing fat and inhibiting interleukin-17.
Preferably, when n is 2, Y is-OMe, Z is-CH, X is-OH (represented by TM5-5) for use in anti-tuberculosis drugs;
n-3, Y is H, Z is nothing, X is-O (CH)2)b-DHA', b ═ 3 (denoted TM 5-6) for use in lipid lowering drugs;
n is 3, Y is H, Z is-CH2CH2Use of a compound of formula (I) wherein X is-OH (as indicated by TM 5-10) in a medicament for inhibiting interleukin-17.
Preferably, when n is 2, X is-OMe, Y is-H, Z is-CH2-, n ═ 2, X is-OMe, Y is-OMe, Z is-CH ═ CH-, n ═ 3, X is-OMe, Y is-OMe, Z is-CH ═ CH-, n ═ 2, X is-NH2Y is-H, Z is-CH2- (TM 6-3, TM6-5, TM6-11 and TM6-12, respectively) in antituberculosis drugs;
n is 3 and X is-NH2Y is-H, Z is-CH2- (TM 6-13) use in antidiabetic agents;
n-2, X-OMe, Y-H, Z (TM 6-2), n-3, X-OMe, Y-H, Z (ortho-para, TM6-6, TM6-8, respectively), n-3, X-OMe, Y-H, Z-CH2CH2- (TM 6-10), n ═ 3, and X is-NH2Y is-H, Z is-CH2- (TM 6-13) for use in a medicament for inhibiting interleukin-17.
Compared with the prior art, the invention has the beneficial effects that: the invention provides a conjugate of dihydroartemisinin and carboxyl-containing phenol/esterphenol/amido phenol, the derivatives connect pharmacophores of dihydroartemisinin and carboxyl-containing phenol/esterphenol/amido phenol medicaments with each other through a proper connecting structure, the synthetic method is simple, and the synthetic yield is high; biological activity tests show that the derivative has various biological activities of resisting tuberculosis, resisting diabetes, reducing blood fat, inhibiting interleukin-17 and the like, and has good application prospect.
Detailed Description
The following detailed description of the present invention is provided in conjunction with the accompanying drawings, but it should be understood that the scope of the present invention is not limited to the specific embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
Example 1 preparation of a dihydroartemisinin carboxyl-containing phenol conjugate
(1) The preparation method of the intermediate IM1 is as follows:
Figure GDA0003405286190000051
adding dihydroartemisinin, diethyl ether and bromohydrin, and adding boron trifluoride-diethyl ether (BF) under cooling in ice bath3.Et2O), reacting for 5-20 h under stirring, and adding saturated NaHCO after the reaction is finished3Terminating the reaction, standing for layering, extracting the water layer with Ethyl Acetate (EA), combining the organic phases, washing with saturated brine, anhydrous MgSO4Drying, filtering, decompressing and rotary-distilling the filtrate to remove the solvent to obtain a crude product, and recrystallizing the crude product by using a petroleum ether-EA mixed solvent to obtain an intermediate IM 1.
(2) DHA conjugates with carboxyl-containing phenols, in this application we refer to TM5, were prepared as follows:
Figure GDA0003405286190000052
in a 100mL round-bottom flask were added 11.2 mmol of carboxyl-containing substituted phenol B, 2mL of Dimethylformamide (DMF) as a solvent, and K2CO3(2.5mmol) and IM1(1mmol), stirring the reaction in a water bath at 45-80 deg.C, and monitoring the progress of the reaction by TLC. After the reaction is completed, 20mL of water and 15mL of EA are added, liquid separation is carried out, the aqueous layer is extracted by 10mL of EA, the organic phases are combined, and saturated NaHCO is added3Washing (5 mL. times.2), adjusting pH to 3-4, washing with water (20 mL. times.2), anhydrous MgSO4Drying, vacuum filtering, rotary steaming under reduced pressure to remove EA to obtain light yellow mucus, and performing column chromatography to obtain pure TM 5.
Example 2 preparation of dihydroartemisinin carboxyl-containing phenol conjugates TM 5-1-TM 5-11
When n is 2 or 3, Y is-H or-OMe, and Z is- (CH) according to the preparation method described in example 12)-mor-CH ═ CH-, X is-OH or-O (C)H2)bA series of TM5-1 to TM5-11 products were prepared with — DHA', m ═ 0, 1, or 2, b ═ 2, or 3, and the respective reaction conditions, yields, product yields, and product melting points are shown in table 1.
TABLE 1 results of synthetic experiments for TM5 series of compounds
Figure GDA0003405286190000053
Figure GDA0003405286190000061
Example 3 preparation of Dihydroartemisinin ester-containing/Acylaminophenol conjugates
Figure GDA0003405286190000062
Into a 100mL round-bottomed flask were added ester group/amido group-containing phenol B2(1.2mmol), DMF 2mL, and K in that order2CO3(2.5mmol) and IM1(1mmol), stirring the reaction in a water bath at 45-80 deg.C, and monitoring the progress of the reaction by TLC. After completion of the reaction, 20mL of water and 15mL of EA were added, 1N HCl was added to adjust the pH to about 7, stirring was continued for 5min, the aqueous layer was separated, extracted with EA10mL, the organic phases were combined, washed with 1N NaOH (5 mL. times.2), and washed with water (20 mL. times.2). Anhydrous Na2SO4Drying, filtering, rotary steaming under reduced pressure to remove EA, and performing column chromatography to obtain TM 6.
