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tumor-targeted anti-drug 6 -Thienylguanine-indolequinone-chloroethylnitrosourea combined molecule and preparation method thereof

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

Active Publication Date: 2022-07-12
BEIJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this combination strategy greatly increases the toxicity to normal cells while acting on tumor cells, that is, it lacks tumor targeting.

Method used

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  • tumor-targeted anti-drug <sup>6</sup> -Thienylguanine-indolequinone-chloroethylnitrosourea combined molecule and preparation method thereof
  • tumor-targeted anti-drug <sup>6</sup> -Thienylguanine-indolequinone-chloroethylnitrosourea combined molecule and preparation method thereof
  • tumor-targeted anti-drug <sup>6</sup> -Thienylguanine-indolequinone-chloroethylnitrosourea 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-dioxo-2,3,4,7-tetrahydro-1H-indol-1-yl)ethyl)-1-(2 Synthesis of -chloroethyl)-1-nitrosourea (compound 1)

[0069] 1) Synthesis of (4-(aminomethyl)thiophen-2-yl)methanol

[0070] Weigh 4-(aminomethyl)thiophene-2-carboxylate ethyl ester (1.85g, 10mmol) and dissolve it in 10mL of anhydrous THF; weigh out LiAlH 4 (0.2g, 5.2mmol) in a 100mL round bottom flask under N 2 Add 10 mL of anhydrous THF and stir for 10 min under protection and ice bath conditions; add 4-(aminomethyl)thiophene-2-carboxylate ethyl ester solution dropwise, react at 0-10 °C for 2 h; continue to stir in ice bath after the reaction is over , quenched with water, 10% sodium hydroxide solution, water (v / v / v=1:2:3 (water: 0.2 mL)). The reaction solution was concentrated by rotary evaporation under reduced pressure at 50 °C, and then the concentrated solution was separated and purified b...

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-dioxo-4,7-dihydro-1H-indol-1-yl)propyl)-1-(2-chloroethyl) )-1-Nitrosourea (Compound 2) Synthesis

[0130] 1) Synthesis of (4-(aminomethyl)thiophen-2-yl)methanol

[0131] Weigh 4-(aminomethyl)thiophene-2-carboxylate ethyl ester (2.22 g, 12 mmol) and dissolve it in 10 mL of anhydrous ether; weigh LiAlH 4 (0.25g, 6.5mmol) in a 100mL round bottom flask under N 2 Add 10 mL of anhydrous ether and stir for 10 min under protection and ice bath conditions; add 4-(aminomethyl)thiophene-2-carboxylate ethyl ester solution dropwise, react at 0-10 °C for 2 h; continue to stir in ice bath after the reaction is over was quenched with water, 10% sodium hydroxide solution, water (v / v / v = 1:2:3 (water: 0.25 mL)). The reaction solution was concentrated by rotary evaporation under reduced pressure at 50°C, and then the concentrated solution was separated and purified b...

experiment example 1

[0191] Experimental Example 1: Evaluation of Antitumor Activity

[0192] 1. Experimental materials and instruments

[0193] Test compound: compound 1, compound 2, free carmustine (BCNU) and BCNU+O prepared in the above preparation examples 6 -TMG;

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

[0195] 2. Experimental method

[0196] Six tumor cells were seeded at 1000 / well in 96-well plates at 37°C, 5% CO. 2 After culturing for 24 h, the concentration of BCNU (positive control group 1), BCNU+O 6 -TMG (positive control group 2), compound 1, compound 2, a total of 4 drug treatment groups, each group has 6 duplicate wells, and a control group is set. The CCK-8 solution was used for 4 hours. The above groups were treated under aerobic and hypoxic conditions for 48 h; then, 10 μL of CCK-8 solution was added to each well; finally, the absorbance value at 450 nm was measured. The cell viab...

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Abstract

A tumor-targeted anti-drug-resistant O 6 The thiophenemethylguanine-indolequinone-chloroethylnitrosourea combined molecule and the preparation method thereof relate to the field of pharmacy. The compound of the present invention uses indolequinone as a hypoxia-activated pharmacophore. Under the condition of tumor hypoxia, indolequinone is reduced to produce a cytotoxic imine substance; CENUs pharmacophore is decomposed to generate chloroethyl carbocation, Leads to DNA interstrand cross-linking; at the same time, releases the AGT inhibitor O 6 ‑TMG derivative, exerts AGT inhibitory effect. Therefore, the compounds of the present invention can not only exert dual anti-tumor effects, but also have anti-drug resistance and tumor hypoxia targeting properties, and have anti-cancer activities with high efficiency and low toxicity.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to an anti-drug-resistant tumor hypoxia targeting O 6 -Thienylguanine-indolequinone-chloroethylnitrosourea combined molecule and its preparation method and antitumor application. Background technique [0002] Chloroethylnitrosoureas (CENUs) chemotherapy drugs are mainly used in the clinical treatment of malignant tumors such as brain tumor, glioma and melanoma. Mainly by inducing DNA to form dG-dC inter-strand cross-linking, the process of DNA replication and transcription cannot be carried out because the DNA double-strand cannot be opened normally, resulting in apoptosis and anti-tumor effect. The two major drawbacks of this type of drugs are the easy generation of drug resistance and the toxic and side effects to normal tissues during the treatment process. O 6 - The DNA repair effect mediated by alkylguanine-DNA alkyltransferase (AGT) reduces the antitumor effect and is the main reaso...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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