Gemcitabine ProTide hypoxic activation prodrug and application thereof

A technology of gemcitabine and oxygen activation, which is applied in organic chemistry, antineoplastic drugs, drug combinations, etc., can solve the problem of limited tumor effect, and achieve the effects of reducing toxic and side effects, excellent anticancer effect, and good safety

Inactive Publication Date: 2017-01-04
JIANGSU QIANZHIKANG BIOLOGICAL MEDICINE SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Traditional anticancer drugs have good lethality against tumors near blood vessels, but have limited effect on tumors in hypoxic areas

Method used

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  • Gemcitabine ProTide hypoxic activation prodrug and application thereof
  • Gemcitabine ProTide hypoxic activation prodrug and application thereof
  • Gemcitabine ProTide hypoxic activation prodrug and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1: Synthesis of 3′-O-(tert-butoxycarbonyl) gemcitabine

[0021] Synthetic route (obtained by reference method, The Journal of Organic Chemistry, 1999, 64: 8319-8322):

[0022]

[0023] Experimental operation: gemcitabine (gemcitabine, 0.60g, 2mmol), Na 2 CO 3 (1.06 g), 40 mL of dioxane, 40 mL of water, and di-tert-butyl dicarbonate (DBDC, 0.44 g, 2 mmol) were stirred at room temperature for 48 hours. Add 20mL water, extract with 2×300mL ethyl acetate, Na 2 SO 4 Dry and concentrate under reduced pressure. Flash column chromatography (CH 2 Cl 2 -Ethyl acetate-EtOH 1:1:0.02) to give 3'-O-(N-tert-butoxycarbonyl) gemcitabine (0.60 g). 1 H NMR(DMSO-d6,300MHz)δ(ppm): 7.64(d,1H)7.40(d,2H)6.21(t,1H)5.81(d,1H)5.25-5.12(m,2H),4.13(t ,1H)3.71-3.60(m,2H)1,45(s,9H).

Embodiment 2

[0024] Example 2: Synthesis of Compound 001

[0025] Synthetic route (obtained by reference method, The Journal of Medicinal Chemistry, 2014, 57:1531-1542):

[0026]

[0027] Add 10mL of redistilled dichloromethane to a 100mL eggplant-shaped flask, add phosphorus oxychloride (0.2g, 1.3mmol) in the dichloromethane, place the reaction system at -78℃, and add triethylamine to it (0.13g, 1.3mmol), after stirring for 15min, add dropwise a solution of phenol (0.153g, 1mmol) in dichloromethane (5mL) for 15min, react at -78°C for 1h, and at room temperature for 1h. Continue to place the entire reaction system at -78°C, add 0.23g (2.3mmol) of triethylamine to it, stir for 15min, add 0.275g (1mmol) of L-alanine 1-(4-nitrate) 10 mL of distilled dichloromethane solution of phenyl)ethanol ester hydrochloride and stirred for 3h. Take another 50mL eggplant-shaped bottle, add 30mL redistilled dichloromethane, add 0.29g (0.8mmol) 3′-O-(tert-butoxycarbonyl) gemcitabine, add 0.2g (2mmol) triethylam...

Embodiment 3

[0043] Example 3: Study on the in vitro inhibitory effect of the target compound on tumor cell proliferation under normoxia and hypoxia

[0044] Take logarithmic growth phase tumor cells, add 0.25% trypsin to digest for 3 minutes, suspend the cells with RPMI-1640 containing 10% calf serum, count, and adjust the cell concentration to 1×10 5 Pcs / mL, inoculate 100μL / well in a 96-well cell culture plate special for Top-count, 37℃, 5% CO 2 Incubate for 24h. Then divide the cells into the experimental group and the control group. The experimental group is added with the target compound solution (0.001μg / mL, 0.01μg / mL, 0.1μg / mL, 1μg / mL, 10μg / mL), each concentration is four duplicate holes , And the volume of each well is made up to 200μL. After adding samples, each group continued to cultivate for 72h (hypoxic group under 5% CO 2 , 95% N 2 Continue to incubate for 72h respectively), before the end of the culture, add to each well 3 H-TdR 3×10 5 Bq, use Top-count to measure the CPM (coun...

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Abstract

The invention discloses a gemcitabine ProTide hypoxic activation prodrug and application thereof. The chemical structural formula is shown in the description. By adopting the gemcitabine ProTide hypoxic activation prodrug, anti-tumor medicinal active substances can be specifically released in a tumor hypoxic area by virtue of difference of micro environments of tumor tissue and normal tissue, an anti-tumor function can be brought into play, toxic and side effects on other tissue can be reduced, and the prodrug has excellent anti-cancer functions on tumor and good security, and can be adopted to prepare medicines for treating tumor.

Description

Technical field [0001] The invention belongs to the field of pharmacy and provides a kind of gemcitabine ProTide hypoxia activation prodrug and its application. Background technique [0002] Gemcitabine is a commonly used clinical antitumor drug, but it is prone to drug resistance. Its ProTide prodrug NUC-1031 can reduce the occurrence of drug resistance and has good antitumor effects. It has entered clinical research (Journal of Medicinal Chemistry 2014, 57, 1531-1542) . But NUC-1031 cannot reduce the side effects of the drug on normal tissues. [0003] [0004] With the rapid growth of tumors, some tumor tissues are getting farther and farther away from the nearest blood vessels, and the oxygen supply is insufficient, resulting in hypoxia (Nature review cancer 2002, 2:38-47). Traditional anti-cancer drugs have good lethality on tumors near blood vessels, but have limited effect on tumors in hypoxic areas. Tumor hypoxia activated prodrugs can specifically release anti-tumor act...

Claims

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Application Information

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IPC IPC(8): C07H19/10C07H1/00C07H1/02A61K31/7068A61P35/00
CPCA61K31/7068C07H1/00C07H1/02C07H19/10A61K2300/00A61P35/00
Inventor 李飞
Owner JIANGSU QIANZHIKANG BIOLOGICAL MEDICINE SCI & TECH CO LTD
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