Example 4 preparation of dihydroartemisinin and ester group/amido group-containing phenol conjugates TM 6-1. about. TM6-13
When n is 2 or 3, X is-OMe or-NH according to the preparation method described in example 32Y is-H or-OMe, Z is- (CH)2)-mor-CH-and m-0, 1 or 2, a series of products TM6-1 to TM6-13 were prepared, and the respective reaction conditions, yields, product yields, and product melting points are shown in table 2.
TABLE 2 experimental results of synthesis of TM6 series of compounds
Figure GDA0003405286190000071
Example 5 testing and characterization of TM5-1 to TM5-11 and TM6-1 to TM6-13
The products of TM5-1 to TM5-11 and TM6-1 to TM6-13 series obtained in example 2 and example 4 were subjected to1HNMR(AV-300)、13C NMR (AV-75) and HR MS (Varian 7.0T) were tested and characterized, and the data are shown below:
(1)TM5-1～TM5-11
Figure GDA0003405286190000081
TM5-1 2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethyl 2-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)benzoate
1H NMR(300MHz,CDCl3)δ:7.77(1H,d,J＝7.5Hz),7.52-7.42(1H,m),7.04-6.93(2H,m),5.47(1H,s),5.41(1H,s),4.90-4.86(2H,m),4.54-4.36(2H,m),4.22-4.15(4H,m),3.94-3.67(2H,m),2.69-2.55(2H,m),2.42-2.30(2H,m),2.05-1.13(20H,m),1.43(6H,s),0.97-0.82(12H,m).13C NMR(75MHz,CDCl3)δ:165.58,158.71,133.41,131.56,120.57,120.33,113.73,104.09,104.07,102.28,101.77,87.96,87.88,81.22,81.14,68.38,66.81,65.58,63.65,52.61,52.48,44.49,44.44,37.26,37.19,36.50,36.45,34.72,34.61,30.91,30.87,26.23,24.74,24.69,24.46,24.39,20.44,13.02,12.99.HR MS calcd for C41H58O13[M+Na]+781.3775,found 781.3777.
TM5-2 2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethyl 3-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)benzoate
1H NMR(300MHz,CDCl3)δ:7.64(1H,J＝8.4Hz),7.56(1H,s),7.33(1H,t,J＝7.8Hz),7.11(1H,dd,J＝1.8and 7.8Hz),5.48(1H,s),5.40(1H,s),4.91(1H,d,J＝3.0Hz),4.87(1H,d,J＝3.0Hz),4.68-4.36(2H,m),4.24-4.14(4H,m),4.01-3.70(2H),2.65-2.60(2H,m),2.43-2.29(2H,m),2.10-1.12(20H,m),1.45(3H,s),1.44(3H,s),0.97-0.80(12H,m).13C NMR(75MHz,CDCl3)δ:166.21,159.03,131.51,129.47,122.18,120.36,114.60,104.18,104.16,102.23,101.97,87.98,87.93,81.17,81.11,67.61,66.45,65.74,63.91,52.62,52.49,44.49,44.42,37.54,37.28,36.49,36.47,34.70,34.58,30.94,30.87,26.26,24.78,24.68,24.50,24.46,20.41,20.36,13.01.
TM5-3 2-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)acetic acid
1H NMR(300MHz,CDCl3)δ:7.13(2H,d,J＝8.1Hz),6.77(2H,d,J＝8.4Hz),5.43(1H,s),4.78(1H,d,J＝3.3Hz),4.30-4.19(2H,m),4.02-3.95(1H,m),3.68-3.60(1H,m),3.55(2H,s),2.64-2.59(1H,m),2.37(1H,td,J＝3.9and 14.4Hz),2.10-1.19(10H,m),1.44(3H,s,H-15),0.95(3H,d,J＝5.7Hz),0.86(3H,d,J＝7.5Hz).13C NMR(75MHz,CDCl3)δ:172.37,155.37,130.43,125.35,115.62,104.34,102.19,88.02,81.21,66.09,64.12,52.54,44.39,40.44,37.58,36.43,34.63,30.86,26.15,24.74,24.45,20.43,12.93.
TM5-4 3-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)propanoic acid
1H NMR(300MHz,CDCl3)δ:7.12(2H,d,J＝8.4Hz),6.83(2H,d,J＝8.4Hz),5.48(1H,s),4.90(1H,d,J＝3.0Hz),4.18-4.05(3H,m),3.80-3.75(1H,m),2.90(2H,t,J＝7.5Hz),2.67-2.62(3H,m),2.37(1H,td,J＝3.6and 14.1Hz),2.06-1.19(12H,m),1.45(3H,s),0.94-0.89(6H,m).13C NMR(75MHz,CDCl3)δ:178.66,157.50,132.51,129.31,114.77,104.20,102.18,88.01,81.25,67.44,66.59,52.62,44.51,37.49,36.50,35.96,34.70,30.97,29.85,26.26,24.79,24.49,20.46,13.06.
Figure GDA0003405286190000091
TM5-5(E)-3-(3-Methoxy-4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)acrylic acid
1H NMR(300MHz,CDCl3)δ:7.63(1H,d,J＝15.9Hz),7.09-7.05(2H,m),6.94-6.88(1H,m),6.30(1H,d,J＝15.9Hz),5.46(1H,s),4.88-4.87(1H,m),4.48-4.08(3H,m),4.07-3.69(4H,m),2.66-2.61(1H,m),2.41-2.31(1H,m),2.05-1.19(10H,m),1.45(3H,s),0.93-0.83(6H,m).13C NMR(75MHz,CDCl3)δ:167.03,150.74,149.74,144.98,127.51,122.58,115.53,112.88,110.25,104.15,101.99,87.96,81.14,66.41,65.87,55.99,52.52,44.41,37.51,36.45,34.61,30.87,26.24,24.70,24.46,20.34,13.00.HR MS calcd for C27H36O9[M+Na]+527.2257,found 527.2258.
