Tridesmoside derivative with hypoglycemic activity and application of tridesmoside derivative

Abstract

The invention belongs to the technical field of compound synthesis, and particularly relates to a tridesmoside derivative with hypoglycemic activity and application of the tridesmoside derivative. The invention provides a tadehagi triquetrum glycoside derivative with hypoglycemic activity, the structural general formula of the tadehagi triquetrum glycoside derivative is as shown in formula I, and the tadehagi triquetrum glycoside derivative has good anti-sugar activity. Therefore, the tadehagi triquetrum glycoside derivative provided by the invention can be applied to products for reducing blood sugar, and provides multiple possibilities for treatment of diabetics.

Description

Technical Field

[0001] The present invention belongs to the technical field of compound synthesis, and particularly relates to a Tadehagi tricuspidatus glycoside derivative with hypoglycemic activity and its application. Background Art

[0002] Diabetes is a chronic metabolic disease, mainly characterized by long-term blood glucose levels higher than the normal range. If diabetes is not effectively managed and controlled, it will cause various adverse effects and complications to the body, such as coronary heart disease, hypertension and stroke caused by diabetes, seriously affecting the physical and mental health of diabetic patients.

[0003] At present, there are various commonly used oral hypoglycemic drugs, but long-term use will cause side effects such as gastrointestinal reactions, obesity, heart failure, and liver damage. Therefore, the development of more efficient and less toxic oral anti-diabetic drugs has become the current trend. Tadehagi tricuspidatus glycoside is a phenylpropanoid glycoside compound isolated from the traditional Chinese medicine Tadehagi tricuspidatus, which has certain hypoglycemic activity, but it belongs to natural products and has limited sources. There is no research report on synthesizing a series of structurally similar derivatives with Tadehagi tricuspidatus glycoside as the lead compound and screening potential drugs with good anti-glycemic activity. Summary of the Invention

[0004] The purpose of the present invention is to provide a Tadehagi tricuspidatus glycoside derivative with hypoglycemic activity and its application. The Tadehagi tricuspidatus glycoside derivative has hypoglycemic activity, providing a possibility for the treatment of diabetic patients.

[0005] The present invention provides a Tadehagi tricuspidatus glycoside derivative with hypoglycemic activity, and the structural general formula of the Tadehagi tricuspidatus glycoside derivative is shown in Formula I:

[0006]

[0007] In Formula I, R is hydrogen, hydroxyl, halogen, methyl, ethyl, methoxy, ethoxy, nitro, hydroxymethyl, hydroxyethyl, aldehyde group, formyl group, acetyl group or benzyloxy group.

[0008] The present invention provides a preparation method of the Tadehagi tricuspidatus glycoside derivative according to the above technical solution, including the following steps:

[0009] Using (E)-cinnamic acid derivative and phenyl-β-D-glucopyranoside as raw materials, and using DCC and DMAP as catalysts, dissolving the raw materials and catalysts in an organic solvent in sequence, and stirring at 10-100 °C to obtain the Tadehagi tricuspidatus glycoside derivative shown in Formula I through Steglich esterification reaction.

[0010] Preferably, the organic solvent includes DMF, N,N-dimethylformamide, tetrahydrofuran, dichloromethane, dichloroethane, chloroform, toluene, acetonitrile, acetone or 1,4-dioxane.

[0011] Preferably, the molar ratio of the (E)-cinnamic acid derivative to phenyl-β-D-glucopyranoside is 1:1-3.

[0012] Preferably, the molar ratio of the (E)-cinnamic acid derivative to DCC is 1:1-3.

[0013] The present invention provides the application of the tadehagi glycoside derivative described in the above technical solution in the preparation of anti-diabetic products.

[0014] Beneficial effects:

[0015] The present invention provides a tadehagi glycoside derivative with hypoglycemic activity. The structural general formula of the tadehagi glycoside derivative is shown in Formula I, and this compound has good anti-glycation activity.

