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APN inhibitor with fluorescent property and application thereof

A technology of inhibitors and properties, applied in the field of APN inhibitors, can solve the problem of weak combination of inhibitors and APN active centers

Active Publication Date: 2015-01-28
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Harbut, M.B.; Velmourougane, G.; Reiss, G.; Chandramohanadas, R.; Greenbaum, D.C., Development of bestatin-based activity-based probes for metallo-aminopeptidases. Bioorg Med Chem Lett, 2008, 18, (22), 5932-5936; and Hahnenkamp, ​​A.; Schafers, M.; Bremer, C.; Holtke, C. Design and synthesis of small-molecule fluorescent photoprobes targeted to aminopeptdase N(APN / CD13) for optical imaging of angiogenesis. Bioconjug Chem 2013,24,1027-1038, reported the fluorescence inhibitor of APN target, but the IC of the reported fluorescence inhibitor 50 Both are at the micromolar level, and because the fluorophore in the above-mentioned fluorescent probe affects the combination of the inhibitor and the enzyme, the combination of the inhibitor and the APN active center is not strong

Method used

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  • APN inhibitor with fluorescent property and application thereof
  • APN inhibitor with fluorescent property and application thereof
  • APN inhibitor with fluorescent property and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Preparation of L1-11

[0071] synthetic route:

[0072]

[0073] Concrete synthetic steps are as follows:

[0074] Intermediate 1a: 6-Amino-1H-benzo[de]isoquinoline-1,3(2H)-dione

[0075] Suspend 4-amino-1,8-naphthalic anhydride (0.30 g, 1.4 mmol) in 28% NH 3 -H 2 In O (30 mL), reflux for 5 hours, concentrate to dryness, and obtain a brown powder after drying, 0.2 g, yield 67.0%. It was directly used in the next step without purification.

[0076] Intermediate 1b: 6-Amino-2-methyl-1H-benzo[de]isoquinoline-1,3(2H)-dione

[0077] Suspend 4-amino-1,8-naphthalene dicarboxylic anhydride (0.30g, 1.4mmol) in ethanol solution (30mL) with a volume concentration of 30% methylamine, reflux for 5 hours, concentrate to dryness, and obtain a brown color after drying Powder, 0.26g, yield 85.7%. It was directly used in the next step without purification.

[0078] Intermediate 1c: 6-Amino-2-ethyl-1H-benzo[de]isoquinoline-1,3(2H)-dione

[0079] Suspend 4-amino-1,8-naphthalic ...

Embodiment 2

[0142] (S)-2-(3-(5-Bromo-2-methyl-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-6-yl)urea base)-N-hydroxyl-4-methylpentanamide [L13]

[0143]

[0144] Intermediate 3b: (S)-Methyl 2-(3-(5-bromo-2-methyl-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinoline -6-yl)ureido)-4-methylpentanamide

[0145] Intermediate 2b (50mg, 0.125mmol) was dissolved in 20mL of acetonitrile, N-bromosuccinimide NBS (26.7mg, 0.15mmol) was added, stirred at room temperature for 24 hours, the solution became turbid, no 2b remained by TLC, filtered The off-white powder was obtained, 55mg, yield 92.6%, melting point 213.8-214.5°C. 1 HNMRδ H (DMSO-d 6 ,300MHz)8.72(s,1H),8.55(s,1H),8.51(dd,J=7.2,Hz,0.9Hz,1H),8.25(dd,J=8.4,Hz,0.9Hz,1H),7.88 (dd,J=8.4,Hz,7.2Hz,1H),7.14(d,J=8.1Hz,1H),4.24-4.32(m,1H),3.68(s,3H),3.39(s,3H), 1.71-1.80 (m, 1H), 1.56-1.63 (m, 2H), 0.94 (t, J=6.9Hz, 6H).

[0146] Inhibitor L13: (S)-2-(3-(5-bromo-2-methyl-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinoline-6 -yl)ureido)-N-hydroxy-4-me...

Embodiment 3

[0149] (S)-2-(3-(5-Bromo-2-methyl-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-6-yl)urea base)-N-hydroxyl-4-methylpentanamide [L24]

[0150]

[0151] synthetic route

[0152] Intermediate 4b: (S)-Methyl 2-(3-(5-chloro-2-methyl-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinoline -6-yl)ureido)-4-methylpentanamide

[0153] Dissolve 2b (160 mg, 0.4 mmol) in 5 mL of acetonitrile, add N-chlorosuccinimide NCS (63.8 mg, 0.48 mmol), add 1 drop of concentrated hydrochloric acid under stirring, turbidity occurs within 3 minutes, and 2b after 5 minutes The response is complete. The yellow-white powder was obtained by filtration, 80mg, yield 46.4%, melting point 227.2-228.0°C. 1 HNMRδ H (DMSO-d 6,400MHz)8.81(s,1H),8.49(d,J=6.8,Hz,1H),8.41(s,1H),8.25(d,J=8.4,Hz,1H),7.89(t,J=8.4 ,Hz,1H),7.13(d,J=8.4Hz,1H),4.25-4.31(m,1H),3.68(s,3H),3.39(s,3H),1.71-1.78(m,1H), 1.55-1.66 (m, 2H), 0.94 (t, J = 6.9Hz, 6H).

[0154] Inhibitor L24: (S)-2-(3-(5-Chloro-2-methyl-1,3-dioxo-2,3-dihydro-1H-benzo...

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Abstract

The invention discloses an APN inhibitor with a fluorescent property. The structural formula of the APN inhibitor is (I) or (II) shown in the specification, wherein R1 is hydrogen, methyl, ethyl, propyl, butyl, amyl, hexyl, benzyl, 2-amino ethyl, 2, 2'-N, N-dimethyl ethyl or hydroxyl; and R2 is hydrogen, halogen or hydrophilic radicals and R is methyl or ethyl. The inhibitor can be used as the aminopeptidase N inhibitor, and can also be used for detecting the tissue distribution of aminopeptidase N and tumor cells and tissue imaging. The APN inhibitor can be used as an anti-solid tumor drug and can also be used for disease diagnosis of abnormal expression of the aminopeptidase N.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to an APN inhibitor with fluorescent properties and an application thereof. Background technique [0002] Aminopeptidase N (APN, CD13) is widely expressed in various organs of normal human tissues, and can degrade and release amino acids from the N-terminus of proteins. Compared with normal tissue cells, this enzyme is overexpressed on the surface of tumor cells and plays an important role in tumor invasion and angiogenesis. In addition, this protease, as a receptor of many viruses, participates in corresponding physiological responses. It is also expressed on the surface of antigen-presenting cells, and weakens the ability of macrophages and NK cells (natural killer cells) to recognize and kill tumor cells by degrading a variety of immune active substances [Zhang, X.P.; Xu, W.F. Aminopeptidase N (APN / CD13) as a target for anti-cancer agent design. Curr Med Chem 200...

Claims

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Application Information

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IPC IPC(8): C07D221/14C07D265/34A61K31/473A61K31/538A61K39/00A61K38/05A61P35/00C12Q1/37
CPCC07D221/14C07D265/34C09K11/06C09K2211/1029C09K2211/1033C12Q1/37G01N21/6486
Inventor 李敏勇杜吕佩陈来中
Owner SHANDONG UNIV
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