TM5-6 3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propyl 2-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)benzoate
1H NMR(300MHz,CDCl3)δ:7.87(1H,d,J＝7.5Hz),7.44(1H,t,J＝7.5Hz),6.99-6.94(2H,m),5.38(1H,s),5.27(1H,s),4.81(2H,d,J＝3.0Hz),4.39(2H,t,J＝6.6Hz),4.20-4.01(4H,m),3.59-3.47(2H,m),2.65-2.57(2H,m),2.40-2.27(2H,m),2.18-1.09(24H,m),1.42(3H,s),1.41(3H,s),0.92-0.80(12H,m).13C NMR(75MHz,CDCl3)δ:166.17,158.72,133.52,132.16,120.08,112.75,103.97,103.91,102.02,101.69,87.81,87.61,81.10,81.03,65.41,64.70,63.85,62.08,52.51,52.39,44.39,44.33,37.33,37.07,36.41,34.56,34.51,30.91,30.89,29.02,28.85,26.16,24.58,24.54,24.51,24.48,20.33,20.31,13.01,12.99.HR MS calcd for C43H62O13[M+Na]+809.4088,found 809.4085.
TM5-7 3-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)benzoic acid
1H NMR(300MHz,CDCl3)δ:7.61(1H,d,J＝7.5Hz),7.51(1H,s),7.32(1H,t,J＝7.8Hz),7.08(1H,dd,J＝1.8and 8.1Hz),5.48(1H,s),4.84(1H,d,J＝3.3Hz),4.57-4.49(1H,m),4.34-4.26(1H,m),4.15-4.08(1H,m),3.53-3.45(1H,m),2.68-2.60(1H,m),2.41-2.31(1H,m),2.05-1.12(12H,m),1.45(3H,s),0.92(3H,d,J＝7.5Hz),0.87(3H,d,J＝5.7Hz).13C NMR(75MHz,CDCl3)δ:166.50,156.28,131.50,129.92,121.79,120.45,116.34,104.61,102.18,88.09,81.25,64.27,61.78,52.51,44.47,37.52,36.45,34.59,31.00,28.64,26.16,24.67,24.64,20.39,13.09.HR MS calcd for C25H34O8[M+Na]+485.2151,found 485.2151.
TM5-8 4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)benzoic acid
1H NMR(300MHz,CDCl3)δ:7.95(2H,d,J＝8.7Hz),6.88(2H,d,J＝8.7Hz),5.40(1H,s),4.81(1H,d,J＝3.3Hz),4.37(2H,t,J＝6.3Hz),4.07-4.00(1H,m),3.59-3.46(1H,m),2.66-2.61(1H,m),2.41-2.30(1H,m),2.07-1.20(12H,m),1.42(3H,s),0.92-0.90(6H,m).13C NMR(75MHz,CDCl3)δ:166.82,160.83,131.98,122.12,115.42,104.37,102.26,88.08,81.27,64.79,61.84,52.56,44.43,37.47,36.48,34.61,31.04,28.99,26.17,24.68,24.59,20.42,13.08.HR MS calcd for C25H34O8[M+Na]+485.2151,found 485.2150.
TM5-9 2-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)acetic acid
1H NMR(300MHz,CDCl3)δ:7.14(2H,d,J＝8.4Hz),6.79(2H,J＝8.4Hz),5.36(1H,s),4.71(1H,d,J＝3.0Hz),4.16(2H,t,J＝6.3Hz),3.91-3.84(1H,m),3.55(2H,s),3.39-3.32(1H,m),2.63-2.55(1H,m),2.37(1H,td,J＝3.6and 14.1Hz),2.06-1.19(12H,m),1.45(3H,s),0.94(3H,d,J＝6.0Hz),0.86(3H,d,J＝7.2Hz).13C NMR(75MHz,CDCl3)δ:172.56,155.34,130.47,125.62,115.69,104.36,102.19,88.03,81.25,64.65,61.97,52.57,44.40,40.58,37.49,36.47,34.61,30.96,28.85,26.18,24.71,24.54,20.43,13.01.HR MS calcd for C26H36O8[M+Na]+499.2308,found 499.2311.
TM5-10 3-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)propanoic acid
1H NMR(300MHz,CDCl3)δ:7.61(1H,d,J＝15.9Hz),7.10-7.05(2H,m),6.92(1H,d,J＝8.1Hz),6.30(1H,d,J＝15.9Hz),5.40(1H,s),4.82(1H,d,J＝3.3Hz),4.28(2H,t,J＝6.3Hz),4.06-3.99(1H,m),3.94(3H,s),3.53-3.45(1H,m),2.66-2.61(1H,m),2.36(1H,td,J＝3.6and 14.4Hz),2.05-1.17(12H,m),1.43(3H,s),0.94-0.90(6H,m).13C NMR(75MHz,CDCl3)δ:178.79,157.62,132.30,129.30,114.55,104.17,101.93,87.89,81.19,64.64,64.35,52.55,44.47,37.21,36.51,35.95,34.64,31.00,29.86,29.35,26.30,24.68,24.58,20.48,13.14.HR MS calcd for C27H38O8[M+Na]+513.2464,found 513.2468.
