CN111960968A - Molecule of polyunsaturated compound, synthesis method and application - Google Patents

Molecule of polyunsaturated compound, synthesis method and application Download PDF

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CN111960968A
CN111960968A CN202010875784.8A CN202010875784A CN111960968A CN 111960968 A CN111960968 A CN 111960968A CN 202010875784 A CN202010875784 A CN 202010875784A CN 111960968 A CN111960968 A CN 111960968A
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卢菲
李洋
许正双
李旺
张涛
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Peking University Shenzhen Graduate School
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Abstract

The invention provides a molecule of a polyunsaturated compound, a synthetic method and application. The product of the invention has no obvious toxicity to cells. The compounds of the present invention have an enhanced ability to promote cellular carbohydrate metabolism compared to metformin. The product of the invention has no obvious influence on cell growth at the concentration of 200 uM. Compared with metformin, the product of the invention has obviously reduced drug concentration for promoting cell glycometabolism, and the effective drug concentration is about 20 times lower than that of metformin. The series of compounds of the invention have stronger sugar consumption promotion effect than metformin, and the effect concentration is obviously reduced.

Description

Molecule of polyunsaturated compound, synthesis method and application
Technical Field
The invention belongs to the field of chemistry, and particularly relates to a molecule, a synthetic method and application of a polyunsaturated compound.
Background
Glucose is an important source of energy required for human life activities and is a necessary nutrient for metabolism of organisms. Glucose is also an important constituent of biological macromolecules. Glycolipids and glycoproteins distributed on cell membranes, forming membrane surface antigens and receptor molecules, play a crucial role in cell recognition and signaling. Meanwhile, glycolipids and glycoproteins are also important components of neural tissues, which are essential for maintaining the normal function of neural cells. Glycosylation modification of protein molecules can form substances with important biological activities, such as antibodies, enzymes, hormones, and the like. Glucose also has effects of improving memory, and stimulating calcium absorption. In addition, since tumor cells obtain energy mainly through glycolysis pathway, their dependence on glucose is much higher than that of normal cells of the body. Therefore, modulating the glucose uptake capacity of cells, either by promoting or inhibiting glucose uptake by cells, would have a wide range of potential for biological applications.
Disclosure of Invention
The invention provides a molecule with the glucose absorption capacity of a cell, which is a derivative with non-conjugated polyene. The method comprises the following specific steps:
a molecule of polyunsaturated compound having the general structural formula:
Figure BDA0002652636150000011
wherein m1 takes the value of 0-7, m2 takes the value of 0-7, and n takes the value of 1-5. I.e., m1 may be 0-7 carbon atoms, and so on.
X is O or NH.
Y is NH2Or NHR. R is C (═ O) Z or C (═ NH) Z. Z is NHAr or NHR1OR OR2. Incidentally, C (═ O) Z, C (═ NH) Z here means a double bond.
Ar is a benzene ring or a substituted benzene ring (the substituent is halogen at any position, straight chain or branched chain alkyl of C1-C8, amino, carboxyl, amide, sulfonic group, sulfonamido or aromatic heterocycle.
R1 and R2 are both C1-C8 straight-chain or branched-chain alkyl, acyl, guanidino, ureido, and thioureido.
Further, the substituted benzene ring refers to halogen at any position, straight-chain or branched-chain alkyl of C1-C8, amino, carboxyl, amide, sulfonic group, sulfonamido or aromatic heterocycle.
Further, sulfonamido refers to: the amino is primary amine or substituted amino. The aromatic heterocyclic ring is as follows: pyridine, thiophene, thiazole, oxazole, imidazole, indole or quinoline.
Further, R1 and R2 may be substituted forms of C1-C8 straight or branched chain alkyl, acyl, guanidino, ureido, thioureido.
One of the synthesis methods of the molecule of the polyunsaturated compound is carried out according to the following steps:
step 1: dissolving omega-3 eicosapentaenoic acid in toluene, adding triethylamine and azido diphenyl phosphate at room temperature, stirring for 6 hours, then distilling under reduced pressure to remove the solvent, and separating the residue by silica gel column chromatography to obtain a light yellow oily compound 1.
Step 2: 1, 4-dioxane was added to a round bottom flask under nitrogen, followed by the addition of compound 1 and n-butanol in that order, and heated to reflux for 10 hours. Cooling to room temperature, distilling under reduced pressure to remove the solvent, diluting the residue with ethyl acetate, washing with saturated ammonium chloride solution and saturated sodium chloride solution in sequence, drying the organic phase with anhydrous sodium sulfate, filtering, spin-drying, and separating with silica gel column chromatography to obtain light yellow oily compound, i.e. the final product.