[0016] Based on the above advantages, the present invention also provides a preparation method of the tadehagi glycoside derivative and its application in the preparation of products for reducing blood sugar. The present invention uses (E)-cinnamic acid derivative and phenyl-β-D-glucopyranoside as raw materials, and can simply and quickly prepare the tadehagi glycoside derivative; the tadehagi glycoside derivative has good anti-glycation activity, laying a scientific foundation for the treatment of diabetic patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required to be used in the embodiments.

[0018] Figure 1 It shows the effect of the tadehagi glycoside derivative provided by the present invention on the blood sugar of modeled mice;

[0019] Figure 2 It shows the synthesis route of the tadehagi glycoside derivative provided by the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0020] The present invention provides a preparation method of a tadehagi glycoside derivative, including the following steps: using (E)-cinnamic acid derivative and phenyl-β-D-glucopyranoside as raw materials, using DCC and DMAP as catalysts, dissolving the raw materials and catalysts in an organic solvent in sequence, and stirring at 80 °C to obtain the tadehagi glycoside derivative shown in Formula I through Steglich esterification reaction.

[0021] In the present invention, the synthesis route of the tadehagi glycoside derivative is also provided, specifically as Figure 2 shown. In Figure 2 , A is (E)-cinnamic acid derivative, and B is phenyl-β-D-glucopyranoside.

[0022] To further illustrate the present invention, the solution provided by the present invention will be described in detail below in conjunction with the accompanying drawings and embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0023] Example 1

[0024] Synthesis of phenyl-β-D-glucopyranoside 6-(E)-4-hydroxycinnamate (Compound 1), the structural formula of which is shown as follows:

[0025]

[0026] The specific synthesis steps are as follows:

[0027] (E)-4-Hydroxycinnamic acid: phenyl glycoside: DCC and DMAP were dissolved in 3.5-fold amount of DMF in a molar ratio of 1:1.3:1.5:0.12 in sequence, and stirred at 80 °C for 30 h, then filtered by suction, washed three times with dichloromethane, the filtrate was extracted 3 times with distilled water to remove most of the high-boiling DMF, the dichloromethane was evaporated to dryness, and silica gel column chromatography was carried out to obtain Compound 1.

[0028] The analysis results are as follows: Compound 1 is a white crystal, and the yield is 8.3%; structural parameters: 1 HNMR(400MHz, C 2 D 6 SO), δ: 3.19~3.03(m, 4H), 3.61~3.65(m, 1H), 4.13~4.17(m, 1H), 4.35~4.39(m, 1H), 4.86~4.88(d, J = 7.2Hz, 1H), 5.17~5.35(m, 2H), 6.33~6.37(d, J = 16Hz, 1H), 6.75~6.77(d, J = 8.8Hz, 2H), 6.90(s, 1H), 6.96~6.98(m, 2H), 7.17~7.21(m, 2H), 7.49~7.53(m, 3H), 10.00(s, 1H); 13 CNMR(400MHz, C 2 D 6 SO), δ: 166.97, 160.44, 157.77, 145.40, 130.88, 129.87, 125.58, 122.35, 116.72, 116.35, 114.53, 100.70, 76.91, 74.28, 73.70, 70.48, 63.90.

[0029] Example 2

[0030] Synthesis of phenyl-β-D-glucoside 6-(E)-4-benzyloxycinnamate (Compound 2), whose structural formula is as follows:

[0031]

[0032] The specific synthesis steps are the same as those in Example 1 above, except that (E)-4-benzyloxycinnamic acid is used to replace (E)-4-hydroxycinnamic acid in the raw materials of Example 1.

[0033] The analysis results are as follows: Compound 2 is a white crystal, and the yield is 19.6%; Structural parameters: 1HNMR (400 MHz, C 2 D 6 SO), δ: 3.19 - 3.26 (m, 3H), 3.61 - 3.66 (m, 1H), 4.14 - 4.19 (m, 1H), 4.36 - 4.39 (m, 1H), 4.86 - 4.88 (d, J = 7.2 Hz, 1H), 5.13 (s, 1H), 5.17 - 5.18 (d, J = 4.8 Hz, 1H), 5.28 - 5.29 (d, J = 5.2 Hz, 1H), 5.35 - 5.36 (d, J = 4.8 Hz, 1H), 6.43 - 6.47 (d, J = 16 Hz, 1H), 6.88 - 6.92 (m, 1H), 6.96 - 7.04 (m, 4H), 7.17 - 7.21 (m, 2H), 7.29 - 7.43 (m, 5H), 7.57 - 7.53 (d, J = 16 Hz, 1H), 7.62 - 7.64 (m, 2H); 13CNMR (400 MHz, C 2 D 6 SO), δ: 166.85, 160.80, 157.77, 144.92, 137.24, 130.71, 129.87, 129.02, 128.49, 128.32, 127.34, 122.35, 116.73, 115.78, 100.70, 76.91, 74.27, 73.70, 70.47, 69.89, 63.98.

