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6-(acetyl-Arg-Gly-Asp-AA-sulfydryl)purine, and synthesis, activity and application thereof

A technology of -gly-asp, mercaptopurine, applied in the preparation of anti-tumor drugs, anti-tumor activity, 6-purine field, can solve problems such as no obvious effect

Active Publication Date: 2020-12-22
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although a large number of studies have attempted to overcome these shortcomings of 6-mercaptopurine in the past few decades, no significant results have been achieved.

Method used

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  • 6-(acetyl-Arg-Gly-Asp-AA-sulfydryl)purine, and synthesis, activity and application thereof
  • 6-(acetyl-Arg-Gly-Asp-AA-sulfydryl)purine, and synthesis, activity and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Embodiment 1 prepares 6-(acetyl-O-ethylmercapto) purine (1)

[0020] Add 50 mL of N,N-dimethylformamide to 2.070 g (13.60 mmol) of 6-mercaptopurine, and stir at 65°C until 6-mercaptopurine is completely dissolved, and the solution is yellow and clear. Add 2.250g (16.32mmol) K 2 CO 3 As a catalyst, stir for 30min, add 1.80mL (16.32mmol) ethyl bromoacetate, and continue the reaction at 65°C. After 24 hours, TLC (petroleum ether / ethyl acetate=1 / 2) showed that 6-mercaptopurine disappeared, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained orange oil was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 1) to obtain 2.360 g (72%) of the title compound as a colorless solid. ESI-MS(m / e):239[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ):δ / ppm=13.651(s,1H),8.503(s,1H),8.499(s,1H),4.175(q,J=7.8Hz,2H),4.036(dd,J 1 =12.0Hz,J 2 =5.4Hz, 1H), 1.254(t, J=7.8Hz, 3H); 13 C-NMR (75MHz, DMSO-d 6 ): δ / ppm=...

Embodiment 2

[0021] Embodiment 2 prepares 6-(carboxymethylmercapto) purine (2)

[0022] 0.310g (1.30mmol) of 6-(acetyl-O-ethylmercapto)purine (1) was completely dissolved in 10mL of methanol, and the solution was clear and transparent. The pH of the solution was adjusted to 13 with 2N NaOH aqueous solution at 0°C. After stirring at 0°C for 4 h, the reaction was complete as monitored by TLC (petroleum ether / ethyl acetate=1 / 2). The reaction solution was saturated KHSO 4 The aqueous solution was adjusted to pH 7, concentrated under reduced pressure, a colorless salt solid precipitated, and 5 mL of water was added to completely dissolve the solid. The solution was heated at 0°C with saturated KHSO 4 The pH of the aqueous solution was adjusted to 2, and the solid was fully separated out after standing, filtered, and the filter residue was washed with distilled water, and allowed to dry naturally at room temperature to obtain 0.245 g (89%) of the title compound as a colorless solid. ESI-MS(m / ...

Embodiment 3

[0023] Example 3 Preparation of Boc-Asp(OBzl)-Phe-OBzl

[0024] Dissolve 1.660g (5.00mmol) Boc-Asp (OBzl) in 30mL of anhydrous tetrahydrofuran, add 0.675g (5.00mmol) 1-hydroxybenzotriazole at 0°C, stir for 10min, then add 1.130g (5.50mmol) dihydrofuran Cyclohexylcarbodiimide, stirred for 30min. Add 2.360g (5.50mmol) of Phe-OBzl to the reaction solution at 0°C, adjust the pH of the reaction mixture to 9 with N-methylmorpholine, and stir at room temperature for 12h. TLC (dichloromethane / methanol=40 / 1) shows The response is complete. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was dissolved in 100mL ethyl acetate, the insoluble matter was filtered off, and the filtrate was washed with saturated NaHCO 3 Wash with aqueous solution (30mL×3), wash with saturated NaCl aqueous solution (30mL×3), 5% KHSO 4 Wash with aqueous solution (30mL×3), wash with saturated NaCl aqueous solution (30mL×3), and wash with saturated NaHCO 3 ...

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Abstract

The invention discloses 6-(acetyl-Arg-Gly-Asp-AA-sulfydryl)purine as shown in a formula in the specification (AA in the formula is Phe, Val and Ser residues), a preparation method of the 6-(acetyl-Arg-Gly-Asp-AA-sulfydryl)purine, the antitumor activity of the 6-(acetyl-Arg-Gly-Asp-AA-sulfydryl)purine, and an application of the 6-(acetyl-Arg-Gly-Asp-AA-sulfydryl)purine in preparing antitumor drugs.

Description

technical field [0001] The present invention relates to 6-(acetyl-Arg-Gly-Asp-AA-mercapto)purines, their preparation method and their antitumor activity. Therefore the present invention relates to their application in the preparation of antitumor drugs. The invention belongs to the field of biomedicine. Background technique [0002] 6-Mercaptopurine is a commonly used drug in the clinical treatment of acute lymphoblastic leukemia in children. However, it is also used to treat choriocarcinoma. However, some side effects limit the clinical application of 6-mercaptopurine. For example, 6-mercaptopurine has more severe myelosuppressive effect, shorter half-life, and higher dose. Although a large number of studies have tried to overcome these disadvantages of 6-mercaptopurine in the past few decades, there is no obvious effect. After several years of exploration, the inventor found that CH 2 CO-Arg-Gly-Asp-AA (where AA is Phe, Val and Ser residues) modifying 6-SH of 6-merca...

Claims

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Application Information

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IPC IPC(8): C07K5/11C07K1/06C07K1/02A61K47/64A61K31/52A61P35/00
CPCC07K5/1019A61K47/64A61K31/52A61P35/00Y02P20/55
Inventor 赵明王玉记樊琦
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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