The second method for synthesizing the molecule of the polyunsaturated compound comprises the following steps:
step 1: EPA was dissolved in 30mL of anhydrous tetrahydrofuran, lithium aluminum hydride was added in portions under ice-bath and reacted for 3 hours until the starting material was completely reacted. After the reaction was quenched by adding a saturated sodium potassium tartrate solution, ethyl acetate was added for dilution, followed by washing with a saturated aqueous sodium bicarbonate solution, a saturated ammonia chloride solution and a saturated sodium chloride solution in this order. The organic phase is dried by anhydrous sodium sulfate, filtered and dried to obtain a light yellow oily compound 3 which is directly put into the next reaction.
Step 2: dissolving the compound 3 in anhydrous tetrahydrofuran, sequentially adding N-hydroxyphthalimide, triphenylphosphine and diethyl azodicarboxylate under the protection of nitrogen, stirring for 3 hours at room temperature, adding ethyl acetate for dilution, and sequentially washing with a saturated sodium bicarbonate aqueous solution, a saturated ammonia chloride solution and a saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, dried and chromatographed on silica gel to give a pale yellow oily compound. The oily compound was dissolved in a mixed solution of tetrahydrofuran and methanol, and the hydrazine hydrate solution was slowly added dropwise with vigorous stirring and the reaction was continued for 2 hours. After the reaction is completed, the solvent is removed by reduced pressure distillation, and the residue is separated by silica gel column chromatography to obtain a light yellow oily compound which is the final product.
The invention relates to the use of a molecule of a polyunsaturated compound which regulates glucose metabolism.
Further, the polyunsaturated compounds provide inhibitory modulation of glucose metabolism.
Further, the present polyunsaturated compound is used in a dosage of 0.01 to 0.10 of metformin with the same inhibitory effect.
Furthermore, the polyunsaturated compound can be used in the fields of sugar metabolism inhibition of type II diabetes mellitus, sugar metabolism inhibition of tumor cells and the like.
Advantageous technical effects
The product of the invention has no obvious toxicity to cells.
The compounds of the present invention have an enhanced ability to promote cellular carbohydrate metabolism compared to metformin.
The product of the invention has no obvious influence on cell growth at the concentration of 200 uM.
Compared with metformin, the product of the invention has obviously reduced drug concentration for promoting cell glycometabolism, and the effective drug concentration is about 20 times lower than that of metformin.
The series of compounds of the invention have stronger sugar consumption promoting effect than metformin, and the acting concentration is obviously reduced, but the maximum using concentration is not suitable to exceed 200 uM.
Drawings
FIG. 1 is a schematic representation of the effect of PUFA compounds on cell growth.
Fig. 2 is a schematic representation of the regulation of glucose absorption by PUFA compounds.
FIG. 3 is a schematic representation of the effect of PUFA-13 and metformin on cell growth.
FIG. 4 is a schematic representation of the effect of PUFA-13 on glucose uptake by cells under short treatment times.
FIG. 5 is a schematic representation of the effect of PUFA-12 and PUFA-13 on the metabolism of glucose by cells at high concentrations.
FIG. 6 is a scheme of the synthesis of example 1.
FIG. 7 is a scheme of the synthesis of example 2.
FIG. 8 is a scheme of the synthesis of example 3.
FIG. 9 is a scheme showing the synthesis of example 4.
FIG. 10 is a scheme showing the synthesis of example 5.
FIG. 11 is a scheme of the synthesis of example 6.
FIG. 12 is a scheme showing the synthesis of example 7.
FIG. 13 is a scheme showing the synthesis of example 8.
FIG. 14 is a scheme showing the synthesis of example 9.
FIG. 15 is a scheme showing the synthesis of example 10.
FIG. 16 is a scheme showing the synthesis of example 11.
FIG. 17 is a scheme showing the synthesis of example 12.
FIG. 18 is a scheme showing the synthesis of example 13.
FIG. 19 is a comparison of the chemical formulas and numbering of the products of examples 1-13 (FIGS. 6-18).
Detailed Description
Technical features of the present invention will now be described in detail with reference to the accompanying drawings.