TM5-11(E)-3-(3-Methoxy-4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)acrylic acid
1H NMR(300MHz,CDCl3)δ:7.12(2H,d,J＝8.4Hz),6.83(2H,d,J＝8.4Hz),5.32(1H,s),4.81(1H,d,J＝3.0Hz),4.13-4.06(1H,m),4.02(2H,t,J＝6.0Hz),3.54-3.47(1H,m),2.90(2H,t,J＝7.5Hz),2.67-2.59(3H,m),2.34(1H,td,J＝3.6and 14.4Hz),2.08-1.12(12H,m),1.44(3H,s),0.88(3H,d,J＝7.2Hz),0.84(3H,d,J＝6.0Hz).13C NMR(75MHz,CDCl3)δ:167.37,148.09,146.88,145.02,127.04,123.25,115.45,114.81,109.40,104.18,102.20,88.01,81.21,64.77,61.59,56.05,52.63,44.48,37.51,36.51,34.68,31.00,29.04,26.31,24.73,24.60,20.45,13.12.HR MS calcd for C28H38O9[M+Na]+541.2414,found 541.2412.
(2)TM6-1～TM6-13
Figure GDA0003405286190000121
TM6-1 Methyl 2-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)benzoate
1H NMR(300MHz,CDCl3)δ:7.84-7.76(1H,m),7.52-7.41(1H,m),7.06-6.96(2H),5.46(1H,s),4.90(1H,d,J＝3.3Hz),4.25-4.18(3H,m),3.93-3.80(4H,m),2.66-2.61(1H,m),2.42-2.31(1H,m),2.05-1.19(10H,m),1.44(3H,s),0.93(3H,d,J＝6.0Hz),0.88(3H,d,J＝7.5Hz).13C NMR(75MHz,CDCl3)δ:166.83,158.42,133.33,131.71,121.37,120.48,113.65,104.13,102.46,88.02,81.24,68.47,66.93,52.64,52.06,44.51,37.26,36.53,34.73,30.95,26.29,24.75,24.42,20.44,12.99.HR MS calcd for C25H34O8[M+Na]+485.2151,found 485.2150.
TM6-2 Methyl 3-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)benzoate
1H NMR(300MHz,CDCl3)δ:7.64(1H,d,J＝7.5Hz),7.56(1H,s),7.34(1H,t,J＝7.8Hz),7.11(1H,d,J＝8.1Hz),5.48(1H,s),4.90(1H,d,J＝3.3Hz),4.21-4.13(3H),3.92(3H,s),3.83-3.75(1H,m),2.67-2.62(1H,m),2.43-2.32(1H,m),2.07-1.17(10H,m),1.45(3H,s),0.93(3H,d,J＝6.0Hz),0.90(3H,d,J＝7.5Hz).13C NMR(75MHz,CDCl3)δ:166.98,158.93,131.48,129.51,122.19,120.04,114.93,104.17,102.21,87.98,81.20,67.62,66.46,52.60,52.29,44.48,37.52,36.49,34.67,30.95,26.28,24.76,24.48,20.41,13.03.
TM6-3 Methyl 2-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)acetate
1H NMR(300MHz,CDCl3)δ:7.19(2H,d,J＝7.8Hz),6.85(2H,d,J＝8.4Hz),5.48(1H,s),4.93-4.86(1H,m),4.17-4.10(3H,m),3.79-3.78(1H,m),3.69(3H,s),3.57(2H,s),2.72-2.54(1H,m),2.42-2.32(1H,m),2.07-1.18(10H,m),1.45(3H,s),0.94-0.89(6H,m).13C NMR(75MHz,CDCl3)δ:172.46,158.11,130.36,126.25,114.79,104.17,102.21,88.00,81.24,67.46,66.55,52.64,52.13,44.52,40.37,37.51,36.51,34.70,30.98,26.30,24.79,24.50,20.45,13.07.
TM6-4 Methyl 3-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)propanoate
1H NMR(300MHz,CDCl3)δ:7.00(2H,d,J＝8.7Hz),6.82(2H,d,J＝8.4Hz),5.48(1H,s),4.90(1H,d,J＝3.3Hz),4.18-4.05(3H,m),3.80-3.74(1H,m),3.67(3H,s),2.89(2H,t,J＝7.5Hz),2.66-2.57(3H,m),2.43-2.32(1H,m),2.06-1.17(10H,m),1.45(3H,s),0.93(3H,d,J＝6.0Hz),0.90(3H,d,J＝7.2Hz).13C NMR(75MHz,CDCl3)δ:173.51,157.46,132.80,129.29,114.73,104.15,102.19,87.99,81.23,67.44,66.59,52.63,51.70,44.52,37.49,36.51,36.07,34.71,30.97,30.17,26.28,24.79,24.48,20.45,13.05.
TM6-5(E)-Methyl 3-(3-methoxy-4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)acrylate
1H NMR(300MHz,CDCl3)δ:7.64(1H,d,J＝15.9Hz),7.09-7.05(2H,m),6.89(1H,d,J＝8.4Hz),6.31(1H,d,J＝15.9Hz),5.48(1H,s),4.88(1H,d,J＝3.0Hz),4.26-4.15(3H,m),3.90-3.80(1H,m),3.88(3H,s),3.80(3H,s),2.66-2.61(1H,m),2.42-2.32(1H,m),2.05-1.16(10H,m),1.45(3H,s),0.92(3H,d,J＝6.0Hz),0.89(3H,d,J＝7.2Hz).13C NMR(75MHz,CDCl3)δ:167.77,150.67,149.75,144.87,127.59,122.49,115.52,112.95,110.25,104.11,102.22,87.98,81.21,68.19,66.48,55.99,52.58,51.73,44.50,37.32,36.50,34.74,30.93,26.26,24.78,24.45,20.45,12.97.HR MS calcd for C28H38O9[M+Na]+541.2414,found 541.2413.
