Tumor-targeting drug-resistant O6-thiophene methyl guanine-indolequinone-chloroethyl nitrosourea combined molecule and preparation method thereof

A technology of chloroethyl nitrosourea and nitrosourea, which is applied in the direction of antineoplastic drugs, drug combinations, active ingredients of heterocyclic compounds, etc., and can solve the problems of lack of tumor targeting and increased toxicity

Active Publication Date: 2021-11-30
BEIJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, this combination strategy greatly increases the toxicity to nor

Method used

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  • Tumor-targeting drug-resistant O6-thiophene methyl guanine-indolequinone-chloroethyl nitrosourea combined molecule and preparation method thereof
  • Tumor-targeting drug-resistant O6-thiophene methyl guanine-indolequinone-chloroethyl nitrosourea combined molecule and preparation method thereof
  • Tumor-targeting drug-resistant O6-thiophene methyl guanine-indolequinone-chloroethyl nitrosourea combined molecule and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Example 1: 3- (2- (3 - ((((5 - (((2-amino -9H- purin-6-yl) oxy) methyl) thiophen-3-yl) methyl) amino) Methyl) -5-methoxy-2-methyl-4,7-dioxide-2,3,4,7-tetrahydro-1H-indole-1-yl) ethyl) -1- (2 Synthesis of chlor-ethyl) -1-nitride (compound 1)

[0069] 1) (4- (aminomethyl) thiophene-2-yl) methanol synthesis

[0070] Weigh 4- (aminomethyl) thiophene-2-carboxylate (1.85 g, 10 mmol) dissolved in 10 ml anhydrous THF; weigh LIALH 4 (0.2g, 5.2mmol) in 100ml round bottom flask, in N 2 10 ml of anhydrous THF was added to 10 ml of anhydrous THF under protective and ice bath, and the mixture of 4- (aminomethyl) thiophene-2-carboxylate solution was added dropwise, and the reaction was reacted at 0-10 ° C for 2 h; the reaction was continued after the reaction was completed. , Water, 10% sodium hydroxide solution, water (V / V / V = ​​1: 2: 3 (water: 0.2 mL)) was quenched. The reaction solution was concentrated under reduced pressure at 50 ° C, and then the concentrate was separated and pu...

Embodiment 2

[0129] Example 2: 3- (3- (3 - ((((5 - (((2-amino -9H- purin-6-yl) oxy) methyl) thiophen-3-yl) methyl) amino) Methyl) -5-methoxy-2-methyl-4,7-oxygen-4,7-dihydro-1H-indole-1-yl) propyl) -1- (2-chloroethyl) ) -1-nitride (compound 2) synthesis

[0130] 1) (4- (aminomethyl) thiophene-2-yl) methanol synthesis

[0131] Weigh 4- (aminomethyl) thiophene-2-carboxylate (2.22 g, 12 mmol) dissolved in 10 ml of no hydrazine; weigh LIALH 4 (0.25g, 6.5mmol) in 100ml round bottom flask, in N 2 10 ml of anhydrous ether was added under protected and ice bath conditions for 10 min; add 4- (aminomethyl) thiophene-2-carboxylic acid ethyl ester solution, 2 h at 0-10 ° C; continued in an ice bath after the reaction is completed Under, water, 10% sodium hydroxide solution, water (V / V / V = ​​1: 2: 3 (water: 0.25 mL)) was quenched. The reaction solution was concentrated under reduced pressure at 50 ° C, and then the concentrate was separated and purified by silica gel column chromatography. The eluent wa...

experiment example 1

[0191] Experimental Example 1: Evaluation of anti-tumor activity

[0192] 1, experimental materials and instruments

[0193] Test compound: Compound 1 obtained in the above preparation Example, Compound 2, free Mamustine (BCNU) and BCNU + O 6 -Tmg;

[0194] Cell line: human glialum cell SF763, SF767, SF126, A549, human breast cancer cells MCF-7, human prostate cancer cell DU145;

[0195] 2, experimental method

[0196] Six tumor cells are inoculated with 96-well plates at 1000 / well, at 37 ° C, 5% CO 2 After 24 hours of culture, BCNU (positive control group 1), BCNU + O at a concentration of 20 μm, 50 μm, 100 μm, 200 μm, 500 μm, 800 μm, 1000 μm, and 2000 μm. 6 -TMG (Positive Control Group 2), Compound 1, Compound 2 A total of 4 pharmaceutical treatment groups, 6 complex apertures per group, and a control group. CCK-8 solution was used for 4 hours. The above groups were treated under aerobic and hypoxic conditions; then, 10 μl of CCK-8 solution was added to each well; finally, the...

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Abstract

The invention discloses a tumor-targeting drug-resistant O6-thiophenemethyl guanine-indolequinone-chloroethyl nitrosourea combined molecule and a preparation method thereof, and relates to the field of pharmacy. According to the compound, indolequinone serves as a hypoxia activation pharmacophore, and under the tumor hypoxia condition, indolequinone is reduced to generate an imine substance with cytotoxicity; the CENUs pharmacophore is decomposed to generate chloroethyl carbocations, so that DNA interstrand cross-linking is caused; and meanwhile, an AGT inhibitor O6-TMG derivative is released, and an AGT inhibition effect is achieved. Therefore, the compound disclosed by the invention not only can play a dual anti-tumor effect, but also has drug resistance and tumor hypoxia targeting property, and has high-efficiency and low-toxicity anti-cancer activity.

Description

Technical field [0001] The present invention relates to the field of pharmaceutical, and more particularly to a drug resistant tumor hypoxic targeting O 6 Thiophene - hydrazine - chloroethyl nitroa - combined molecule and preparation method thereof and anti-tumor application. Background technique [0002] Chlor-ethyl nitrosyl urea (CENUS) chemotherapy drug is mainly used for malignant tumors such as brain tumors, glioma and melanoma. Mainly by inducing DNA forming DG-DC share, the DNA's replication and transcription processes cannot be performed due to the DNA double strand, resulting in apoptosis, and play anti-tumor effects. During treatment, it is prone to drug resistance and the poisonous side effect on normal tissue is two major drawbacks of such drugs. O 6 - Alkylburine-DNA alkyl transferase (AGT) mediated DNA repair effect reduces anti-tumor effects, and is the main cause of tumor cells to CENUS to produce resistance. Therefore, AGT inhibitor assisted CENUS combined treatm...

Claims

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Application Information

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IPC IPC(8): C07D473/18A61K31/52A61P35/00A61P35/02
CPCC07D473/18A61P35/00A61P35/02Y02P20/55
Inventor 赵丽娇王娇娇李多孙国辉张娜钟儒刚
Owner BEIJING UNIV OF TECH
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