Example 1
Referring to fig. 6, synthesis of compound 1:
omega-3 Eicosapentaenoic acid (EPA) (2.0g,6.6mmol) was dissolved in 10mL of toluene, triethylamine (2.2mL, 15mmol) and Diphenylphosphorylazide (DPPA) (2.75g,10mmol) were added at room temperature, after stirring for 6 hours, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to give compound 1(1.62g, 75%) as a pale yellow oil.
Under nitrogen protection, 10mL of 1, 4-dioxane was added to a round-bottom flask, followed by the addition of compound 1(327mg, 1mmol) and n-butanol (0.91mL, 10mmol) in that order, and the mixture was heated to reflux for 10 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was diluted with 50mL of ethyl acetate and then washed successively with a saturated ammonium chloride solution and a saturated sodium chloride solution, and after the organic phase was dried over anhydrous sodium sulfate, it was filtered off and subjected to column chromatography on silica gel to give PUFA-003(246mg, 66%) as a pale yellow oily compound.1H NMR(300MHz,CDCl3)5.41–5.12(m,10H),4.61(s,1H),4.07–3.89(m,2H),3.16–3.00(m,2H),2.80–2.65(m,8H),2.07–1.90(m,4H),1.56–1.40(m,4H),1.36–1.19(m,2H),0.95–0.75(m,6H)-ppm；HRMS C24H39NO2Na+[M+Na]+Theoretical value: 396.2873, found: 396.2873.
example 2
Referring to FIG. 7, the synthesis route of omega-3 Docosahexaenoic acid (DHA) as raw material is as aboveOperation reference example 1 gave PUFA-004.1H NMR(300MHz,CDCl3)5.50–5.13(m,12H),4.64(s,1H),3.94(t,J＝6.7Hz,2H),3.19–3.01(m,2H),2.83–2.64(m,11H),2.25–2.10(m,2H),2.07–1.88(m,2H),1.58–1.38(m,2H),1.36–1.20(m,2H),0.97–0.74(m,6H)ppm；HRMS C26H41NO2Na+[M+Na]+Theoretical value: 422.3030, found: 422.3030.
example 3
Referring to FIG. 8, experimental procedure the synthesis of PUFA-005 from reference example 1 was carried out using the reaction of intermediate 1 with p-methylaniline.1HNMR(300MHz,CDCl3)7.56(s,1H),7.05(d,J＝8.4Hz,2H),6.93(d,J＝8.3Hz,2H),5.75(t,J＝5.7Hz,1H),5.40–5.14(m,10H),3.13–2.97(m,2H),2.84–2.59(m,8H),2.17(s,3H),2.10–1.85(m,4H),1.47–1.29(m,2H),0.89(t,J＝7.5Hz,3H)ppm；HRMS C27H38N2ONa+[M+Na]+Theoretical value: 429.2876, found: 429.2876.
example 4
Referring to fig. 9, experimental procedures reference example 1 was performed to synthesize PUFA-006 using reaction of intermediate 2 with p-methylaniline.1H NMR(300MHz,CDCl3)7.09–6.95(m,4H),6.21(s,1H),5.51–5.10(m,12H),4.73(t,J＝5.8Hz,1H),3.19(td,J＝6.7,5.6Hz,2H),2.73(dt,J＝10.5,5.7Hz,10H),2.22(s,3H),2.21–2.15(m,2H),2.06–1.90(m,2H),0.88(t,J＝7.5Hz,3H)ppm；HRMS C29H41N2O+[M+H]+Theoretical value: 433.3213, found: 433.3202.
example 5
Referring to FIG. 10, experimental procedure reference example 1 gave PUFA-007 synthesized using reaction of intermediate 1 with furfuryl amine.1H NMR(300MHz,CDCl3)7.24(dd,J＝1.9,0.8Hz,1H),6.21(dd,J＝3.2,1.9Hz,1H),6.11(dd,J＝3.2,0.9Hz,1H),5.80(s,1H),5.39–5.12(m,11H),4.32(d,J＝5.5Hz,2H),2.79–2.63(m,10H),2.10(dd,J＝8.3,6.9Hz,2H),2.06–1.91(m,5H),1.69–1.56(m,2H),0.87(t,J＝7.5Hz,3H)ppm；HRMS C25H36N2O2Na+[M+Na]+Theoretical value: 419.2669, found: 419.2668.
