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

A his-gly-lys, -gly-lys technology, applied in the direction of anti-tumor drugs, organic active ingredients, medical preparations of non-active ingredients, etc., can solve the problems of side effects, existence, and large dosage of oral mucosa

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

In addition, the large dosage of methotrexate in treatment will cause liver toxicity, side effects of oral mucosa and multi-drug resistance.
In order to overcome these shortcomings, although great efforts have been made to study the structural modification of methotrexate, problems still exist.

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Embodiment 1 prepares Boc-Gly-Lys(Cbz)-OBzl(1)

[0019] 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

[0020] Embodiment 2 prepares Gly-Lys(Cbz)-OBzl(2)

[0021] 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) 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

[0022] Example 3 Preparation of Fmoc-His(Trt)-Gly-Lys(Cbz)-OBzl(3)

[0023] 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] + , 1 H 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 for His-Gly-Lys), disclose their preparation method, disclose their antitumor activity. It is further disclosed that they have no myelosuppressive toxicity of methotrexate, no hepatotoxicity of methotrexate, no nephrotoxicity of methotrexate, and strong antitumor activity. Therefore, the present invention discloses their application in the preparation of methotrexate drugs with no myelosuppressive toxicity, no hepatotoxicity, no nephrotoxicity and strong antitumor activity.

Description

technical field [0001] The present invention relates to His-Gly-Lys modified methotrexate (R in the formula 1 R for His-Gly-Lys 2 is OH, R 1 R for OH 2 For His-Gly-Lys, and R 1 and R 2 Simultaneously His-Gly-Lys), related to their preparation methods, related to their anti-tumor activity, related to their advantages in reducing the risk of myelosuppressive toxicity caused by methotrexate, and related to their reduction of the risk of myelosuppressive toxicity caused by methotrexate Predominance of the risk of hepatic and renal toxicity. Therefore, the present invention relates to their application in the preparation of drugs that have no bone marrow toxicity, no liver toxicity, no nephrotoxicity and can inhibit tumor growth. 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 lymp...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/06C07K1/06A61K31/519A61K47/64A61P35/00
CPCC07K7/06A61P35/00A61K38/00Y02P20/55
Inventor 赵明彭师奇梁梦
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES