A hydrogen peroxide-responsive nitrogen mustard antitumor prodrug and its preparation method

Abstract

The invention discloses a hydrogen peroxide-responsive nitrogen mustard anti-tumor pro-drug and a preparation method thereof, and belongs to the field of pharmaceutical chemistry. The compound contains an alpha-ketoamide structure and a nitrogen mustard structure, can rapidly respond to H2O2, can be used as the nitrogen mustard anti-tumor pro-drug, has good response effect to H2O2, has high cell selectivity and small toxic and side effects, provides an effective, safe and highly selective anti-tumor drug, enriches the types of nitrogen mustard anti-tumor drugs, and has a good market prospect.

Description

technical field

[0001] The invention relates to a hydrogen peroxide-responsive nitrogen mustard antitumor prodrug and a preparation method thereof, belonging to the field of medicinal chemistry. Background technique

[0002] Tumor is a kind of disease that seriously threatens human health, and it is still a big problem in the medical field. Due to poor selectivity to tumor cells, traditional chemotherapy tends to produce relatively large toxic and side effects during treatment. Nitrogen mustard is an important alkylating antitumor drug, but its clinical application is severely limited due to its short half-life, severe side effects, poor selectivity, and low therapeutic efficiency.

[0003] Prodrugs activated in the unique microenvironment of tumor cells are effective tools to reduce the toxic side effects of chemotherapeutic drugs. Compared with normal cells, tumor cells are in a variety of oxidative stress states due to insufficient oxygen supply, high metabolic demand a...

Examples

Embodiment 1

[0073] Embodiment 1: the synthesis of compound C

[0074] The first step: the synthesis of p-nitrophenylglyoxylic acid (intermediate 1)

[0075]

[0076] Concrete operation: p-Nitroacetophenone (1g) is dissolved in pyridine (10mL), adds SeO 2 (1g), the mixture was passed through nitrogen protection, and stirred at 90°C for 4h, wherein p-nitroacetophenone and SeO 2 The molar ratio is 1:1.5, cooling and filtering after the reaction is completed, the filter cake is washed 3 times with ethyl acetate, and the organic layer is collected and washed with 2M HCl, and finally the organic layer is combined, dried with anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The yellow intermediate 1 was eluted by column chromatography.

[0077]The second step: the synthesis of N-(4-nitrophenyl)diethanolamine (intermediate 4)

[0078]

[0079] Specific operation: Dissolve p-nitrofluorobenzene (1mL) in dimethyl sulfoxide (DMSO), then add diethan...

Embodiment 2

[0090] Embodiment 2: the synthesis of compound A

[0091]

[0092] Specific operation: Dissolve compound C (100mg) in DMF (3mL), add halide LiCl (40.07mg), stir at 60°C for 3h, after the reaction, wash with water and saturated brine in sequence, add ethyl acetate for extraction, The organic layer was collected, dried by adding anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and eluted by column chromatography to obtain a dark brown solid A. 1 H NMR (400MHz, Chloroform-d) δ8.83(s,1H,NH),8.64–8.56(m,2H,Ar-H),8.38–8.29(m,2H,Ar-H),7.63–7.56( m,2H,Ar-H),6.78–6.68(m,2H,Ar-H),3.76(m,2H,NCH 2 ),3.65(m,2H,ClCH 2 ). 13 C NMR (101MHz, Chloroform-d) δ186.27, 157.38, 150.84, 144.06, 137.87, 132.57, 126.70, 123.50, 122.01, 112.33, 53.50, 40.36. Mass spectrometry (ESI-MS, m / z): Calcd for [M+ H] + ,409.06; found 410.061.m.p:141–143℃.

Embodiment 3

[0093] Embodiment 3: the synthesis of compound B

[0094]

[0095] Specific operation: Dissolve compound C (100mg) in DMF (3mL), add halide NaBr (97mg), stir at 60°C for 3h, after the reaction, wash with water and saturated brine, add ethyl acetate for extraction, collect The organic layer was dried by adding anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and column chromatography was eluted to obtain dark brown solid B. 1 H NMR (400MHz, Chloroform-d) δ8.83(s,1H,NH),8.65–8.56(m,2H,Ar-H),8.40–8.29(m,2H,Ar-H),7.65–7.54( m,2H,Ar-H),6.77–6.65(m,2H,Ar-H),3.80(t,J=7.5Hz,2H,NCH 2 ), 3.48 (dd, J=8.1, 6.9Hz, 2H, BrCH 2 ). 13 C NMR (101MHz, Chloroform-d) δ186.26, 157.38, 150.85, 143.74, 137.86, 132.58, 126.81, 123.50, 122.06, 112.32, 53.30, 28.16. Mass spectrometry (ESI-MS, m / z): Calcdfor[M+H ] + ,496.96; found 497.963.m.p:95–96℃.

