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Multi-target nicotinamide phosphoribosyl transferase nitrogen mustard inhibitor with antitumor activity and preparation and application thereof

A technology of anti-tumor activity and phosphoribose, which is applied in the field of medicine to achieve the effect of low toxicity

Active Publication Date: 2019-05-21
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Moreover, there are almost no reports on the research based on NAMPT / DNA multi-target inhibitors, which also makes this invention highly innovative

Method used

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  • Multi-target nicotinamide phosphoribosyl transferase nitrogen mustard inhibitor with antitumor activity and preparation and application thereof
  • Multi-target nicotinamide phosphoribosyl transferase nitrogen mustard inhibitor with antitumor activity and preparation and application thereof
  • Multi-target nicotinamide phosphoribosyl transferase nitrogen mustard inhibitor with antitumor activity and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example one (E)-N-(4-(1-(4-(bis(2-chloroethyl)amino)benzoyl)piperidin-4-yl)butyl)-3-(pyridine-3 -Based) acrylamide preparation

[0066] (1) Preparation of intermediate 2c: methyl 4-(1-(4-nitrobenzoyl)piperidin-4-yl)butyrate

[0067] Dissolve compound 1 (1.0g, 4.8mmol) in methanol (30mL), and add SOCl dropwise 2 (1.1g, 9.6mmol), react for 4h. After the reaction, the solvent was evaporated under reduced pressure and dissolved in dichloromethane (30mL), and 4-nitrobenzoyl chloride (1.8g, 9.6mmol), NaHCO 3 (0.8g, 9.6mmol), react at room temperature overnight. After the reaction, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography using a dichloromethane / methanol mixed solvent (100:1) as the mobile phase to obtain Intermediate 2c as a colorless oil, 0.9 g in total, and 57% yield.

[0068] 1 H-NMR(DMSO-d 6 ,300MHz)δ:7.25(d,J=8.64Hz,2H), 6.75(d,J=8.64Hz,2H), 3.56(s,3H), 2.74(t,J=7.54Hz,2H), 2.26( t,J=7.54Hz,2H),1.78-1.89(m,3H),1.62...

Embodiment 2

[0085] Example 2 Compound 7a~c, 9a~c, 12 and 14 enzyme inhibitory activity and in vitro antitumor activity

[0086] 1 Compound 7a~c, 9a~c, 12 and 14 inhibit NAMPT enzyme

[0087] The enzyme described below refers specifically to NAMPT.

[0088] 1.1 Preparation of NAMPT enzyme

[0089] BL21(DE3)plysS cells transformed with the recombinant plasmid (NAMPT-pET28a+) were inoculated into 2×YT medium (37 μg / mL chloramphenicol and 100 μg / mL kanamycin). The cells are collected by induction and centrifugation, and the cells are lysed. The supernatant is incubated with the Ni-NTA column (purchased from QIAGEN) on ice to wash away the impurities, and finally the target protein is eluted, and the protein is finally obtained.

[0090] 1.2 Experimental method

[0091] First add 0.5μL of compound solutions of different concentrations to a 96-well plate, then add 20μL of enzyme reaction mixture solution (enzyme reaction components other than the substrate), incubate at room temperature for 5 minutes, ad...

Embodiment 3

[0117] Example 3 Anti-tumor effect of target compound in vivo

[0118] 1 The effect of compound 9a and 9b on the transplanted tumor of CT-26 normal mouse colon cancer

[0119] According to the results of in vitro anti-tumor activity, firstly, the in vivo anti-tumor activity of compounds 9a and 9b was evaluated with the mouse colon cancer CT-26 normal mouse xenograft model. FK866 and chlorambucil were the positive control drugs.

[0120] The dosage of compound 9a, FK866 and chlorambucil was 5 mg / kg, once a day; compound 9b was 2 mg / kg, once a day; continuous intraperitoneal injection was administered for 14 days. The results show that( figure 1 ), compounds 9a and 9b can effectively inhibit tumor growth, and the tumor inhibition rates are 71.1% and 53.5%, respectively, which are significantly higher than the positive control drug (FK866 tumor inhibition rate is 18.9%, chlorambucil is 21.6%), of which compound 9a is in vivo Anti-tumor activity is better than 9b, and all have statistic...

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Abstract

The invention relates to the technical field of medicines, in particular to a multi-target nicotinamide phosphoribosyl transferase nitrogen mustard inhibitor with the antitumor activity and preparation and application thereof. The invention provides a compound based on inhibition of two targets NAMPT / DNA, and the structural general formula thereof is shown as a formula (I). The compound has excellent NAMPT enzyme inhibiting activity, has relatively strong in-vitro antitumor activity and an excellent in-vivo tumor-inhibiting effect, has low toxicity, has the characteristics of high efficiency and low toxicity, and is a superior antitumor medicine. The invention further provides a preparation method of a derivative thereof, and application thereof to preparation of an NAMPT inhibitor, a DNAinhibitor, an NAMPT / DNA two-target inhibitor and the antitumor medicine.

Description

Technical field [0001] The invention relates to the technical field of medicine, in particular to a nicotinamide phosphoribosyl transferase nitrogen mustard inhibitor with multi-target anti-tumor activity and its preparation and application. Background technique [0002] At present, cancer has become a serious threat to human health and life. At present, the clinical treatment of malignant tumors mainly adopts the method of combination medication, but this method has many shortcomings, such as the need to confirm the rationality of drug compatibility, possible drug-drug interactions, and complex pharmacokinetic properties. [0003] At present, targeted therapy has become an important direction of cancer treatment, and the treatment model of one drug, one target is often adopted. However, tumors are different from general diseases. Their growth and survival depend not only on the conduction of a receptor or a signal pathway, which makes the strategy of acting on a target only unabl...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D211/22C07D211/26A61P35/00
Inventor 盛春泉董国强黄亚辉武善超刘娜
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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