Narciclasine derivative, and preparation and application thereof in preparation of antitumor drugs
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A technology of narciscycline and its derivatives, applied in the field of medicine, can solve problems such as poor selectivity and narrow therapeutic window
Inactive Publication Date: 2017-03-29
孙青 +1
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Unfortunately, the IC of narcicycline on normal endothelial cells 50 The value is 87-97nM, and its IC on tumor cells 50 The values are very close, indicating that although narciscycline has good anti-tumor activity, its selectivity is poor and its therapeutic window is narrow. Therefore, it is necessary to improve its therapeutic window through structural modification, so that it can obtain selectivity while reducing toxic and side effects. Novel derivatives with improved and further optimized anti-tumor activity
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Embodiment 1
[0058] Example 1: (3aS, 3bR, 12S, 12aR)-6,12-dihydroxy-2,2-dimethyl-3b,4,12,12a-tetrahydrobis([1,3]dioxo)[ 4,5-c: Preparation of 4′,5′-j]phenanthridin-5(3aH)-one
[0059]
[0060] Take 92 mg (0.30 mmol) of narciscycline, 100 mg (0.96 mmol) of 2,2-dimethoxypropane and 60 mg (0.35 mmol) of p-toluenesulfonic acid, dissolve them in 5 ml of anhydrous N , in N-dimethylformamide, stirred and reacted at room temperature 25° C. for 12 hours, and monitored the reaction by thin-layer chromatography. After the reaction is complete, add 0.8 milliliters of pyridine dropwise to the reaction mixture to quench the reaction, and continue to stir for 1 hour, then add 30 milliliters of water to the resulting mixture, a precipitate is precipitated, filter, wash the filter cake with water, and place the filter cake in a vacuum After drying in a drying oven at 55°C for 6 hours, 77 mg of a light brown powdery product was obtained, with a yield of 74%. 1 H NMR (500MHz, deuterated dimethyl sulfoxi...
Embodiment 2
[0061] Embodiment 2: the preparation of ethyl sodium thiosulfate
[0062]
[0063]Take 2.725 g (25 mmol) of bromoethane and dissolve it in 24 ml of ethanol to obtain a clear solution; take another 3.16 g (20 mmol) of anhydrous sodium thiosulfate and dissolve it in 18 ml of water. Mix ethyl bromide ethanol solution and sodium thiosulfate aqueous solution, stir and reflux at 110°C for 15 hours, evaporate the solvent, wash the crude product with ether, and dry to obtain 3.15 g of white crystals, with a yield of 96%, which is ready for use in the next reaction .
Embodiment
[0064] Embodiment: 3: the preparation of n-propyl sodium thiosulfate
[0065]
[0066] With reference to the molar ratio of feeding described in Example 2, reaction conditions and post-treatment mode: get 3.075 grams (25 mmoles) of 1-bromopropane to react to obtain 3.48 grams of white crystals, with a yield of 95%, and directly throw it into the next step for subsequent reactions.
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Abstract
The invention provides a narciclasine derivative represented by the following structural formula I, wherein R1 is alkyl, cycloalkyl, benzyl or substituted benzyl, R2 is alkyl, cycloalkyl, benzyl or substituted benzyl, and n is an integer from 1 to 10. The narciclasine derivative is subjected to a tumor cell toxicity killing effect test, and results prove that the narciclasine derivative has strong toxicity killing effects on lung gland tumor cells, intestinal tumor cells, breast tumor cells, liver tumor cells, prostate tumor cells, melanoma tumor cells, endometrial tumor cells and neuroglia tumor cells, so the narciclasine derivative can be used for preparation of antitumor drugs. The invention provides a preparation method of the narciclasine derivative. The narciclasine derivative has a novel side-chain structure, shows excellent inhibitory activity on a variety of tumor cell strains, has drug efficacy better than that of narciclasine, allows toxic and side effects of the compound to be improved, provides new drugs for treatment of malignant tumors, and is of great clinical application value.
Description
technical field [0001] The invention relates to medicines, in particular to medicines and their preparations, in particular to narciscycline derivatives, their preparations and their application in the preparation of antitumor medicines. Background technique [0002] Narcissicine has strong anti-tumor activity. According to the data released by the American Cancer Society, Narcissicine has an IC of 60 kinds of tumor cells. 50 The value is between 50-63nM, the antitumor activity is significant (NCI database.Available at: http: / / dtp.nci.nih.gov / ). Ceriotti et al. found in the mouse sarcoma 180 cell experiment that narciscycline had an anti-mitotic effect (Tumori. 1966, 53(5): 437-445). Carrasco et al. found in rabbit reticulocytes and yeast cell-free system experiments that narciscycline can effectively inhibit the biosynthesis of eukaryotic ribosomal proteins and play an anti-tumor effect. Its mechanism of action is to bind to the 60S ribosome group to inhibit the peptide bo...
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