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New high-efficiency low-toxicity actinomycin type D antineoplastic compound

A high-efficiency and low-toxicity technology of actinomycin, applied in the field of new analogs of actinomycin D, can solve the problems of high toxicity and decreased anti-tumor activity

Inactive Publication Date: 2009-05-13
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Various methods have been used in the prior art to modify the structure of actinomycin D, for example: N substitution at the 8-position of phenoxazinone (J.Am.Chem.Soc., 1994, 116:4154); Amino substitution analogs at the 7-position of azinone (J.Med.Chem., 1983, 26:448; J.Med.Chem., 1988, 31:1540, etc.); modification of the 2-position amino group of phenoxazinone or introduction of free base (Chem.Ber., 1967, 100:1051; J.Med.Chem., 1979, 22:1051, etc.); the analogs of amino acid replacement and modification of the cyclic pentapeptide 2, 3, 4, and 5 respectively (J. Med.Chem., 1991, 94: 1297; Biochemistry, 1996, 35: 13240, etc.), some of the analogs obtained by these technical measures show better biological activity, but as a drug, the resulting product Still more toxic
[0007] A Chinese patent discloses an "analogue of actinomycin D" (application number: 200410026093.1), which simultaneously replaces the amino acids at the 2-position and 5-position of the two ring pentapeptides in the molecule of actinomycin D. On the basis of high transcriptional inhibitory activity, the antitumor activity was further improved, but subsequent antitumor activity and toxicity studies found that the steric hindrance effect of the side chain caused by the replacement of the 2-position amino acid with D-Phe, although resulting in two rings Large changes in the spatial position between them showed a decline in antitumor activity

Method used

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  • New high-efficiency low-toxicity actinomycin type D antineoplastic compound
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  • New high-efficiency low-toxicity actinomycin type D antineoplastic compound

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Effect test

Embodiment 1

[0018] Embodiment 1: [D-MeLeu 5 ] 2 Synthesis of AMD

[0019] 1 Dissolve 0.63 g (2.26 mmol) of the compound N-benzyloxycarbonyl-N-methylglycine tert-butyl ester in 6 ml of anhydrous methanol (MeOH), add 80 mg of 10% Pd / C, stir for 2 hours after hydrogenation, and filter. Concentrate, add Z-Pro 0.535g (2.15mmol) to the residue, dissolve with dry dichloromethane (DCM) and cool to -10°C, add 0.44g (2.15mmol) of DCC in dichloromethane solution, at -10 After reacting at ℃ for 2 hours, react overnight at room temperature. The DCU generated by the reaction was filtered off, the filtrate was concentrated, and the residue was dissolved in ethyl acetate (EtOAc), followed by 10% citric acid aqueous solution, 10% sodium bicarbonate (NaHCO 3 ) aqueous solution, saturated sodium chloride (NaCl) aqueous solution, and anhydrous sodium sulfate (NaCl) 2 SO 4 )dry. After filtration, the solvent was evaporated under reduced pressure, and the crude product was subjected to silica gel column ...

Embodiment 2

[0027] Embodiment 2: [D-MeLeu 5 ] 2 In vitro antitumor activity experiment of AMD

[0028] The compounds of the present invention and actinomycin D parent, through the human liver cancer cell BEL-7402, human breast cancer cell MCF-7, tongue cancer cell TB, human liver cancer cell HepG-2, human gastric adenocarcinoma cell SGC-7901 and other tumors The cell lines were tested and compared with anti-tumor activity in vitro by MTT method. The MTT method is the colorimetric method of tetramethylazolium salt microenzyme reaction. MTT is a thiazole salt, the chemical name is 3-(4,5-dimethyl-2-thiazole)-2,5-diphenyltetrazolium bromide, and its aqueous solution is yellow-orange. After the oxidized MTT enters the cell, it is reduced by dehydrogenase to form blue-purple formazan (Formazan) particles, which are deposited in or around the cell. Since the production of formazan is related to the number of cells, the type of cells, and the time of action. When the type of cells and the a...

Embodiment 3

[0040] Embodiment 3: [D-MeLeu 5 ] 2 Study on the DNA binding activity of AMD

[0041] When actinomycin D intercalates with DNA, the visible spectrum shows red shift and color reduction effect; when actinomycin D analogues bind to DNA in a similar way to the parent, and the intercalation is the main factor, the ultraviolet-visible The spectrum showed red shift and color reduction effect; when the binding method of actinomycin D analogs and DNA was dominated by hydrophobic stacking, the ultraviolet-visible spectrum showed only color reduction effect, or had a weak red shift. By research [D-MeLeu 5 ] 2 UV-Vis spectra of AMD and actinomycin D precursors bound to DNA can be studied [D-MeLeu 5 ] 2 Changes in the way AMD binds to DNA.

[0042] I Materials and methods: Instrument: HP-8453 UV-Vis spectrophotometer of Hewlett-Packard Company. Materials: Calf thymus DNA was purchased from Sigma, A260 / A280>1.8 was detected before use, and the purity met the experimental requirement...

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Abstract

The invention relates to a high-efficiency low-toxicity actinomycin D-type antitumor new compound, which has a structural formula shown as above. On the basis of not changing the space positions of two actinomycin D loops or affecting the chimeric effect of actinomycin D and DNA, the compound replaces actinomycin D cyclic pentapeptide 5-site amino acid with D-type N methyl leucine (D-MeLeu), and changes the direction and volume of the prior 5-site N methylvaline side-chain group. Obtained [D-MeLeu<5>]2AMD shows better antitumor activity and lower toxicity, and has the potential value of being used for clinical resistance to tumors.

Description

technical field [0001] The present invention relates to a new compound, specifically a new analogue of actinomycin D, the preparation method and antitumor effect of the compound. Background technique [0002] Actinomycin D (Actinomycin D, AMD, also known as dactinomycin), is one of the national basic medical insurance drug varieties, and is widely used in clinical treatment of various malignant tumors, such as Wilm's Tumor, Wilm's Tumor, Choriocarcinoma of pregnancy, malignant hydatidiform mole, Hodgkin's malignant lymphoma (Hodgkin's disease) and other malignant tumors, have significant curative effect. In recent years, it has been found that actinomycin D has the effect of anti-HIV virus, and has the effect of inducing apoptosis on Kaposi's tumor cells which are susceptible to infection in AIDS patients. However, the strong toxicity of actinomycin D limits the scope of application of this drug. [0003] The actinomycin D molecule contains two cyclic pentapeptides and a p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/64A61K38/12A61P35/00
Inventor 王锐张邦治倪京满
Owner LANZHOU UNIVERSITY
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