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PSMA activated anti-tumor prodrug CPT-Y and preparation method and application thereof

An anti-tumor effect, CPT-W12 technology, used in anti-tumor drugs, pharmaceutical formulations, drug combinations, etc., can solve the problems of toxic side effects, poor targeting, and poor water solubility

Inactive Publication Date: 2021-02-02
薪火炙药(北京)科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this type of drug has poor targeting, and often causes a series of toxic and side effects such as vomiting, diarrhea, bone marrow suppression, and hemorrhagic cystitis in clinical practice. In addition, this type of drug also has the defects of poor water solubility and poor stability.
These defects limit its further development and clinical application, so it is of great significance to develop a new generation of camptothecin derivatives with high efficiency, low toxicity and good water solubility

Method used

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  • PSMA activated anti-tumor prodrug CPT-Y and preparation method and application thereof
  • PSMA activated anti-tumor prodrug CPT-Y and preparation method and application thereof
  • PSMA activated anti-tumor prodrug CPT-Y and preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0213] The preparation of embodiment 1 intermediate WT-A

[0214] Sequentially weigh 500mg (1.18mmol) 1-tert-butyl fluorenylmethoxycarbonyl-L-glutamate, 338mg (1.76mmol) EDCI and 238mg (1.76mmol) HOBt into a 50mL single-necked bottle, add 20mL of anhydrous dichloro Make it dissolve with methane, stir and react at room temperature for 0.5h, continue to add 382mg (1.29mmol) L-di-tert-butyl glutamate hydrochloride and 380mg (2.94mmol) DIPEA, stir at room temperature for 4h, TLC [V (petroleum ether ): V (ethyl acetate) = 2: 1] to monitor the complete reaction, the reaction solution was diluted to 50mL with dichloromethane, washed three times with 25mL of 1M hydrochloric acid solution, then washed with 25mL of saturated sodium bicarbonate solution, and then Dehydrate with saturated brine, collect the organic layer, dry the organic layer with an appropriate amount of anhydrous sodium sulfate, filter, evaporate to dryness under reduced pressure, mix the sample with silica gel, flash ...

Embodiment 2

[0215] The preparation of embodiment 2 intermediate WT-B

[0216] Weigh 600mg (0.90mmol) of WT-A into a 50mL single-necked bottle, add 20mL of anhydrous DMF and ultrasonically dissolve it, then add 229mg (2.70mmol) of piperidine, stir and react at room temperature for 0.5h, TLC [V (petroleum ether ): V (ethyl acetate) = 2: 1] to monitor the complete reaction, the reaction solution was directly spin-dried by a diaphragm pump, then added 50 mL of ethyl acetate to dissolve, and the organic layer was washed 3 times with 30 mL of distilled water each time, and dehydrated with saturated saline. Dry over sodium sulfate, filter, mix with silica gel, flash silica gel column chromatography (PE / EA=3 / 1 to 0 / 1), and obtain 340 mg of colorless oil WT-B. Yield: 85.0%; 1 H NMR (500MHz, CDCl 3 ):δ1.40(d,27H,9×-CH 3 ),1.79(m,2H),2.03(m,2H),2.19(m,2H),2.32(m,2H),3.29(m,1H),4.42(m,1H),6.62(d,J= 7.3Hz,1H); 13 C NMR (125MHz, CDCl 3 ):δ27.8,28.0,28.1,30.3,31.6,32.9,52.3,54.5,80.7,81.3,82.2,171...

Embodiment 3

[0217] The preparation of embodiment 3 intermediate WT-C

[0218] Sequentially weigh 200mg (0.47mmol) 1-tert-butyl fluorenylmethoxycarbonyl-L-glutamate, 135mg (0.71mmol) EDCI and 95mg (0.71mmol) HOBt into a 50mL single-necked bottle, add 10mL of anhydrous dichloro Make it dissolve with methane, stir and react at room temperature for 0.5h, continue to add 230mg (0.52mmol) WT-B and 152mg (1.18mmol) DIPEA, stir at room temperature for 4h, TLC [V (petroleum ether): V (ethyl acetate) = 1:1] to monitor the completion of the reaction, dilute the reaction solution to 50mL with dichloromethane, wash with 25mL of 1M hydrochloric acid solution three times each time, then wash with 25mL of saturated sodium bicarbonate solution, then dehydrate with saturated saline, and collect the organic layer , the organic layer was dried with an appropriate amount of anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, mixed with silica gel, flash silica gel column chromato...

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Abstract

The invention provides a compound with a structural general formula 1 or a structural general formula 2, a preparation method of the compound and an application of the compound in the preparation of anti-tumor drugs. Prostate specific membrane antigen (PSMA) specific targeting polypeptide and camptothecin are bonded through chemical bonds to construct an amphiphilic PSMA activated prodrug CPT-Y (CPT-Wn and CPT-Hn). The construction of the amphiphilic compound can improve water solubility, stability and half-life period of camptothecin, so that the bioavailability is improved. Meanwhile, the compound CPT-Y can directionally transport camptothecin to a tumor site to be released through the PSMA-mediated active targeting effect, so that the lethality of camptothecin to healthy cells and normal tissues is reduced, and the anti-tumor effect is improved while drug resistance is improved.

Description

technical field [0001] The invention relates to a compound and its preparation method and application, specifically a compound with targeted anti-tumor activity, its preparation method and application, and belongs to the field of medicinal chemistry. Background technique [0002] Cancer is one of the major diseases that seriously threaten human health and life, with complex pathogenic factors and high morbidity and mortality. Chemotherapy is still one of the main means of clinical treatment of malignant tumors. Most of the conventional chemotherapeutic drugs have the defects of poor targeting, high toxicity and side effects, low bioavailability and drug resistance, which lead to poor clinical efficacy and poor quality of life of patients. Therefore, it is of great clinical value and significance to find new targeted anti-tumor drugs. [0003] Camptothecin (CPT) is a natural antineoplastic drug isolated from the traditional Chinese medicine Camptotheca acuminata. Good anti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/64A61K31/4745A61P35/00
CPCA61K47/64A61K31/4745A61P35/00
Inventor 徐冰王鹏龙郭文博
Owner 薪火炙药(北京)科技有限公司
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