example 6
Referring to fig. 11, experimental procedures reference example 1 gave PUFA-008 via reaction of intermediate 2 with furfuryl amine.1H NMR(300MHz,CDCl3)7.21(d,J＝1.8Hz,1H),6.18(dd,J＝3.2,1.9Hz,1H),6.07(d,J＝3.2Hz,1H),5.46–5.20(m,12H),5.20–5.07(m,1H),4.90(t,J＝5.7Hz,1H),4.21(d,J＝5.7Hz,2H),3.09(td,J＝6.8,5.6Hz,2H),2.85–2.64(m,12H),2.24–2.06(m,2H),2.06–1.90(m,2H),0.88(t,J＝7.5Hz,3H)ppm；HRMS C27H39N2O2 +[M+H]+Theoretical value: 423.3006, found: 423.3007.
example 7
Referring to fig. 12, experimental procedure reference example 1 was performed to synthesize PUFA-012 using reaction of intermediate 2 with glycine ethyl ester.1H NMR(500MHz,CDCl3)5.49–5.22(m,12H),4.14(q,J＝2.5Hz,2H),3.93(d,J＝5.5Hz,2H),3.25–3.14(m,2H),2.82–2.64(m,10H),2.29–2.17(m,2H),2.12–1.96(m,2H),1.24(t,J＝3.5Hz,3H),0.93(t,J＝7.5Hz,3H)ppm；HRMS C26H41N2O3 +[M+H]+Theoretical value: 429.3112, found: 429.3115.
example 8
Referring to FIG. 13, EPA (3.1g, 10mmol) was dissolved in 30mL of anhydrous tetrahydrofuran, lithium aluminum hydride (380mg, 10mmol) was added in portions under ice bath and reacted for 3 hours until the starting material was completely reacted. After quenching the reaction by adding a saturated sodium potassium tartrate solution (10mL), 100mL of ethyl acetate was added for dilution, followed by washing with a saturated aqueous sodium bicarbonate solution, a saturated ammonium chloride solution and a saturated sodium chloride solution in this order. The organic phase is dried by anhydrous sodium sulfate, filtered and dried to obtain a light yellow oily compound 3 which is directly put into the next reaction. Compound 3(2.5g, 8.7mmol) was dissolved in 30mL of anhydrous tetrahydrofuran, N-hydroxyphthalimide (1.6g, 10mmol), triphenylphosphine (2.6g, 10mmol), diethyl azodicarboxylate (1.7g, 10mmol) were added sequentially under nitrogen, stirred at room temperature for 3 hours, diluted with 70mL of ethyl acetate and then diluted sequentially with saturated sodium bicarbonateAqueous solution, saturated ammonia chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, dried and chromatographed on a silica gel column to give a pale yellow oily compound (2.35g, 62%). The aforementioned oily compound (2.35g, 5.4mmol) was dissolved in a mixed solution of tetrahydrofuran and methanol (70mL, THF: MeOH ═ 2:5), and a hydrazine hydrate solution was slowly added dropwise with vigorous stirring and the reaction was continued for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to give PUFA-010(1.5g, 91%) as a pale yellow oily compound.1H NMR(300MHz,CDCl3)5.41–5.22(m,10H),3.64–3.49(m,2H),2.74(dt,J＝10.9,5.3Hz,8H),1.98(p,J＝8.0,7.6Hz,4H),1.60–1.42(m,2H),1.42–1.25(m,2H),0.88(t,J＝7.5Hz,3H)ppm；HRMS C20H34NO+[M+H]+Theoretical value: 304.2635, found: 304.2634.
example 9
Referring to FIG. 14, experimental procedures reference example 8 was performed to synthesize PUFA-011 using DHA as a starting material.1H NMR(300MHz,CDCl3)5.39–5.12(m,12H),3.56(t,J＝6.5Hz,2H),2.82–2.64(m,10H),2.09–1.87(m,4H),1.62–1.46(m,2H),0.87(t,J＝7.5Hz,3H)ppm；HRMS C22H35NONa+[M+Na]+Theoretical value: 330.2791, found: 330.2791.
