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PSMA activated antitumor prodrug CPT-X, and preparation method and applications thereof

An anti-tumor effect, CPT-HT-J-ZL12 technology, applied in anti-tumor drugs, peptide preparation methods, pharmaceutical formulations, etc., can solve problems such as poor water solubility, large toxic and side effects, and poor targeting

Active Publication Date: 2020-03-27
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

Although camptothecin and its derivatives have shown good anti-tumor activity in in vivo and in vitro experiments, most of these compounds have the disadvantages of poor targeting and high toxic and side effects, and they have strong toxic and side effects on the digestive system and urinary system , easy to cause diarrhea, hemorrhagic cystitis, severe bone marrow suppression, etc. In addition, this kind of compound also has the defects of poor water solubility and poor stability, and its lactone ring is easy to crack in human plasma, resulting in inactivation or reduced activity. Therefore, 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 antitumor prodrug CPT-X, and preparation method and applications thereof
  • PSMA activated antitumor prodrug CPT-X, and preparation method and applications thereof
  • PSMA activated antitumor prodrug CPT-X, and preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0094] The preparation of embodiment 1 HT-A

[0095] Sequentially weigh 500mg (1.215mmol) Fmoc-L-aspartate-4-tert-butyl ester, 349.37mg (1.8225mmol) EDCI and 246.26mg (1.8225mmol) HOBT into a 50mL single-necked bottle, add 20ml of anhydrous di Chloromethane was dissolved, stirred and reacted at room temperature for 0.5h, continued to add 395.48mg (1.337mmol) L-di-tert-butyl glutamate hydrochloride and 392.57mg (3.0375mmol) DIPEA, stirred at room temperature for 4 hours, 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 each time, and then washed with 25ml of saturated sodium bicarbonate The solution was washed, followed by dehydration with saturated brine, and the organic layer was collected. The organic layer was dried with an appropriate amount of anhydrous sodium sulfate, filtered, evaporated to dryness under reduc...

Embodiment 2

[0096] The preparation of embodiment 2 intermediate HT-B

[0097] Weigh 588mg (0.900mmol) of HT-A into a 50mL single-necked bottle, add 20ml of anhydrous DMF and ultrasonically dissolve it, then add 229mg (2.7mmol) of piperidine, stir and react at room temperature for 0.5h, TLC [V (petroleum ether ): V (ethyl acetate)=2: 1] monitoring reaction is complete, the direct diaphragm pump of reaction solution is spin-dried, then adds 50ml ethyl acetate to dissolve, and organic layer washes 3 times with 30ml distilled water each time, saturated saline dehydration, no 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 HT-B. Yield: 87.9%; 1 H-NMR (500MHz, CDCl 3 ): δ1.43(s, 9H, 3×-CH 3), 1.44(s, 9H, 3×-CH 3 ), 1.46(s, 9H, 3×-CH 3 ), 1.89(m, 2H), 2.29(m, 2H), 2.58(dd, J=16.7, 8.0Hz, 1H), 2.79(dd, J=16.7, 3.7Hz, 1H), 3.66(dd, J= 8.0, 3.7Hz, 1H), 4.45(td, J=8.4, 4.9Hz, 1H), 7.89(d, J=8.4H...

Embodiment 3

[0098] The preparation of embodiment 3 intermediate HT-C

[0099] Sequentially weigh 255mg (0.6mmol) 1-tert-butyl fluorenylmethoxycarbonyl-L-glutamate, 172mg (0.9mmol) EDCI and 122mg (0.9mmol) 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 284mg (0.66mmol) HT-B and 194mg (1.5mmol) DIPEA, stir at room temperature for 4 hours, TLC [V (petroleum ether): V (ethyl acetate) =1: 1] monitoring reaction is complete, the reaction solution is diluted to 50ml with dichloromethane, washes three times with 25ml 1M hydrochloric acid solution each time, then washes with the saturated sodium bicarbonate solution of 25ml, dehydrates with saturated saline subsequently, collects 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 chroma...

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Abstract

The invention provides a compound having a general structure formula 1, and a preparation method and applications thereof in preparation of antitumor drugs. The PSMA activated prodrug CPT-HT-J-ZLn shows strong cytotoxic selectivity on tumor cells with PSMA positive expression and PSMA negative expression and is more active to tumor cells LNCaP-FGC with PSMA positive expression than to tumor cellsPC-3, DU145, HepG2, Hela and MCF-7 with PSMA negative expression; and the activity of the compound CPT-HT-J-ZLn12 to the LNCaP-FGC (IC50=1.00+ / -0.20 [mu]M)(PSMA<+>) respectively is 40, 40, 21, 5 and 40 times that of the cells HepG2 (IC50>40.00 [mu]M), Hela (IC50>40.00 [mu]M), MCF-7 (IC50=21.68+ / -4.96 [mu]M), DU145 (IC50=5.40+ / -1.22 [mu]M) and PC-3 (IC50=42.96+ / -3.69 [mu]M) with PSMA negative expression.

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 still one of the major diseases that seriously threaten human health and life, especially in China, where the situation is even more grim. According to the latest data released by the National Cancer Center of China in February 2018, about 10,000 people are diagnosed with cancer every day in China, an average of 7 people every minute, which brings a heavy economic burden to individuals, families and society. At present, the most common and effective means of treating cancer is to remove cancerous tissue through surgery, and chemotherapy and radiotherapy are used as adjuvant. Radiotherapy and chemotherapy are still the most effective methods for inoperable cancer patients or patients with ...

Claims

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Application Information

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IPC IPC(8): C07K7/02C07K1/02A61K38/08A61P35/00
CPCA61K38/00A61P35/00C07K7/02
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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