[0034] Example 3

[0035] Synthesis of phenyl-β-D-glucoside 6-(E)-4-methylcinnamate (Compound 3), whose structural formula is as follows:

[0036]

[0037] The specific synthesis steps are the same as those in Example 1 above, except that (E)-4-methylcinnamic acid is used to replace (E)-4-hydroxycinnamic acid in the raw materials of Example 1.

[0038] The analysis results are as follows: Compound 3 is a white crystal with a yield of 16.8%; Structural parameters: 1 HNMR(400MHz, CD 3 OD), δ: 2.34(s, 3H), 3.40~3.48(m, 3H), 3.68~3.73(m, 1H), 4.32~4.37(m, 1H), 4.50~4.54(m, 1H), 4.87~4.89(d, J = 7.6Hz, 1H), 6.43~6.47(d, J = 16Hz, 1H), 6.88~6.92(m, 1H), 7.03~7.05(m, 2H), 7.16~7.22(m, 4H), 7.44~7.46(d, J = 8Hz, 2H), 7.62~7.66(d, J = 16Hz, 1H); 13 CNMR(400MHz, CD3OD), δ: 167.19, 157.67, 145.25, 140.96, 131.65, 129.39, 129.06, 127.99, 122.12, 116.53, 116.22, 100.94, 76.57, 74.14, 73.56, 70.48, 63.45, 20.14.

[0039] Example 4

[0040] Synthesis of phenyl-β-D-glucoside 6-(E)-3-chlorocinnamate (Compound 4), the structural formula is as follows:

[0041]

[0042] The specific synthesis steps are the same as those in Example 1 above, except that (E)-3-chlorocinnamic acid is used to replace (E)-4-hydroxycinnamic acid in the raw materials.

[0043] The analysis results are as follows: Compound 4 is a white crystal with a yield of 18.8%; Structural parameters: 1 HNMR(400MHz, CD 3 OD), δ: 3.43~3.54(m, 3H), 3.68~3.73(m, 1H), 4.36~4.41(m, 1H), 4.54~4.57(m, 1H), 4.91~4.93(d, J = 7.6Hz, 1H), 6.55~6.59(d, J = 16Hz, 1H), 6.94~6.96(m, 1H), 7.05~7.08(m, 2H), 7.19~7.23(m, 2H), 7.40~7.42(m, 2H), 7.52~7.54(m, 1H), 7.61~7.65(m, 2H); 13CNMR (400 MHz, CD 3 OD), δ: 166.53, 157.64, 143.41, 136.49, 134.68, 130.23, 129.94, 129.06, 127.71, 126.20, 122.13, 119.13, 116.54, 100.89, 76.91, 74.27, 73.70, 70.47, 69.89, 63.98.

[0044] Example 5

[0045] Synthesis of phenyl-β-D-glucoside 6-(E)-4-bromocinnamate (Compound 5), the structural formula is as follows:

[0046]

[0047] The specific synthesis steps are the same as those in Example 1 above, only replacing (E)-4-hydroxycinnamic acid in Example 1 with (E)-4-bromocinnamic acid in the raw materials.