example 10
Referring to FIG. 15, the compound PUFA-010(303mg, 1mmol) and N-cyano-N ', N' -dimethylguanidine (120mg,1.1mmol) were sequentially dissolved in 10mL of N-butanol solution, concentrated hydrochloric acid solution (100uL) was added at room temperature, followed by heating to reflux for 12 hours, cooling to room temperature after the starting material was completely disappeared and the solvent was distilled off under reduced pressure, and the residue was isolated using a preparative thin layer chromatography plate to give PUFA-001(15mg, 3.6%) as an oily compound.1HNMR(500MHz,Chloroform-d)5.49–5.25(m,10H),3.86(t,J＝6.6Hz,2H),2.96(s,6H),2.89–2.77(m,8H),2.16–2.02(m,4H),1.70–1.61(m,2H),1.51–1.39(m,2H),0.98(t,J＝7.5Hz,3H)ppm；MS-ESI C24H42N5O+[M+H]+Theoretical value: 416, found: 416.
example 11
Referring to FIG. 16, experimental procedures reference example 11 was carried out using PUFA-011 as a starting material to synthesize PUFA-002.1H NMR(500MHz,CDCl3)5.50–5.23(m,12H),3.88(t,J＝6.5Hz,2H),3.22(s,6H),2.90–2.75(m,10H),2.24–2.02(m,4H),1.76–1.62(m,2H),0.97(t,J＝7.5Hz,3H)ppm；MS-ESI C26H44N5O+[M+H]+Theoretical value: 442, found: 442.
example 12
Referring to FIG. 17, experimental procedures reference example 11 gave PUFA-009 synthesized using PUFA-010 and spermidine as starting materials.1H NMR(500MHz,Chloroform-d)5.51–5.27(m,10H),3.89(t,J＝6.6Hz,2H),2.83(dt,J＝17.2,5.7Hz,8H),2.15–2.05(m,2H),1.64(h,J＝6.3Hz,4H),1.41(dq,J＝24.5,7.5Hz,2H),1.04–0.93(m,3H)ppm；MS-ESI：C22H38N5O+[M+H]+Theoretical value: 388, found: 388.
example 13
Referring to fig. 18, experimental procedure reference example 1 gave PUFA-015 using reaction of intermediate 1 with ethyl glycinate.1H NMR(300MHz,Chloroform-d)5.57–5.24(m,10H),5.15(t,J＝5.4Hz,1H),4.89(t,J＝5.8Hz,1H),4.21(q,J＝7.1Hz,2H),4.00(d,J＝5.4Hz,2H),3.19(td,J＝7.4,5.8Hz,2H),2.84(dt,J＝10.5,5.3Hz,8H),2.19–2.00(m,4H),1.68–1.49(m,2H),1.29(t,J＝7.2Hz,3H),0.98(t,J＝7.5Hz,3H).HRMS：C24H38N2O3Na+[M+Na]+Theoretical value: 425.2775, found: 425.2785.
example 14 cytotoxicity assays for PUFA Compounds
Referring to fig. 1, HepG2 cells were seeded at 1.5 x 10^5 per well in 24-well plates, after 24 hours 50uM or 100uM PUFA1-PUFA15 compound was added per well, after 48 hours of incubation, cells were trypsinized, the number of cells counted, and the number of cells in compound-treated wells was set to 100% with DMSO as control, and the relative cell number was obtained by comparing the number of cells in compound-treated wells to the number of DMSO wells. As shown in fig. 1, compounds No. 1, 2, 3, 4, 8, 9, and 14 have strong cytotoxic effects, and cause significant cell death at both 50uM and 100uM, whereas compound No. 13 has significant toxicity to cells at 100uM, and the remaining compounds have insignificant toxicity to cells at 100 uM.
Example 15 Effect of PUFA Compounds on glucose uptake by cells
Referring to FIG. 2, HepG2 cells were seeded at 5 x 10^3 per well in 96-well plates and after 24 hours, the culture medium in the wells was discarded and replaced with medium containing the desired concentration of small compounds. After 48 hours of treatment with the small molecule compound, 20. mu.L of the culture medium per well was added to 180. mu.L of the glucose assay reagent, reacted at 37 ℃ for 15 minutes, and the relative consumption of glucose was calculated by reading at a wavelength of 505 nm. DMSO is used as a drug blank control, and metformin is used as a drug positive control. As shown in FIG. 2, the consumption of glucose by cells was increased compared to DMSO in 100uM small molecule treatment. Compared with metformin, the PUFA series compounds have enhanced capability of promoting the glycometabolism of cells.
Metformin is a biguanide oral hypoglycemic agent, is one of the most common oral hypoglycemic agents clinically used at present, can promote the utilization of glucose through anaerobic glycolysis, and is suitable for treating type 2 diabetes which is ineffective in simple diet control and physical exercise treatment, especially for treating patients with obesity and diabetes accompanied with hyperinsulinemia. At the cellular level, PUFA series compounds show stronger sugar consumption promoting capability than metformin, but the sugar reducing effect of the PUFA series compounds still needs to be further verified at the animal level.
