A compound capable of suppressing glutathione S-transferase and a preparing method thereof

A technology of sulfhydryl transferase and glutathione, which is applied in the field of anti-tumor drugs, can solve the problems of toxicity and side effects that limit clinical application, and achieve the effects of overcoming cisplatin resistance, low toxicity and side effects, and significant anti-tumor activity

Active Publication Date: 2019-04-02
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, severe toxic side effects and congenital or acquired cisplatin resistance limit the clinical application of cisplatin and other platinum drugs

Method used

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  • A compound capable of suppressing glutathione S-transferase and a preparing method thereof
  • A compound capable of suppressing glutathione S-transferase and a preparing method thereof
  • A compound capable of suppressing glutathione S-transferase and a preparing method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: the preparation of compound 1

[0042] Weigh 1.15g NBDHEX, 1.16g succinic anhydride and 1.42g DMAP in a 100ml round bottom flask, add 40ml dichloromethane, heat and reflux for 6 hours, after TLC detects that the NBDHEX reaction is complete, then wash once with 1M hydrochloric acid solution, Washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography, and gradient eluted with a mixed solvent of dichloromethane and methanol to obtain 1.33 g of the product with a yield of 86.3%.

[0043] ESI-MS: [M-H] - =396.08. 1 H-NMR (ppm, 300MHz, CDCl 3 ): δ8.43(d, J=9.0Hz, 1H), δ7.18(d, J=6.0Hz, 1H), δ4.14(t, J=7.5Hz, 2H), δ3.30(t, J=7.5Hz, 2H), δ2.67(4H), δ1.95~1.82(m, 2H), δ1.75~1.67(m, 2H), δ1.67~1.53(m, 2H), δ1. 53~1.42(m,2H).

Embodiment 2

[0044] Embodiment 2: the preparation of compound 2a

[0045] Weigh 218.6mg of Compound 1 and 176.0mg of TBTU into a 25ml round bottom flask, add 7ml of DMF, and stir at 40°C for 15min. Measure 85 μl of TEA and add it, and continue to stir for 15 minutes. Then weighed 176.3 mg of tetravalent platinum complex A and added it, raised the temperature to 50°C, and stirred in the dark for 24 hours, distilled off the solvent under reduced pressure, purified by silica gel column chromatography, and carried out gradient washing with a mixed solvent of petroleum ether and ethyl acetate. After removal, 110.0 mg of the product was obtained, with a yield of 30.1%.

[0046] ESI-MS: [M-H] - =730.0734. 1 H-NMR (ppm, 300MHz, DMSO-d 6 ): δ8.55(d, J=6.0Hz, 1H), δ7.50(d, J=6.0Hz, 1H), δ6.12(-NH 3 ,6H),δ4.00(t,J=7.5Hz,2H),δ3.52(t,J=7.5Hz,2H),δ2.60~2.30(m,4H),δ1.83~1.70(m ,2H), δ1.65~1.30(m,6H). 13 C-NMR (ppm, 75MHz, DMSO-d 6 ): δ173.87, 172.60, 149.65, 143.16, 140.45, 132.82, 132.57, 122.62...

Embodiment 3

[0047] Embodiment 3: the preparation of compound 2b

[0048] Weigh 198.7mg of compound 1 and 176.0mg of TBTU into a 25ml round bottom flask, add 7ml of DMF, and stir at 40°C for 15min. Measure 85 μl of TEA and add it, and continue to stir for 15 minutes. Then weighed 167.0 mg of tetravalent platinum complex B and added it, raised the temperature to 50°C, and stirred in the dark for 24 hours, distilled off the solvent under reduced pressure, purified by silica gel column chromatography, and carried out gradient washing with a mixed solvent of petroleum ether and ethyl acetate. 75.0 mg of the product was obtained with a yield of 21.0%.

[0049] ESI-MS: [M-H] - =712.0870. 1 H-NMR (ppm, 500MHz, DMSO-d 6 ): δ8.60(d, J=10.0Hz, 1H), δ7.55(d, J=10.0Hz, 1H), δ5.93(-NH 3 ,6H),δ4.04(t,J=7.5Hz,2H),δ3.40(t,J=7.5Hz,2H),δ2.47(s,4H),δ1.85~1.77(m,2H ), δ1.68~1.57(m,2H), δ1.56~1.47(m,2H), δ1.45~1.37(m,2H). 13 C-NMR (ppm, 125MHz, DMSO-d 6 ): δ173.27, 172.03, 149.10, 142.58, 139.95, 132.2...

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Abstract

A compound capable of suppressing glutathione S-transferase and a preparing method thereof are provided. The compound has a structure shown as a following formula II shown in the specification and isa compound 1 for short. The method includes weighing NBDHEX and equivalent or excessive succinic anhydride into a reaction vessel, adding a solvent, stirring and reacting the mixture at room temperature or under a heating condition, performing vacuum evaporation after the reaction is finished to remove the solvent, then dissolving a product with dichloromethane, then washing the product with an acid solution and saturated sodium chloride solution or water in order, drying the product with anhydrous sodium sulfate or anhydrous magnesium sulfate, then performing vacuum evaporation to remove thesolvent to obtain a crude product, and purifying the crude product with column chromatography on silica gel to obtain a yellow solid product. The prepared compound has a capability of obviously suppressing activity of glutathione S-transferase.

Description

technical field [0001] The invention relates to a compound with the function of inhibiting glutathione sulfhydryl transferase, belonging to the field of antitumor drugs. It specifically includes small organic molecules with the function of inhibiting glutathione sulfhydryl transferase, and tetravalent platinum complexes containing single or two small organic molecules with this function in the axial position. The invention also relates to the preparation method and application of the compound. Background technique [0002] Glutathione sulfhydryltransferases (GSTs) are a class of phase II metabolic enzymes widely present in animals and plants, which can catalyze the sulfhydryl groups of reduced glutathione (GSH) Chemotherapeutic drugs, platinum-based antineoplastic drugs, etc.) combined to form a more polar complex. These complexes are generally more water-soluble and more easily excreted from the cell. Studies have found that glutathione sulfhydryl transferase is highly e...

Claims

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Application Information

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IPC IPC(8): C07D271/12C07F15/00A61P35/00
CPCA61P35/00C07D271/12C07F15/0093
Inventor 苟少华陈宏
Owner SOUTHEAST UNIV
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