[0048] The analysis results are as follows: Compound 5 is a white crystal, and the yield is 19.1%; Structural parameters: 1 HNMR (400 MHz, CD 3 OD), δ: 3.40 - 3.48 (m, 3H), 3.68 - 3.72 (m, 1H), 4.34 - 4.39 (m, 1H), 4.50 - 4.54 (m, 1H), 4.87 - 4.89 (d, J = 7.2 Hz, 1H), 6.53 - 6.57 (d, J = 16 Hz, 1H), 6.91 - 7.05 (m, 3H), 7.16 - 7.20 (m, 2H), 7.49 - 7.61 (m, 5H); 13 CNMR (400 MHz, CD 3 OD), δ: 166.70, 157.65, 143.70, 133.57, 131.93, 129.60, 129.05, 124.24, 122.12, 118.32, 116.51, 100.91, 76.55, 74.09, 73.55, 70.43, 63.54.

[0049] Example 6

[0050] Synthesis of phenyl-β-D-glucoside 6-(E)-3-nitrocinnamate (Compound 6), the structural formula is as follows:

[0051]

[0052] The specific synthesis steps are the same as those in Example 1 above, except that (E)-3-nitrocinnamic acid is used to replace (E)-4-hydroxycinnamic acid in Example 1 in the raw materials.

[0053] The analysis results are as follows: Compound 6 is a white crystal, and the yield is 16.1%; Structural parameters: 1 HNMR(400MHz, CD 3 OD), δ: 3.41~3.48(m, 3H), 3.70~3.74(m, 1H), 4.36~4.40(m, 1H), 4.53~4.57(m, 1H), 4.88~4.91(d, J = 7.6Hz, 1H), 6.68~6.72(d, J = 16Hz, 1H), 6.92~6.94(m, 1H), 7.04~7.06(m, 2H), 7.18~7.22(m, 2H), 7.63~7.76(m, 2H), 7.99~8.01(m, 1H), 8.24~8.26(m, 1H), 8.43~8.44(m, 1H); 13CNMR(400MHz, CD 3 OD), δ: 166.91, 158.32, 149.55, 143.06, 136.99, 134.14, 130.71, 129.75, 125.00, 123.17, 122.82, 121.32, 117.20, 101.52, 77.24, 74.72, 74.23, 71.12, 64.34.

[0054] Example 7

[0055] Synthesis of phenyl-β-D-glucoside 6-(E)-4-fluorocinnamate (Compound 7), and its structural formula is shown as follows:

[0056]

[0057] The specific synthesis steps are the same as those in Example 1 above, except that (E)-4-fluorocinnamic acid is used to replace (E)-4-hydroxycinnamic acid in Example 1 in the raw materials.

[0058] The analysis results are as follows: Compound 7 is a white crystal, and the yield is 16.9%; Structural parameters: 1 HNMR(40MHz, C 2 D 6SO), δ: 3.23 - 3.26 (m, 3H), 3.62 - 3.66 (m, 1H), 4.17 - 4.22 (m, 1H), 4.37 - 4.40 (m, 1H), 4.87 - 4.88 (d, J = 7.2 Hz, 1H), 5.17 - 5.19 (d, J = 4.4 Hz, 1H), 5.28 - 5.30 (d, J = 5.2 Hz, 1H), 5.35 - 5.36 (d, J = 4.8 Hz, 1H), 6.56 - 6.60 (d, J = 16 Hz, 1H), 6.87 - 6.98 (m, 3H), 7.17 - 7.25 (m, 4H), 7.58 - 7.62 (d, J = 16 Hz, 1H), 7.75 - 7.78 (m, 2H); 13 CNMR(400MHz, C 2 D 6 SO), δ: 166.55, 162.62, 157.75, 143.97, 131.33, 131.24, 129.87, 122.35, 118.34, 116.72, 116.41, 100.70, 76.90, 74.22, 73.70, 70.44, 64.13.

[0059] Application Example 1 Evaluation of the Hypoglycemic Activity of the Compound

[0060] Grouping: Twenty-five male BALB / C mice (6 - 8 weeks old) were placed in an environment with good ventilation, room temperature of 23 ± 2°C, relative humidity of 45% - 65%, and a 12h / 12h light-dark cycle, with free access to food and water. After one week of environmental adaptation, the 25 mice were randomly divided into 2 groups, including a blank control group (5 mice) and a type 2 diabetes model group (20 mice).