technical field

[0001] The invention relates to a hydrogen peroxide-responsive nitrogen mustard antitumor prodrug and a preparation method thereof, belonging to the field of medicinal chemistry. Background technique

[0002] Tumor is a kind of disease that seriously threatens human health, and it is still a big problem in the medical field. Due to poor selectivity to tumor cells, traditional chemotherapy tends to produce relatively large toxic and side effects during treatment. Nitrogen mustard is an important alkylating antitumor drug, but its clinical application is severely limited due to its short half-life, severe side effects, poor selectivity, and low therapeutic efficiency.

[0003] Prodrugs activated in the unique microenvironment of tumor cells are effective tools to reduce the toxic side effects of chemotherapeutic drugs. Compared with normal cells, tumor cells are in a variety of oxidative stress states due to insufficient oxygen supply, high metabolic demand a...

Examples

Embodiment 1

[0073] Embodiment 1: the synthesis of compound C

[0074] The first step: the synthesis of p-nitrophenylglyoxylic acid (intermediate 1)

[0075]

[0076] Concrete operation: p-Nitroacetophenone (1g) is dissolved in pyridine (10mL), adds SeO 2 (1g), the mixture was passed through nitrogen protection, and stirred at 90°C for 4h, wherein p-nitroacetophenone and SeO 2 The molar ratio is 1:1.5, cooling and filtering after the reaction is completed, the filter cake is washed 3 times with ethyl acetate, and the organic layer is collected and washed with 2M HCl, and finally the organic layer is combined, dried with anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The yellow intermediate 1 was eluted by column chromatography.

[0077]The second step: the synthesis of N-(4-nitrophenyl)diethanolamine (intermediate 4)

[0078]

[0079] Specific operation: Dissolve p-nitrofluorobenzene (1mL) in dimethyl sulfoxide (DMSO), then add diethan...

Embodiment 2

[0090] Embodiment 2: the synthesis of compound A

[0091]

[0092] Specific operation: Dissolve compound C (100mg) in DMF (3mL), add halide LiCl (40.07mg), stir at 60°C for 3h, after the reaction, wash with water and saturated brine in sequence, add ethyl acetate for extraction, The organic layer was collected, dried by adding anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and eluted by column chromatography to obtain a dark brown solid A. 1 H NMR (400MHz, Chloroform-d) δ8.83(s,1H,NH),8.64–8.56(m,2H,Ar-H),8.38–8.29(m,2H,Ar-H),7.63–7.56( m,2H,Ar-H),6.78–6.68(m,2H,Ar-H),3.76(m,2H,NCH 2 ),3.65(m,2H,ClCH 2 ). 13 C NMR (101MHz, Chloroform-d) δ186.27, 157.38, 150.84, 144.06, 137.87, 132.57, 126.70, 123.50, 122.01, 112.33, 53.50, 40.36. Mass spectrometry (ESI-MS, m / z): Calcd for [M+ H] + ,409.06; found 410.061.m.p:141–143℃.

Embodiment 3

[0093] Embodiment 3: the synthesis of compound B

[0094]

[0095] Specific operation: Dissolve compound C (100mg) in DMF (3mL), add halide NaBr (97mg), stir at 60°C for 3h, after the reaction, wash with water and saturated brine, add ethyl acetate for extraction, collect The organic layer was dried by adding anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and column chromatography was eluted to obtain dark brown solid B. 1 H NMR (400MHz, Chloroform-d) δ8.83(s,1H,NH),8.65–8.56(m,2H,Ar-H),8.40–8.29(m,2H,Ar-H),7.65–7.54( m,2H,Ar-H),6.77–6.65(m,2H,Ar-H),3.80(t,J=7.5Hz,2H,NCH 2 ), 3.48 (dd, J=8.1, 6.9Hz, 2H, BrCH 2 ). 13 C NMR (101MHz, Chloroform-d) δ186.26, 157.38, 150.85, 143.74, 137.86, 132.58, 126.81, 123.50, 122.06, 112.32, 53.30, 28.16. Mass spectrometry (ESI-MS, m / z): Calcdfor[M+H ] + ,496.96; found 497.963.m.p:95–96℃.

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