Figure GDA0003405286190000131
TM6-6 Methyl 2-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)benzoate
1H NMR(300MHz,CDCl3)δ:7.83(1H,d,J＝7.8Hz),7.44(1H,t,J＝7.5Hz),7.00-6.93(2H,m),5.27(1H,s),4.82(1H,d,J＝3.0Hz),4.25-4.11(3H),3.91(3H,s),3.57-3.50(1H,m),2.62-2.57(1H,m),2.37-2.26(1H,m),2.14-0.95(12H,m),1.42(3H,s),0.86(3H,d,J＝7.2Hz),0.81-0.78(3H,m).13C NMR(75MHz,CDCl3)δ:166.96,158.59,133.52,132.05,120.20,120.13,112.81,103.99,101.78,87.70,81.11,65.27,63.77,52.48,52.20,44.41,37.12,36.49,34.57,30.99,29.08,26.27,24.62,24.59,20.43,13.10.HR MS calcd for C26H36O8[M+Na]+499.2308,found499.2306.
TM6-7 Methyl 3-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)benzoate
1H NMR(300MHz,CDCl3)δ:7.63(1H,d,J＝7.5Hz),7.55(1H,s),7.34(1H,t,J＝8.1Hz),7.11(1H,d,J＝8.1Hz),5.28(1H,s),4.82(1H,d,J＝3.3Hz),4.18-4.08(3H),3.91(3H,s),3.55-3.45(1H,m),2.64-2.59(1H,m),2.38-2.28(1H,m),2.11-1.10(12H,m),1.44(3H,s),0.88(3H,d,J＝7.5Hz),0.81(3H,d,J＝5.2Hz).13C NMR(75MHz,CDCl3)δ:166.93,158.95,131.37,129.39,121.98,119.99,114.38,104.00,101.82,87.73,81.02,64.70,63.99,52.40,52.17,44.32,37.12,36.39,34.46,30.87,29.08,26.20,24.52,20.30,13.01.HR MS calcd forC26H36O8[M+Na]+499.2308,found 499.2306.
TM6-8 Methyl 4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)benzoate
1H NMR(300MHz,CDCl3)δ:7.99(2H,d,J＝8.7Hz),6.92(2H,d,J＝9.0Hz),5.28(1H,s),4.81(1H,d,J＝3.3Hz),4.18-4.09(3H),3.88(3H,s),3.54-3.48(1H,m),2.64-2.59(1H,m),2.39-2.28(1H,m),2.11-1.10(12H,m),1.44(3H,s),0.88(3H,d,J＝7.5Hz),0.85-0.80(3H,m).13C NMR(75MHz,CDCl3)δ:166.93,162.88,131.69,122.62,114.09,104.14,101.94,87.83,81.09,64.85,64.02,52.49,51.97,44.39,37.20,36.46,34.58,30.94,29.06,26.29,24.65,24.58,20.32,13.10.HR MS calcd for C26H36O8[M+Na]+499.2308,found499.2306.TM6-9 Methyl 2-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)acetate
1H NMR(300MHz,CDCl3)δ:7.18(2H,d,J＝8.4Hz),6.85(2H,d,J＝8.4Hz),5.33(1H,s),4.81(1H,d,J＝2.7Hz),4.13-4.01(3H,m),3.68(3H,s),3.56(2H,s),3.53-3.48(1H,m),2.64-2.59(1H,m),2.40-2.29(1H,m),2.08-1.13(12H,m),1.44(3H,s),0.88(3H,d,J＝7.5Hz),0.84(3H,d,J＝6.0Hz).13C NMR(75MHz,CDCl3)δ:172.43,158.16,130.32,126.05,114.56,104.11,101.93,87.86,81.14,64.63,64.34,52.54,52.10,44.45,40.38,37.22,36.49,34.61,30.98,29.31,26.30,24.66,24.56,20.39,13.12.HR MS calcd for C27H38O8[M+Na]+513.2464,found 513.2462.
TM6-10 Methyl 3-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)propanoate
1H NMR(300MHz,CDCl3)δ:7.10(2H,d,J＝8.4Hz),6.82(2H,d,J＝8.7Hz),5.32(1H,s),4.81(1H,d,J＝3.3Hz),4.13-4.00(3H,m),3.67(3H,s),3.54-3.47(1H,m),2.89(2H,t,J＝7.5Hz),2.62-2.57(3H,m),2.39-2.29(1H,m),2.08-1.12(12H,m),1.45(3H,s),0.88(3H,d,J＝7.2Hz),0.84(3H,d,J＝6.0Hz).13C NMR(75MHz,CDCl3)δ:173.52,157.53,132.59,129.26,114.47,104.09,101.90,87.84,81.13,64.59,64.32,52.53,51.69,44.44,37.17,36.49,36.06,34.62,30.97,30.17,29.32,26.29,24.65,24.55,20.45,13.11.HR MS calcd for C28H40O8[M+Na]+527.2621,found 527.2623.
