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Prodrug compound of dithiocarbamic acid metal complex as well as preparation method and application of prodrug compound

A technology of dithiocarbamic acid and metal complexes, applied in the field of pharmacy, can solve the problem that prodrugs are limited to certain specific stimuli or disease environments, achieve good clinical practicability, good druggability, and overcome single design types Effect

Pending Publication Date: 2022-08-09
SUN YAT SEN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, more technologies are prodrugs designed by utilizing the difference in biological activity of different metal oxidation states, such as common tetravalent platinum drugs, which makes the response of prodrugs only limited to certain specific stimuli or disease environments

Method used

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  • Prodrug compound of dithiocarbamic acid metal complex as well as preparation method and application of prodrug compound
  • Prodrug compound of dithiocarbamic acid metal complex as well as preparation method and application of prodrug compound
  • Prodrug compound of dithiocarbamic acid metal complex as well as preparation method and application of prodrug compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] Example 1: Preparation of ROS-sensitive copper diethyldithiocarbamate complex prodrug compound DPBD-Cu prepare

[0078] (1) The preparation process of DPBD compound is as follows:

[0079]

[0080] 1) Preparation of intermediate compound 1: mono-Boc-ethylenediamine (4.00g, 24.97mmol, 1eq), 2-chloromethylpyridine hydrochloride (9.01g, 54.93mmol, 2.2eq) and anhydrous sodium sulfate (13.23g) g, 124.84 mmol, 5 eq) was dissolved in 200 mL of methanol, and heated to reflux for 72 h under nitrogen protection. After the reaction was completed, the solvent was evaporated, redissolved in dichloromethane, and suction filtered. The filtrate was concentrated and purified by silica gel column chromatography (dichloromethane / methanol=20:1).

[0081] 2) DPA-NH 2 Preparation: Intermediate compound 1 (6.00g, 17.52mmol, 1eq) was dissolved in 150mL of dichloromethane, placed in an ice bath, trifluoroacetic acid (26ml, 20eq) was slowly added dropwise under the ice bath, and the re...

Embodiment 2

[0089] Example 2: Preparation of ROS-sensitive copper diethyldithiocarbamate prodrug compound DPPBD-Cu prepare

[0090] (1) The preparation process of DPPBD compound is as follows:

[0091]

[0092] 1) Preparation of intermediate compound 7: 2,6-bis(hydroxymethyl)-p-cresol (10g, 59.46mmol, 1eq) and imidazole (8.91g, 130.80mmol, 2.2eq) were dissolved in 40mL of anhydrous DMF, Place in ice bath. Tert-butyldimethylsilyl chloride was dissolved in 40 mL of anhydrous DMF, dropped into the above reaction solution under an ice bath, and stirred at room temperature for 2 h. The reaction solution was diluted with 200 mL of ethyl acetate, and washed three times with water (100 mL×3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=50:1).

[0093] 2) Preparation of intermediate compound 8: Intermediate compound 7 (5.11 g, 12...

Embodiment 3

[0098] Example 3: Preparation of negative control DPD-Cu

[0099] (1) The preparation process of DPD compound is as follows:

[0100]

[0101] 1) Preparation of intermediate compound 11: α-Bromophenylacetic acid (0.50g, 2.33mmol, 1eq) was dissolved in 5mL of anhydrous acetonitrile, sodium diethyldithiocarbamate (0.42g, 2.44mmol, 1.05eq) was dissolved in In 5 mL of anhydrous acetonitrile, drop it into the above solution, and stir the reaction at room temperature until a white precipitate forms. After completion of the reaction, the reaction solution was filtered, concentrated, redissolved in 25 mL of double distilled water, adjusted to pH value of about 5 with 1M HCl, extracted with dichloromethane (50 mL×3), and collected all the dichloromethane layers. Dry with anhydrous sodium sulfate, suction filtration, and concentrate the filtrate to obtain.

[0102] 2) Preparation of DPD: intermediate compound 11 (0.425 g, 1.50 mmol, 1 eq) and DPA-NH 2 (0.436g, 1.80mmol, 1.2eq) w...

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Abstract

The invention discloses a prodrug compound of a dithiocarbamic acid metal complex as well as a preparation method and application of the prodrug compound. According to the prodrug compound disclosed by the invention, dithiocarbamic acid and metal ions can be carried in a single small molecule at the same time, and the dithiocarbamic acid and the metal ions are kept in an inert state; under specific conditions, the dithiocarbamic acid prototype is triggered and released, the metal chelating function of the dithiocarbamic acid prototype is recovered, and the dithiocarbamic acid prototype and metal ions carried in molecules are subjected to intramolecular metal coordination reaction to form the dithiocarbamic acid metal complex with biological activity. The prodrug compound disclosed by the invention can realize selective in-situ activation of a metal complex, and has a good application prospect in tumor prevention and treatment and diseases related to abnormal metal ion metabolism; meanwhile, a feasible thought and a feasible method are provided for the prodrug design of the metal coordination type drug.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and relates to a prodrug compound of a metal complex of dithiocarbamate, and a preparation method and application thereof. Background technique [0002] prodrug [0003] Prodrugs are a classic strategy for drug development. Usually, chemical modification is used to link the key groups of active drugs to obtain inactive or low-activity prodrugs, which can be converted into original active drugs to play a role under specific conditions in vivo. In recent years, prodrugs that can be selectively activated at disease sites have received increasing attention. For example, in the design of anti-tumor drugs, researchers use the differences between tumor tissue and normal tissue in microenvironment, specific enzymes and specific surface antigens to design prodrugs, thereby improving the targeting of drugs, reducing adverse reactions, and expanding treatment. window, or improve the physicochemical prop...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02A61P35/00A61P3/00
CPCC07F5/025A61P35/00A61P3/00Y02P20/55
Inventor 赵春顺黄泽倩罗勇张涛
Owner SUN YAT SEN UNIV
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