[0061] Establishment of a type 2 diabetes mouse model: Twenty mice in the experimental group were used to establish a type 2 diabetes model. After continuous feeding with a high-sugar and high-fat diet for four weeks, streptozotocin (STZ, 50 mg / kg) was intraperitoneally injected for three consecutive days. One week later, blood was collected from the tail to measure the fasting blood glucose of the mice. If the fasting blood glucose value > 11.1 mmol / L, it can be determined that the mouse model was successfully established.

[0062] Drug dissolution and administration conditions: The derivative powder of Tadehagi triquetrum glycoside prepared in Examples 1 - 7 was dissolved in ethanol with a volume concentration of 100% until completely dissolved, and then gradient diluted with water until the powder precipitated to explore the appropriate ethanol concentration. Designed according to a gavage dosage of 10 mg / kg body weight each time, among which Compounds 3, 4, and 7 can be dissolved in ethanol with a volume concentration of 20% - 50%, and the dosage is between 3 - 10 μL / g.

[0063] Administration method: The successfully modeled mice were randomly divided into 4 groups, with 5 mice in each group, including a model group (0.2 mL of water per time), a compound 3 administration group, a compound 4 administration group, and a compound 7 administration group. All groups were gavaged once every morning at a dose of 10 mg / kg body weight for 3 consecutive days and then the administration was stopped.

[0064] Detection of mouse indicators: Every three days after the administration was stopped, the mice were fasted for 12 hours and then the fasting blood glucose index and body weight were measured. It was detected once before the administration, marked as the 0th time, and detected three times after the administration was stopped, marked as the 1st, 2nd, and 3rd times, for a total of four detections. The results are shown in Figure 1 (In Figure 1 , the bar chart of each group successively represents the results of the blank group, the model group, compound 3, compound 4, and compound 7; compared with the blank group P < 0.001; compared with the model group ***P < 0.001, n = 5).

[0065] Detection results: After the administration, the body weight and blood glucose of the mice were detected synchronously. No obvious changes were found in the body weight detection results.

[0066] The blood glucose detection results showed that compared with the blank group, the blood glucose of the mice in the model group increased significantly (P < 0.001), indicating that the modeling was successful; compared with the model group, the blood glucose of the modeled mice given compound 3, 4, and 7 decreased significantly (P < 0.001), indicating that the derivatives of tadehagi glycoside 3, 4, and 7 all had hypoglycemic effects on the hyperglycemic modeled mice, that is, compounds 3, 4, and 7 had good hypoglycemic activity.

[0067] Although the above embodiments have described the present invention in detail, they are only a part of the embodiments of the present invention, not all of them. People can also obtain other embodiments based on these embodiments without creative efforts, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A cucurbitacin derivative having hypoglycemic activity, characterized in that: The general structural formula of the cucurbitacin derivative is shown in Formula I: In formula I, R is hydrogen, hydroxy, halogen, methyl, ethyl, methoxy, ethoxy, nitro, hydroxymethyl, hydroxyethyl, aldehyde, formyl, acetyl or benzyloxy.

2. The method for preparing the cucurbitacin derivatives according to claim 1, characterized in that: The steps include: Using (E)-cinnamic acid derivatives and phenyl-β-D-pyranoglucoside as raw materials, DCC and DMAP as catalysts, the raw materials and catalysts are dissolved in an organic solvent in sequence, and stirred at 10-100° C., and the cucurbitacin derivatives shown in formula I are obtained through a Steglich esterification reaction.

3. The preparation method according to claim 2, characterized in that: The organic solvent includes DMF, N,N-dimethylformamide, tetrahydrofuran, dichloromethane, dichloroethane, chloroform, toluene, acetonitrile, acetone or 1,4-dioxane.

4. The preparation method according to claim 2 or 3, characterized in that: The molar ratio of the (E)-cinnamic acid derivative to phenyl-β-D-pyranoglucoside is 1:1-3.

5. The preparation method according to claim 2 or 3, characterized in that: The molar ratio of the (E)-cinnamic acid derivative to DCC is 1:1-3.

6. Use of the cucurbitacin derivatives according to claim 1 in the preparation of products for lowering blood sugar.

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