TM6-11(E)-Methyl 3-(3-methoxy-4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)acrylate
1H NMR(300MHz,CDCl3)δ:7.63(1H,d,J＝15.9Hz),7.08-7.05(2H,m),6.85(1H,d,J＝8.1Hz),6.31(1H,d,J＝15.9Hz),5.27(1H,s),4.81(1H,d,J＝3.0Hz),4.16-4.12(3H,m),3.90(3H,s),3.80(3H,s),3.55-3.45(1H,m),2.64-2.59(1H,m),2.39-2.29(1H,m),2.13-1.11(12H,m),1.43(3H,s),0.88(3H,d,J＝7.5Hz),0.81(3H,d,J＝5.4Hz).13C NMR(75MHz,CDCl3)δ:167.79,150.72,149.58,144.94,127.38,122.54,115.41,112.16,109.80,104.05,101.90,87.84,81.09,65.68,64.06,55.96,52.47,51.73,44.41,37.24,36.50,34.58,30.93,29.08,26.31,24.70,24.56,20.49,13.11.HR MS calcd for C29H40O9[M+Na]+555.2570,found 555.2569.
TM6-12 2-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)acetamide
1H NMR(300MHz,CDCl3)δ:7.19(2H,d,J＝8.1Hz),6.89(2H,d,J＝8.1Hz),5.47(1H,s),4.90(1H,d,J＝3.0Hz),4.18-4.11(3H),3.81-3.76(1H,m),3.54(2H,s),2.67-2.62(1H,m),2.43-2.32(1H,m),2.06-1.11(10H,m),1.45(3H,s),0.94(3H,d,J＝5.7Hz),0.91(3H,d,J＝7.5Hz).13C NMR(75MHz,CDCl3)δ:174.31,158.27,130.60,127.06,115.22,104.19,102.21,88.00,81.22,67.47,66.44,52.61,44.49,42.50,37.54,36.49,34.70,30.95,26.28,24.80,24.50,20.46,13.06.HR MS calcd for C25H35NO7[M+Na]+484.2311,found 484.2311.
TM6-13 2-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)acetamide
1H NMR(300MHz,CDCl3)δ:7.18(2H,d,J＝8.4Hz),6.89(2H,d,J＝8.1Hz),5.34(1H,s),4.81(1H,d,J＝3.0Hz),4.12-4.02(3H),3.56-3.45(3H,m),2.63-2.59(1H,m),2.40-2.30(1H,m),2.09-1.11(12H,m),1.44(3H,s),0.90-0.85(6H,m).13C NMR(75MHz,CDCl3)δ:174.39,158.37,130.54,126.86,114.99,104.13,101.96,87.86,81.12,64.73,64.41,52.51,44.41,42.47,37.27,36.46,34.61,30.95,29.32,26.27,24.67,24.55,20.42,13.11.HR MS calcd for C26H37NO7[M+Na]+498.2468,found 498.2466.
example 6, TM5 and TM6 target molecules antitubercular Activity test
American Gift pharmaceutical Company (Eli Lilly and Company) tested the anti-tuberculosis activity of the TM 5-1-TM 5-11 samples prepared in example 2 and the TM 6-1-TM 6-13 samples prepared in example 4, and first tested the percentage inhibition rate of a single concentration of sample on Mycobacterium tuberculosis; secondly, screening out high-activity molecules to carry out multi-concentration test; finally, various cells were tested. The test results are shown in table 3.
TABLE 3 TM5 and TM6 series of target molecules against M.tuberculosis H37Inhibition rate of Rv
Figure GDA0003405286190000161
Figure GDA0003405286190000171
The results in Table 3 show that under the test concentration of a 20 mu M sample, 6 compounds with better anti-tuberculosis activity than DHA exist, wherein TM6-3 (containing 4-hydroxyphenylacetate structure) reaches 50.8%; the structure analysis shows that the carboxyl-containing phenol, the ester-containing phenol and the amido-containing phenol have good antitubercular activity when the structures are proper, wherein molecules containing ferulic acid (TM5-5) and methyl ferulate (TM6-5 and TM6-11) almost have good antitubercular activity. The invention discovers for the first time that the conjugate of carboxyl-containing phenol, ester-containing phenol and amido-containing phenol of DHA has antitubercular activity.
Example 7 glucagon-like peptide-1 (GLP-1) Activity assay of TM5 and TM6 target molecules
GLP-1 activity of the target molecule was tested by American Gift pharmacy. The study tested the results of GLP-1 secretion by the target molecule. The experimental procedure was as follows:
before the experiment, the culture medium of the human NCI-H716 cells was changed to a differentiation medium. On the day of the experiment, the cells were first washed 2 times with HBSS buffer containing BSA and DPP-IV inhibitor (final concentrations 0.1% and 1%, respectively) and then resuspended with this buffer (HBSS buffer containing BSA and DPP-IV inhibitor at final concentrations 0.1% and 1%, respectively). Next, cells were seeded at a density of 10000 cells/50. mu.L/well into poly-D-lysine-coated black-bottomed 384-well plates.
Preparing a compound to be tested: the test compound was initially at a concentration of 40 μ M and diluted down in a 3-fold gradient.
Compound dose-response curve determination: the above formulated compounds were added to 384-well plate wells that had been previously seeded with cells, followed by incubation at 37 ℃ for 2 hours. Upon stimulation with the compound, the cells secrete GLP-1 into the culture medium. GLP-1 secreted by the cells was quantified using the Alpha LISA assay kit in 384-well plate format. The signal was collected using a fully functional microplate reader Envision from Perkin Elmer. The amount of GLP-1 polypeptide synthesized by the cell is calculated by fitting the collected signal to a GLP-1 standard curve.