FIG. 19 is a comparison of the chemical formulas and numbering of the products of examples 1-13 (FIGS. 6-18).
Example 16 detection of the cytotoxic Effect of PUFA-13 and metformin in high concentrations
Referring to FIG. 3, HepG2 cells were seeded at 5 x 10^3 per well in 96-well plates and after 24 hours, the culture medium in the wells was discarded and replaced with medium containing the desired concentration of small compounds. After 46 hours of treatment with the small molecule compound, 20uL of CCK8 detection reagent was added to each well, and after 1 hour of incubation at 37 ℃, the plates were read at 495nm wavelength to calculate the relative growth rate of the cells. Metformin was used as a positive control. As shown in FIG. 3, PUFA-13 had no significant effect on cell growth at a concentration of 200uM, while metformin had no significant effect on cell growth at a concentration of 2 mM.
Example 17 Effect of PUFA-13 on glucose uptake by cells with short treatment times
Referring to FIG. 4, HepG2 cells were seeded at 5 x 10^3 per well in 96-well plates and after 24 hours, the culture medium in the wells was discarded and replaced with medium containing the desired concentration of small compounds. After 24 hours of treatment of the small molecule compound, 20. mu.L of culture solution per well was added to 180. mu.L of glucose assay reagent, reacted at 37 ℃ for 15 minutes, and the relative consumption of glucose was calculated by reading at 505 nm. DMSO is used as a drug blank control, and metformin is used as a drug positive control. As shown in fig. 4, compared to metformin, the drug concentration of PUFA-13 for promoting cellular glycometabolism was significantly reduced, and the effective drug concentration was about 20 times lower than that of metformin.
Example 18 Effect of PUFA-12 and PUFA-13 on cellular metabolism of glucose at high concentrations
Referring to FIG. 5, HepG2 cells were seeded at 5 x 10^3 per well in 96-well plates and after 24 hours, the culture medium in the wells was discarded and replaced with medium containing the desired concentration of small compounds. After 48 hours of treatment with the small molecule compound, 20. mu.L of the culture medium per well was added to 180. mu.L of the glucose assay reagent, reacted at 37 ℃ for 15 minutes, and the relative consumption of glucose was calculated by reading at a wavelength of 505 nm. DMSO is used as a drug blank control, and metformin is used as a drug positive control. As shown in FIG. 5, both PUFA-12 and PUFA-13 have a stronger sugar metabolism promoting effect than metformin, and PUFA-12 has a stronger glucose consumption promoting effect than PUFA-13. However, under the condition of high-concentration drug treatment, the cell growth state is obviously deteriorated, the metabolic capability is also weakened correspondingly, and the PUFA-13 has more obvious influence on the cell growth than the PUFA-12.
These results suggest that the PUFA series compounds have a stronger sugar consumption promoting effect than metformin and significantly lower acting concentrations, but the maximum use concentration should not exceed 200 uM.

Claims (10)

1. A molecule of a polyunsaturated compound, characterized in that: a compound having the general structural formula:
Figure FDA0002652636140000011
wherein m1 takes the value of 0-7, m2 takes the value of 0-7, and n takes the value of 1-5; i.e., m1 may be 0-7 carbon atoms, and so on;
x is O or NH;
y is NH2Or NHR; r is C (═ O) Z or C (═ NH) Z; z is NHAr or NHR1OR OR2(ii) a Incidentally, C (═ O) Z, C (═ NH) Z herein means a double bond;
ar is a benzene ring or a substituted benzene ring (the substituent is halogen at any position, straight chain or branched chain alkyl of C1-C8, amino, carboxyl, amide, sulfonic group, sulfonamido or aromatic heterocycle;
r1 and R2 are both C1-C8 straight-chain or branched-chain alkyl, acyl, guanidino, ureido, and thioureido.
2. A molecule of polyunsaturated compound according to claim 1, characterized in that: the substituted benzene ring refers to halogen at any position, straight-chain or branched-chain alkyl of C1-C8, amino, carboxyl, amide, sulfonic group, sulfonamido or aromatic heterocycle.
3. A molecule of polyunsaturated compound according to claim 2, characterized in that: sulfonamido refers to: the amino is primary amine or substituted amino; the aromatic heterocyclic ring is as follows: pyridine, thiophene, thiazole, oxazole, imidazole, indole or quinoline.
