Antitumor compound targeting FAP-alpha enzyme and preparation method and application thereof

A compound and anti-tumor technology, applied in the direction of anti-tumor drugs, organic chemical methods, active ingredients of heterocyclic compounds, etc., can solve the problems of limited application, achieve the effects of reducing toxicity and in vivo toxicity, high product purity, and high yield

Active Publication Date: 2017-05-10
广州药本君安医药科技股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

These side effects limit its clinical application

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  • Antitumor compound targeting FAP-alpha enzyme and preparation method and application thereof
  • Antitumor compound targeting FAP-alpha enzyme and preparation method and application thereof
  • Antitumor compound targeting FAP-alpha enzyme and preparation method and application thereof

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Embodiment 1

[0045] A kind of embodiment of the preparation method of Z-GP-procarbazine of the present invention, described preparation method comprises the following steps:

[0046] 1.1.1 Preparation of N-isopropyl p-toluamide

[0047] Weigh 273mg (2.0mmol) of p-toluic acid into a 25mL round bottom flask, add 5.0mL (68.8mmol) of thionyl chloride (excess), heat and reflux in an oil bath at 78°C for 2h; remove excess dichloride by rotary evaporation Sulfone to obtain p-toluamide; re-dissolve p-toluamide in 2.0 mL of dry dichloromethane (DCM); another 1.0 mL (11.7 mmol) of isopropylamine was dissolved in 2.0 mL of dry DCM , to obtain liquid A; control the temperature at 30°C, gradually add liquid A dropwise into the reaction system, continue stirring for 30 minutes after the addition, and stir for 3 hours at room temperature; then raise the temperature to 40°C, continue the reaction for 30 minutes, stop heating; The solution was poured into 50 mL of ice water, extracted 4 times with dichlor...

Embodiment 2

[0061] Example 2 Investigation experiment of Z-GP-Pcb targeted release characteristics

[0062]Experimental method: HPLC chromatographic conditions are as follows: high performance liquid chromatograph Agilent 1200; Chromatographic column CosmosilC18 reverse-phase chromatographic column (4.6 * 250mm, 5 μ m); Mobile phase (0min, 55% methanol and 45% water (containing 2mM ammonium formate); 10min, 65% methanol and 35% water (containing 2mM ammonium formate); 15min, 75% methanol and 25% water (containing 2mM ammonium formate); 30min, 85% methanol and 15% water (containing 2mM ammonium formate); 40min, 85% methanol and 15% water (containing 2mM ammonium formate); flow rate 1mL / min; detection wavelength: 254nm; injection volume 2μL.

[0063] The method for establishing the Z-GP-procarbazine detection standard curve is as follows: dissolve Z-GP-procarbazine in the enzymolysis buffer (50mM Tris-HCl, 1.0M NaCl, pH 7.4), and set 5 concentration gradients of 0.012725 . 2μg / ml and 5μg / ...

Embodiment 3

[0065] Example 3 Investigation experiment on the change of cytotoxicity before and after enzymatic hydrolysis of Z-GP-Pcb

[0066] Experimental method: Z-GP-Pcb and Pcb were treated with NCI-H460 cell line (purchased from Shanghai Cell Bank, Chinese Academy of Sciences) for 48 hours in the drug concentration range of 0.1-50 μM, and the cytotoxicity of the two was compared by MTT method; Z-GP-Pcb was co-incubated with FAP-alpha, and the supernatant of the incubation was taken to treat the NCI-H460 cell line for 48 hours. The effect of FAP-alpha enzymolysis on the cytotoxicity of Z-GP-Pcb was analyzed by MTT method. Whether Z-GP-Pcb can restore its potential cytotoxicity under enzymatic hydrolysis.

[0067] Experimental results: The results of cytotoxicity experiments showed that the cytotoxicity of Z-GP-Pcb to NCI-H460 was significantly lower than that of Pcb ( figure 2 ); under the action of FAP-alpha enzymolysis, Z-GP-Pcb restores its cytotoxicity ( image 3 ).

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Abstract

The invention discloses an antitumor compound targeting an FAP-alpha enzyme. The antitumor compound is named Z-GP-procarbazine; a dipeptide part (Z-GP) in the compound can be removed by specific hydrolysis of the FAP-alpha enzyme to release procarbazine. The Z-GP-procarbazine can significantly lower the toxicity and in-vivo toxicity of normal cells, can be free from the dipeptide part (Z-GP) in vivo and in vitro through specific hydrolysis of the FAP-alpha enzyme to release an enzymolysis product, and can significantly inhibit the growth of tumors in nude mice bearing tumors and lower the toxicity to non-target organs, thus reducing the deficiency of severe toxic and side effects of procarbazine as an anticancer drug. The invention provides a tumor targeting drug based on FAP-alpha. In addition, the invention discloses a preparation method of the Z-GP-procarbazine. The method has the characteristics of mild reaction conditions, simple experiment steps, high yield, high purity of a product, economical efficiency, practicability and the like. In addition, the invention discloses use of the Z-GP-procarbazine, a derivative of the Z-GP-procarbazine and a physiologically-acceptable salt of the Z-GP-procarbazine in preparation of antitumor drugs.

Description

technical field [0001] The invention relates to a compound and a preparation method thereof, in particular to an anti-tumor compound targeting FAP-alpha enzyme, a preparation method and application thereof, belonging to the field of anti-tumor drugs. Background technique [0002] At present, the clinical chemotherapy drugs for tumors are mainly cytotoxic drugs. Although they have strong anti-tumor activity, due to the lack of selectivity of these chemotherapy drugs, they often cause serious side effects. Therefore, the targeted delivery of cytotoxic drugs has significant significance for reducing the adverse reactions of tumor chemotherapy. [0003] Procarbazine (Pcb) is mainly used clinically to treat Hodgkin's disease, and it also has a certain effect on other malignant tumors such as malignant lymphoma, lung cancer, and multiple myeloma. In 1982, the hydrochloride of the drug was approved by the FDA in the United States in the form of oral capsules, mainly for the treatm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16A61K31/40A61P35/00
CPCC07B2200/09C07D207/16
Inventor 王日康陈河如张磊张潮
Owner 广州药本君安医药科技股份有限公司
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