Calculation of percent relative agonism: relative percent agonism was determined by dividing the signal obtained at each data point for the remaining test compounds by the highest signal (Maximum response) for the standard compound, using as the standard the compound that stimulates the cell to secrete the most GLP-1. The calculation formulas of the excitation ratio (stimulation (%)) and the inhibition ratio (inhibition (%)) are as follows:
Figure GDA0003405286190000181
where Max and Min are defined based on the highest and lowest signals for each experiment. IC (integrated circuit)50Or EC50The calculated activation rate or inhibition rate is calculated by fitting the calculated activation rate or inhibition rate to a standard 4parameter logistic and non-linear regression fitting equation.
The results are shown in tables 4 and 5:
TABLE 4 GLP-1 percent agonist Activity of TM5 and TM6 target Compounds
Figure GDA0003405286190000182
Figure GDA0003405286190000191
TABLE 5 EC for GLP-1 agonistic activity of TM6-13 target compound50Value of
Figure GDA0003405286190000192
As can be seen from Table 4, when the sample concentration is 20. mu.M, DHA has no GLP-1 agonistic activity, the GLP-1 agonistic activity of 3 target compounds in TM5 series is more than 20%, the activity is preferably TM5-10 (containing 4-hydroxy phenylpropionic acid structural unit), and reaches 32.7%; the TM6 series has 1 target compound with GLP-1 agonistic activity of more than 20%, preferably TM6-13 (containing 4-hydroxyphenylacetamide structural unit). As can be seen from Table 5, the EC for the molecule tested, TM6-1350The activity is 13.9 mu M.
Example 8 study of inhibition activity of TM5 and TM6 on blood lipid lowering target PCSK9
Proprotein convertase subtilisin/kexin type 9 (PCSK 9) is a lipid metabolism regulatory protein found in 2003, belongs to Proprotein Convertase (PC) family, consists of a signal peptide, a prodomain, a catalytic domain and a carboxy-terminal domain, and is expressed in a large amount in the liver, small intestine and kidney and in a small amount in the skin and nervous system. A large number of studies have found that PCSK9 mediates degradation of Low Density Lipoprotein Receptor (LDLR) and modulates plasma low density lipoprotein cholesterol (LDL-C) levels. Therefore, therapeutic approaches to inhibit or reduce PCSK9 levels are effective in treating hypercholesterolemia, and PCSK9 has become the hotspot of hypercholesterolemia research as a new therapeutic target.
The American Gift pharmaceutical company performed PCSK9 inhibition activity tests on TM5 and TM6 series of molecules, and the activity results are shown in Table 6.
TABLE 6 results of PCSK9 inhibitory Activity of part TM5 target Compounds
Figure GDA0003405286190000201
Figure GDA0003405286190000211
As can be seen from table 6, in the first round of single concentration activity screening, the Basal _ PCSK9 HepG2 SP inhibitory activity of some target compounds was better, and at a sample concentration of 5 μ M, the PCSK9 inhibitory rate of 12 target compounds was over 40%, and the highest was 98.0%, and the cytotoxicity of other target compounds was very low (percentage inhibitory rate was less than ± 6%) except for TM 5-2; multiple concentration screening, IC of 5 compounds out of 11 target compounds tested50Values below 4. mu.M, where the IC of TM5-5 and TM5-650Values as low as 0.39 and 0.83 μ M, respectively; at the same time, the tested molecules have very low cytotoxicity, most of the IC50A value greater than 50 μ M; in the last round of activity screening (confirmation), the inhibition rates of TM5-6, TM5-10 and TM6-6 on PCSK9 ELISA RPH were all over 90%, the TM5-6 inhibition activity was the best, 101.4%, and the related IC was50The value is also lower. The invention discovers for the first time that the DHA and carboxyl-containing phenol/esterphenol/amido phenol conjugate has the activity of reducing blood fat, and the activity of partial molecules is very good.
Example 9, TM5 and TM6 Studies on Interleukin IL-17 inhibitory Activity
Interleukin 17 (IL-17) is secreted mainly from Th17 cells and acts on T cells, macrophages, granulocytes, skin cells, fibroblasts and other cells. Six IL-17 family members have been discovered to date, each IL-17A, B, C, D, E, F. IL-17 is an important inflammatory factor, and after being combined with a corresponding receptor IL-17RA/IL-17RC on the cell surface, the IL-17 stimulates target cells to secrete various inflammatory cytokines, chemokines, antimicrobial proteins and the like, thereby playing an important role in resisting infection of organisms, particularly extracellular bacteria and fungal infection. Meanwhile, the inflammatory properties of IL-17 make it closely related to various autoimmune diseases such as Rheumatoid Arthritis (RA), Multiple Sclerosis (MS), Systemic Lupus Erythematosus (SLE), psoriasis and the like. Therefore, the development of small molecule inhibitors of IL-17 is a very promising research topic.
Determination of the inhibitory Activity of IL-17: cultured cells stimulated with recombinant IL-17A were tested for inhibitory activity against 10. mu.M single concentration (SP) and multiple concentration (CRC) of the target compound
Figure GDA0003405286190000221
(homogeneous immunoassay kit based on chemiluminescence of beads, PerkinElmer) IL-17 inhibitory activity of the target compound was determined.
American Gift pharmaceutical company performed IL-17 bioactivity tests on our compounds, and the results are shown in Table 7.
