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his-gly-lys modified methotrexate, its synthesis, anti-metastatic activity and application

A technology of his-gly-lys and -gly-lys is applied in the preparation of anti-tumor metastases, anti-tumor metastases, and the field of methotrexate, and can solve problems such as limiting the application and curative effect of methotrexate.

Active Publication Date: 2022-04-22
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, bone marrow toxicity, liver toxicity, nephrotoxicity, oral mucosal side effects and drug resistance severely limit the application and efficacy of methotrexate.

Method used

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  • his-gly-lys modified methotrexate, its synthesis, anti-metastatic activity and application
  • his-gly-lys modified methotrexate, its synthesis, anti-metastatic activity and application
  • his-gly-lys modified methotrexate, its synthesis, anti-metastatic activity and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Embodiment 1 prepares Boc-Gly-Lys(Cbz)-OBzl(1)

[0017] Dissolve 1.02g (5.81mmol) Boc-Gly with 60mL of anhydrous tetrahydrofuran to obtain No. 1 solution. 0 ℃ and stirring, 1.43g (6.98mmol) dicyclohexyl carbodiimide and 0.79g (5.85mmol) N-hydroxybenzotriazole anhydrous tetrahydrofuran solution was added to the No. 1 solution and stirred for 30 minutes. Then add 2.35g (5.78mmol) HCl Lys(Cbz)-OBzl, adjust the pH of the reaction solution to 9 with N-methylmorpholine, remove the ice bath, and stir well at room temperature for 17 hours after TLC (dichloromethane / Methanol=30 / 1) shows that the reaction is complete, and the reaction is terminated. Filtered and concentrated, the residue was dissolved in 100mL ethyl acetate, and the solution was washed successively with saturated aqueous sodium bicarbonate (30mL×3), saturated aqueous sodium chloride (30mL×3), and 5% aqueous potassium hydrogensulfate (30mL ×3), washed with saturated sodium chloride aqueous solution (30mL×3), wa...

Embodiment 2

[0018] Embodiment 2 prepares Gly-Lys(Cbz)-OBzl(2)

[0019] 1.75 g (3.32 mmol) of compound (1) was dissolved in anhydrous ethyl acetate. Under stirring at 0°C, 20 mL of hydrogen chloride in ethyl acetate (4M) was added, and after stirring for 9 hours, TLC (dichloromethane / methanol=30 / 1) spotting showed that the reaction was complete. Under the condition of warm water bath, the reaction solution was repeatedly concentrated under reduced pressure, then the concentrate was dissolved with anhydrous ethyl acetate, the reaction solution was repeatedly concentrated under reduced pressure (3 times), and then the reactant was washed repeatedly with anhydrous ether to obtain 1.40 g (98 %) the target compound as a yellow viscous oil. ESI-MS(m / e):428[M+H] + .

Embodiment 3

[0020] Example 3 Preparation of Fmoc-His(Trt)-Gly-Lys(Cbz)-OBzl(3)

[0021] Using the method of Example 1, 2.02g (65%) of the target compound was obtained as a colorless powder from 1.87g (3.02mmol) of Fmoc-His (Trt) and 1.40g (3.02mmol) of compound (2). ESI+MS(m / e):1029[M+H] + , 1H NMR (300MHz, DMSO-d 6 ):δ / ppm=8.20(t,J=5.4Hz,1H),7.90(s,1H),7.88(s,1H),7.68-7.64(m,2H),7.43-7.20(m,27H), 7.06-7.03(m,6H),6.73(s,1H),5.12(s,1H),5.07(s,2H),5.00-4.99(m,2H),4.30-4.12(m,4H),3.75- 3.67 (m, 2H), 2.97-2.89 (m, 3H), 2.83-2.74 (m, 1H), 1.68-1.55 (m, 2H), 1.38-1.24 (m, 4H).

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Abstract

The invention discloses the His-Gly-Lys modified methotrexate of the following general formula (R in the formula 1 R for His‑Gly‑Lys 2 is OH,R 1 R for OH 2 is His‑Gly‑Lys, and R 1 and R 2 Simultaneously His-Gly-Lys), disclose their preparation method, and disclose their inhibitory effect on tumor metastasis. Therefore, the present invention discloses their application in the preparation of anti-tumor metastasis drugs.

Description

technical field [0001] The present invention relates to His-Gly-Lys modified methotrexate, their preparation method and their anti-tumor metastasis effect. Therefore, the present invention relates to their application in the preparation of anti-tumor metastasis drugs. The invention belongs to the field of biomedicine. Background technique [0002] Cancer refers to the uncontrolled and abnormal proliferation of cells, which has the opportunity to spread to other parts of the body through the blood system or lymphatic system. It is a major medical problem worldwide. According to the data on the incidence and death of malignant tumors in various regions of my country in 2015 released by the National Cancer Center in early 2019, leukemia ranks among the top ten malignant tumors with the highest mortality rate. As one of the earliest drugs used to treat acute leukemia, methotrexate has a clinical application history of more than 70 years. However, bone marrow toxicity, liver t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/097C07K1/06A61K47/64A61K31/519A61P35/04
CPCC07K5/0821C07K1/06A61K47/64A61K31/519A61P35/04
Inventor 赵明彭师奇梁梦
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES