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Semen euphorbiae diterpene derivatives with MDR reversal activity and application of Semen euphorbiaediterpene derivatives

A technology of stephenia and derivatives, which is applied in the field of stephenia diterpene derivatives, and can solve the problems such as insignificant reversal effect

Active Publication Date: 2021-08-20
CHENGDU INST OF BIOLOGY CHINESE ACAD OF S
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the published euphorbia factor and its derivatives, the reversal effect is not significant

Method used

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  • Semen euphorbiae diterpene derivatives with MDR reversal activity and application of Semen euphorbiaediterpene derivatives
  • Semen euphorbiae diterpene derivatives with MDR reversal activity and application of Semen euphorbiaediterpene derivatives
  • Semen euphorbiae diterpene derivatives with MDR reversal activity and application of Semen euphorbiaediterpene derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0098] Example 1: Preparation and Determination of Compound 1 to 41

[0099] 1. Preparation of Compounds 1, 37, 40. In a 1% (m / V) NaOH / MeOH solution system, compounds 18, 38, 39 were respectively used as the raw material (Compound 18, in such a push), the normal temperature reaction was 24 h. After the reaction, it was extracted with ethyl acetate, concentrated, and the chromatography column was separated (eluting with EtOAc EtOAc). The core magnetic resonance data of Compound 1, 37, 40 is shown below.

[0100] Compound 1: HRMS-ESI-TOF: [M + Na] +373; MP 226-228 ° C; 1 H NMR (400 MHz, ACETONE) δ 7.29 (D, J = 11.6Hz, 1H, H-12), 5.07 (S, 1H, H-17α), 4.96 (D, J = 8.5 Hz, 1H, H-7 ), 4.81 (S, 1H, 17β), 4.68 (S, 1H, OH-15), 4.37 (S, 1H, H-3), 4.32 (S, 2H, OH-5, OH-7), 4.06 (S, 1H, OH-3), 3.07 (DD, J = 13.2, 8.8 Hz, 1H, H-1α), 2.21 (DD, J = 8.4, 3.3 Hz, 1H , H-4), 1.96-1.85 (M, 2H, H-2, H-8α), 1.69-1.61 (M, 4H, H-1β, H-20), 1.45 (DD, J = 11.6, 8.4 Hz , 1H, H-11), 1.31-1.25 (M, 2H, H-...

Embodiment 2

[0155] Example 2: Test of biological external activity of Compound 1 to 41

[0156]1, cytotoxic test of the hematoperpenoid derivatives. Specific operation: According to 1 × 110 / well, the MCF-7, MCF-7 / ADR cells are inoculated with 96-well plates, and 100 μl of medium medium containing 10% fetal bovine serum 15 h is added to the cell growth. To 70% of the coverage area, the final concentration gradient was added 1 μm, 5 μm, and the compound was dissolved with DMSO, and the drug volume was 1 μl. The final concentration gradient is 0.01 μm, 0.1 μm, 1 μm, 5 μm, and 10 μm, a multi-succytic star having a 10 μm as a positive control, and the compound DMSO is dissolved, and the administration volume is 1 μl. The DMSO is set for a negative control, and the administration volume is 1 μL. Each group sets 3 holes as parallel. After 48 hours of culture at 37 ° C, the original medium was removed, and the CCK-8 solution was diluted 10 times with a serum MEM medium, and 100 μl of dilution was...

Embodiment 3

[0167] Example 3: Orthopedic aggregation experiment

[0168] This example provides compounds 8, 31 for tonifying experimental tests in Rhodamin 123 (RH123). Specific operation: MCF-7 / ADR and MCF-7 cells in 2 × 10 6 The density of the aperture was inoculated into a 24-well plate, incubated for 16 h at 37 ° C, pretreatment of compound 8 and compound 31 (concentration of 2, 10 and 20 μM) with reversal resistance, and the final concentration of 20 μm. Villapimi as a positive control. The cells were then incubated with RH123 having a final concentration of 5 μm at 37 ° C to prevent light for 1 h. The cells were washed twice with PBS, resuspended in the PBS buffer, and analyzed by flow cytometry. Experimental results figure 1 Table 3 shows. figure 1 For the compound 8, the compound 31 accumulates the change in Rhodamine in MCF-7 / ADR cells, respectively.

[0169] Table 3 Compound 8, 31 inhibits P-GP-mediated rhodamine outbound experimental results display table

[0170]

[0171] Co...

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PUM

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Abstract

The invention belongs to the field of organic chemistry, and particularly relates to Semen euphorbiae diterpene derivatives with MDR reversal activity and application of the Semen euphorbiae diterpene derivatives. According to the invention, the novel Semen euphorbiae diterpene derivatives are extracted from euphorbia plant Semen euphorbiae, and are subjected to structural modification, a series of compounds are designed and synthesized, and the reversal activity in MCF-7 / ADR cells is superior to that of verapamil, wherein the reversal multiple of the compound 17 is up to 460.32.

Description

Technical field [0001] The present invention belongs to the field of organic chemistry, and in particular to a type of gantin ditrinder derivative having MDR reversal activity and its application. Background technique [0002] Multi-drug resistance (MDR) refers to a drug resistance to a drug resistance to other structures and functionally produced drug resistance; MDR is one of the main causes of malignant tumor chemotherapy failure. One of the main mechanisms that cause MDR is the overexpression of P-GP. P-GP can reduce the accumulation of intracellular anticancer drugs as an energy-dependent outer draft, thereby reducing the efficacy of the drug. Therefore, compounds that can inhibit P-GP activity may have the potential to reverse MDR. [0003] In many compounds, the big factor L 1 -L 11 It was found to have an anti-tumor, antiviral, anti-inflammatory, and most desirable reversed agents that were considered to be mediated by P-GP mediated MDR. However, the exposed bouncing fact...

Claims

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Application Information

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IPC IPC(8): C07C49/743C07C49/753C07C205/57C07C69/33C07C69/612C07C69/618C07C69/78C07C69/76C07D493/10C07D303/06A61P35/00
CPCC07C49/743C07C49/753C07C205/57C07C69/33C07C69/612C07C69/618C07C69/78C07C69/76C07D493/10C07D303/06A61P35/00C07B2200/07C07C2603/38
Inventor 焦威向玲邵华武王飞张中辉
Owner CHENGDU INST OF BIOLOGY CHINESE ACAD OF S
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