Table 7 results on IL-17 Activity of target Compounds
Figure GDA0003405286190000222
Figure GDA0003405286190000231
Table 7 activity results show: the TM5 and TM6 series target molecules have certain inhibition effect on IL-17 under the condition of 10 mu M sample concentration, the IL-17 secretion inhibition activity of most molecules exceeds 50 percent, and the cytotoxicity is very low (% stim)<20%) and has a difference from IL-5 secretion inhibiting activity, and shows a certain selectivity; the tested molecules have different (2 times or more than 10 times) IL-17 and IL-5 secretion inhibition activities, and have high or low activity and low IC50<1 mu M; the tested molecules showed very low cytotoxicity (IC) against anti CD3/anti CD28/IL23_ PBMC50>30 μ M). In the second round of testing on HEK-293 cells, both tests differed in their results and IC50There are high and low, and the lowest reaches 0.134 μ M. Overall, there were 6 target compounds tested for two rounds of activity, suggesting that these several compounds have value for further research and potential for application. The invention discovers that the DHA and carboxyl-containing phenol/ester group phenol/amido phenol conjugate has biological activity in the aspect of immune diseases for the first time.
The undescribed parts of the present invention are the same as or practiced with the prior art.

Claims (7)

1. Dihydroartemisinin carboxyl/ester group phenol/amido phenol conjugate, or a pharmaceutically acceptable salt thereof, characterized by having a general structural formula of formula I:
Figure FDA0003488883560000011
wherein n is 2 or 3, Y is-H or-OMe, and Z is- (CH)2)-mor-CH-, m-0, 1 or 2, X is-OH, -O (CH)2)b-DHA', -OMe or-NH2B is 2 or 3;
wherein DHA' is the residue of dihydroartemisinin DHA with C-12 hydroxyl hydrogen removed.
2. A method for the synthesis of a dihydroartemisinin carboxyl/ester-group-containing phenol/amido-phenol conjugate as claimed in claim 1, wherein when X is-OH or-O (CH)2)b-DHA', b ═ 2 or 3, denoted TM5, the synthesis of said TM5 proceeding according to the following reaction equation, comprising the following steps:
Figure FDA0003488883560000012
wherein n is 2 or 3, Y is-H or-OMe, and Z is- (CH)2)-mor-CH ═ CH-, X is-OH or-O (CH)2)b-DHA', m ═ 0, 1 or 2, b ═ 2 or 3;
adding raw materials B1, IM1 and K2CO3And a solvent dimethylformamide, heating, stirring and dissolving, reacting for 1-15 h, and after the reaction is finished, performing post-treatment to obtain TM 5.
3. The method for synthesizing a dihydroartemisinin carboxyl-containing phenol/ester-based phenol/amido phenol conjugate as claimed in claim 2, wherein the mass ratio of the raw materials IM1 and B1 is 1: 1-2, and the reaction temperature is 40-85 ℃.
4. A process for the synthesis of a dihydroartemisinin carboxyl/ester/amido phenol conjugate as claimed in claim 1, wherein when X is-OMe or-NH2When denoted by TM6, the synthesis of TM6 proceeds according to the following reaction equation, comprising the steps of:
Figure FDA0003488883560000021
wherein n is 2 or 3, and X is-OMe or-NH2Y is-H or-OMe, Z is- (CH)2)-mor-CH ═ CH-, m ═ 0, 1, or 2;
adding raw materials B2, IM1 and K2CO3And a solvent dimethylformamide, heating, stirring and dissolving, reacting for 1-10 h, and after the reaction is finished, carrying out post-treatment to obtain the dihydroartemisinin ester-containing or acylaminophenol conjugate, namely TM 6.
5. The method for synthesizing a dihydroartemisinin carboxyl-containing phenol/ester-based phenol/amido-phenol conjugate as claimed in claim 4, wherein the mass ratio of the raw material IM1 to the raw material B2 is 1: 1-2, and the reaction temperature is 40-85 ℃.
6. Use of a dihydroartemisinin carboxyl-containing phenol/esterphenol/amidophenol conjugate or a pharmaceutically acceptable salt thereof as claimed in claim 1 for the preparation of a medicament,
the application of the compound represented by TM5-5 in preparing antituberculosis drugs;
the application of compounds represented by TM5-3, TM5-4, TM5-7 and TM5-10 in preparing antidiabetic drugs;
the application of compounds represented by TM5-1, TM5-2, TM5-3, TM5-4, TM5-5, TM5-6, TM5-7, TM5-8, TM5-10 and TM5-11 in preparing lipid-lowering medicines;
the application of compounds represented by TM5-4 and TM5-10 in preparing medicines for inhibiting interleukin-17;
the structural formula of each compound is shown as follows:
Figure FDA0003488883560000022
Figure FDA0003488883560000031
7. use of a dihydroartemisinin carboxyl-containing phenol/esterphenol/amidophenol conjugate or a pharmaceutically acceptable salt thereof as claimed in claim 1 for the preparation of a medicament,
the application of compounds represented by TM6-3, TM6-5, TM6-11 and TM6-12 in the preparation of antituberculosis drugs;
the use of a compound represented by TM6-13 for the manufacture of a medicament for the treatment of diabetes;
the application of the compounds represented by TM6-6 and TM6-11 in preparing lipid-lowering medicaments;
the application of compounds represented by TM6-2, TM6-6, TM6-8, TM6-10 and TM6-13 in preparing medicines for inhibiting interleukin-17;
the structural formula of each compound is shown as follows:
Figure FDA0003488883560000032
Figure FDA0003488883560000041
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