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Moleplant seed diterpene derivatives and application thereof

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

Active Publication Date: 2021-08-03
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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  • Moleplant seed diterpene derivatives and application thereof
  • Moleplant seed diterpene derivatives and application thereof
  • Moleplant seed diterpene derivatives and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Example 1: Preparation and determination of compounds 1-41

[0079] 1. Preparation of compounds 1, 37 and 40. In a 1% (m / v) NaOH / MeOH solution system, compounds 18, 38, and 39 were respectively used as raw materials (compound 18 corresponds to compound 1, and so on), and reacted at room temperature for 24 h. After the reaction, it was extracted with ethyl acetate, concentrated, and separated by chromatographic column (eluted with a mixed solution of petroleum ether and ethyl acetate) to obtain the target product. The NMR data of compounds 1, 37, and 40 are shown below, respectively.

[0080] Compound 1: HRMS-ESI-TOF: [M+Na]+373; mp 226-228°C; 1 H NMR (400MHz, Acetone) δ7.29 (d, J = 11.6Hz, 1H, H-12), 5.07 (s, 1H, H-17α), 4.96 (d, J = 8.5Hz, 1H, H-7 ),4.81(s,1H,17β),4.68(s,1H,OH-15),4.44(s,1H,H-5),4.37(s,1H,H-3),4.32(s,2H, OH-5,OH-7),4.06(s,1H,OH-3),3.07(dd,J=13.2,8.8Hz,1H,H-1α),2.21(dd,J=8.4,3.3Hz,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,...

Embodiment 2

[0135] Embodiment 2: In vitro activity test of compounds 1-41

[0136] 1. Cytotoxicity detection of diterpene derivatives of stephenae. Specific operation: Inoculate MCF-7 and MCF-7 / ADR cells in a 96-well plate according to the limited number of 1×110 cells / well, add 100 μL of MEM medium containing 10% fetal bovine serum to each well and culture for 15 hours until the cells grow To cover 70% of the well area, compound No. 1-41 with a final concentration gradient of 1 μM, 5 μM, 20 μM, 50 μM, and 100 μM was sequentially added. The compounds were all dissolved in DMSO, and the administration volume was 1 μL. Doxorubicin with a final concentration gradient of 0.01 μM, 0.1 μM, 1 μM, 5 μM, and 10 μM was set as a positive control, the compound was dissolved in DMSO, and the administration volume was 1 μL. Set DMSO as the negative control, and the administration volume was 1 μL. Three wells were set up in each group as parallel samples. After culturing at 37°C for 48 hours, the ori...

Embodiment 3

[0148] Example 3: Intracellular Aggregation Experiment

[0149] This example provides the intracellular aggregation test of compounds 8 and 31 for Rhodamine 123 (Rh123). Specific operation: MCF-7 / ADR and MCF-7 cells were mixed with 2×10 6 Inoculate into 24-well plates at a density of 24 wells, incubate at 37°C for 16 h, pre-treat with compound 8 and compound 31 (concentrations of 2, 10 and 20 μM, respectively) screened for drug resistance reversal for 1 h, and use a final concentration of 20 μM Verapamil was used as a positive control. The cells were then incubated with Rh123 at a final concentration of 5 μM at 37°C in the dark for 1 h. Cells were washed twice with PBS, resuspended in PBS buffer, and analyzed by flow cytometry. Experimental results such as figure 1 , Table 3. figure 1 It is a schematic diagram of the rhodamine accumulation changes of compound 8 and compound 31 in MCF-7 / ADR cells respectively.

[0150] Table 3 Compounds 8 and 31 inhibit P-gp-mediated rhodam...

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Abstract

The invention belongs to the field of organic chemistry, and particularly relates to moleplant seed diterpenoid derivatives with high MDR reversal activity and application thereof. The novel moleplant seed diterpene derivatives are extracted from euphorbia plant moleplant seeds, the compounds 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 29 is as high as 911.94.

Description

technical field [0001] The invention belongs to the field of organic chemistry, and in particular relates to a class of diterpene derivatives of stephenae and applications thereof. Background technique [0002] Multidrug resistance (MDR) refers to the phenomenon of drug resistance to one drug, accompanied by resistance to other structurally and functionally irrelevant drugs; MDR is one of the main reasons for the failure of chemotherapy for malignant tumors. One of the main mechanisms leading to the occurrence of MDR is the overexpression of P-gp. As an energy-dependent efflux pump, P-gp can reduce the accumulation of anticancer drugs in cells, thereby reducing the efficacy of drugs. Therefore, compounds capable of inhibiting P-gp activity may have the potential to reverse MDR. [0003] Among many compounds, Euphorbia factor L 1 -L 11 It has been found to have anti-tumor, anti-viral, anti-inflammatory and other activities, and is regarded as the most promising reversal a...

Claims

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Application Information

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IPC IPC(8): C07D307/94A61P35/00
CPCC07D307/94A61P35/00
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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