4. A molecule of polyunsaturated compound according to claim 1, characterized in that: r1 and R2 can also be substituted forms of C1-C8 straight or branched chain alkyl, acyl, guanidino, ureido, thioureido.
5. A method of synthesizing a molecule of polyunsaturated compound according to any one of claims 1 to 4, characterized in that: the method comprises the following steps:
step 1: dissolving omega-3 eicosapentaenoic acid in toluene, adding triethylamine and azido diphenyl phosphate at room temperature, stirring for 6 hours, then distilling under reduced pressure to remove the solvent, and separating the residue by silica gel column chromatography to obtain a light yellow oily compound 1;
step 2: adding 1, 4-dioxane into a round-bottom flask under the protection of nitrogen, sequentially adding a compound 1 and n-butanol, and heating to reflux for 10 hours; cooling to room temperature, distilling under reduced pressure to remove the solvent, diluting the residue with ethyl acetate, washing with saturated ammonium chloride solution and saturated sodium chloride solution in sequence, drying the organic phase with anhydrous sodium sulfate, filtering, spin-drying, and separating with silica gel column chromatography to obtain light yellow oily compound, i.e. the final product.
6. A method of synthesizing a molecule of polyunsaturated compound according to any one of claims 1 to 4, characterized in that: the method comprises the following steps:
step 1: dissolving EPA in 30mL of anhydrous tetrahydrofuran, adding lithium aluminum hydride in batches in ice bath, reacting for 3 hours until the raw materials completely react, adding saturated sodium potassium tartrate solution, quenching the reaction, adding ethyl acetate for dilution, then sequentially using saturated sodium bicarbonate water solution, saturated ammonia chloride solution and saturated sodium chloride solution for washing, drying an organic phase with anhydrous sodium sulfate, filtering, and spin-drying to obtain a light yellow oily compound 3 which is directly put into the next reaction;
step 2: dissolving a compound 3 in anhydrous tetrahydrofuran, sequentially adding N-hydroxyphthalimide, triphenylphosphine and diethyl azodicarboxylate under the protection of nitrogen, stirring for 3 hours at room temperature, adding ethyl acetate for dilution, sequentially washing with a saturated sodium bicarbonate aqueous solution, a saturated ammonia chloride solution and a saturated sodium chloride solution, drying an organic phase with anhydrous sodium sulfate, filtering, spin-drying, and separating by using a silica gel column chromatography to obtain a light yellow oily compound; dissolving the oily compound in a mixed solution of tetrahydrofuran and methanol, slowly dropwise adding a hydrazine hydrate solution under vigorous stirring, continuously reacting for 2 hours, removing the solvent by reduced pressure distillation after the reaction is completed, and separating the residue by silica gel column chromatography to obtain a light yellow oily compound, namely the final product.
7. Use of a molecule of a polyunsaturated compound according to any one of claims 1 to 4, characterized in that: the polyunsaturated compounds have a regulating effect on glucose metabolism.
8. Use of a molecule of a polyunsaturated compound according to claim 7, characterized in that: the polyunsaturated compounds provide for the inhibitory regulation of glucose metabolism.
9. Use of a molecule of a polyunsaturated compound according to claim 7, characterized in that: the polyunsaturated compound is used in a dosage of 0.01 to 0.10 of metformin with the same inhibitory effect.
10. Use of a molecule of a polyunsaturated compound according to claim 7, characterized in that: the polyunsaturated compound can be used in the fields of sugar metabolism inhibition of type II diabetes mellitus or sugar metabolism inhibition of tumor cells and the like.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002076404A2 (en) * 2001-03-23 2002-10-03 Protarga, Inc. Fatty alcohol drug conjugates

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002076404A2 (en) * 2001-03-23 2002-10-03 Protarga, Inc. Fatty alcohol drug conjugates

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* Cited by examiner, † Cited by third party
Title
DARRELL WELLS等: "Nonionic Urea Surfactants: Formation of Inverse Hexagonal Lyotropic Liquid Crystalline Phases by Introducing Hydrocarbon Chain Unsaturation", 《J. PHYS. CHEM. B》 *
EDWARD W. NG等: "Unique Analogues of Anandamide: Arachidonyl Ethers and Carbamates and Norarachidonyl Carbamates and Ureas", 《J. MED. CHEM.》 *

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