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Strictosidine lactam derivatives and preparation method and use thereof

A technology of glycoside lactams, isoxaudioside, applied in the fields of enzymatic chemistry, medicinal chemistry and pharmacology

Inactive Publication Date: 2012-07-25
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Isosidine synthase can catalyze tryptamine and cleaved strychnine to obtain isosidine through Pictet-Spengler reaction (Ma X, Koepke J, Panjikar S, Fritzsch G, Stockigt J, The structure of Rauvolfia serpentine strictosidine synthase is a novel six-bladed beta-propeller foldin plant proteins. The Plant Cell, 2006, 18, 907-920), but the high selectivity of isosidine synthase to substrates limits its catalysis of other tryptamine derivatives and split cycloma Chrysantrine's reaction

Method used

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  • Strictosidine lactam derivatives and preparation method and use thereof
  • Strictosidine lactam derivatives and preparation method and use thereof
  • Strictosidine lactam derivatives and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1 :(3α,15β,16α,17β)-12-aza-19,20-didehydro-16-vinyl-isosorbinolactam-17-β-D-glucoside (compound I-1) preparation

[0024]

[0025] This example relates to a general synthesis method of a class of novel isoflavin lactam derivatives with cytotoxic activity as shown in formula (I). Specifically, it relates to the synthesis of (3α, 15β, 16α, 17β)-12-aza-19,20-didehydro-16-vinyl-isocurzin lactam-17-β-D-glucoside:

[0026] Dissolve 10 mg isoflavin synthase in phosphate buffer (50 mM, pH=7.0) at room temperature, and fix it on a Ni-NTA column. Take 1.61 g of 7-azatryptamine (10 mmol) and dissolve it in 100 mL of phosphate buffer (50 mM, pH=7.0). Then 3.88 g of serocycline (10 mmol) was dissolved in 100 mL of phosphate buffer (50 mM, pH=7.0). The mixture of the two was passed through a Ni-NTA column, the resulting effluent was cooled with liquid nitrogen and then freeze-dried, washed with methanol to remove the salt, and then prepared for liquid phase separation to obtain...

Embodiment 2

[0032] Example 2 : Preparation of Compound I-2 and I-3

[0033] According to the method of Example 1, using 7-methyltryptamine and 5-chlorotryptamine as raw materials, they are catalyzed by isofumarin synthase and mutants, and coupled with schiscycline to form the corresponding 12-methyl isocyanide. Visidin and 10-chloroisobridin are used as raw materials, and compounds I-2 and I-3 are prepared after being catalyzed by potassium carbonate and lithium carbonate, respectively.

[0034] Compound I-2: light yellow solid; yield 56.1%; Rf (chloroform / methanol 4:1) 0.56; ESI-MS m / z[M+H] + 513; 1 H NMR (500MHz, CD 3 OD): δ 7.65 (1H, d, J=8.0 Hz, H-9), 7.45 (1H, d, J=8.0 Hz, H-11), 7.37 (1H, s, H-19), 7.15 ( 1H, dd, J=8.0, 7.2 Hz, H-10), 5.64 (1H, m, CH 2 CH-16), 5.39 (1H, d, J = 2.1 Hz, H-17), 5.37 (1H, dd, J = 16.8, 1.4 Hz, CH 2 CH-16E), 5.32(1H, dd, J=10.5, 2.1Hz, CH 2 CH-16Z), 5.10 (1H, m, H-3), 4.93 (1H, dd, J=12.6, 5.6 Hz, H-5b), 4.56 (1H, d, J=8.4 Hz, H-1') , 3.85(1H, dd, J=11.9, 2...

Embodiment 3

[0037] Example 3: Cytotoxic activity of compound I-1 on A549 cells

[0038] A549 (human lung cancer) cells were cultured with RPMI 1640 medium containing 10% fetal bovine serum, 100 U / ml penicillin and 100 U / ml streptomycin. 5×10 cells per well 3 Added to 96-well plate with 5% CO at 37℃ 2 Incubate for 24 hours in a humid air incubator.

[0039] The cell survival rate was determined by the modified MTT method. After the cells were incubated for 24 hours, the newly prepared dimethyl sulfoxide solution of compound I-1 was added to each well in a concentration gradient, so that the final concentration of the compound in the well was 100 μg / ml and 33.3 μg / ml, respectively. 11.1 μg / ml and 3.7 μg / ml. After 72 hours, add 10 microliters of MTT (5 mg / ml) phosphate buffer, then continue to incubate at 37°C for 4 hours, centrifuge for 5 minutes to remove unconverted MTT, and add 200 microliters of dimethylsulfoxide to each well Sulfone is used to dissolve the reduced MTT crystals formazan,...

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Abstract

The invention provides novel strictosidine lactam derivatives and pharmaceutically acceptable salts thereof, which have the following general structural formula. The invention also provides a preparation method, which is characterized in that serotonin derivatives and split-ring brucine are catalyzed by immobilized strictosidine synthase and mutants to obtain the novel strictosidine derivatives, and then the strictosidine derivatives are catalyzed by base to synthesize the derivatives by one step. The in vitro cytotoxicity activity test of compounds provided by the invention shows that the derivatives inhibit the growth of tumor cells and can be applied to the preparation of drugs for preventing and controlling tumor diseases.

Description

Invention field [0001] The present invention belongs to the fields of enzyme chemistry, medicinal chemistry and pharmacology, and relates to isocumarin lactam derivatives and preparation methods, as well as the use of such compounds in the preparation of anti-tumor drugs. Background of the invention [0002] Alkaloids have received more and more attention due to their diversity of biological activities. At present, the research on it has developed to the level of enzymes. Among them, the research on the isoflavin synthase from Catharanthus roseus and Snake root is more thorough (Hampp N, Zenk MH, Homogenous strictosidine synthase from cellsuspension cultures of Rauvolfia serpentine.Phytochemistry , 1988, 27, 3811-3815), this enzyme is a key enzyme for catalyzing the synthesis of isocavidin, which is a key intermediate in the synthesis of many terpene indole alkaloids. [0003] Isocudidine synthase can catalyze tryptamine and serocycline through the Pictet-Spengler reaction to obta...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H17/00A61K31/706A61P35/00A61P35/02C12P19/60
Inventor 邹宏斌祝华建约阿施·史托克希特俞永平
Owner ZHEJIANG UNIV
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