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Dihydroxydibenzo[b,f][1,5]dioxocane compounds, preparation method, pharmaceutical composition and application thereof

A technology of dihydroxydiphenyl and dioxa, which is applied in the field of chemistry and can solve the problems of weak targeting, drug resistance of cancer cells, poor selectivity and the like

Inactive Publication Date: 2021-04-09
KUNMING MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Most of the cancer chemotherapy drugs currently used clinically have many problems such as large toxic and side effects, uncertain curative effect, poor selectivity, weak targeting, and drug resistance of cancer cells, which make the clinical application and effect of cancer chemotherapy treatment limited. very restrictive

Method used

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  • Dihydroxydibenzo[b,f][1,5]dioxocane compounds, preparation method, pharmaceutical composition and application thereof
  • Dihydroxydibenzo[b,f][1,5]dioxocane compounds, preparation method, pharmaceutical composition and application thereof
  • Dihydroxydibenzo[b,f][1,5]dioxocane compounds, preparation method, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Example 1: Compound 3-ethoxy-10-aldehyde-9-hydroxy-4,7-dimethyl-6,12-dioxo-6,12-dihydroxydibenzo represented by formula (1) Extraction, isolation and structural identification of [b,f][1,5]dioxocane-1-carboxylic acid.

[0084] 1. Extraction and isolation from lichen plants

[0085] Step (1), the lichen red snow tea is naturally dried and then pulverized, extracted with 60%-70% ethanol as the extraction solvent, and the extract is concentrated to obtain a paste AMH primary extract

[0086] Step (2), mix the AMH primary extract and distilled water in a volume ratio of 1:1 to obtain a first suspension; then mix the first suspension with 95% ethanol or anhydrous ethanol to ethanol The final volume concentration is greater than 80%, shake and stand for alcohol precipitation, separate the upper ethanol extract, and concentrate the ethanol extract to obtain a paste-like primary anticancer efficacy site AMH-A;

[0087] Step (3), mix AMH-A and distilled water at a volume ratio...

Embodiment 2

[0101] Example 2: Compound 3-ethoxy-10-aldehyde-9-hydroxy-4,7-dimethyl-6,12-dioxo-6,12-dihydroxydibenzo represented by formula (1) [b,f][1,5]Dioxocane-1-carboxylic acid's anti-tumor effect, combined anti-tumor effect, toxicological safety and biological experiment results of anti-tumor mechanism

[0102] The compound 3-ethoxy-10-aldol-9-hydroxy-4,7-dimethyl-6,12-dioxo-6,12-of the present invention is illustrated by some specific experimental examples below. Dihydroxydibenzo[b,f][1,5]dioxane-1-carboxylic acid (represented by A in the chart below, the same below) has significant, selective, and cell-targeted anti-tumor effects , and its combined antitumor effect with clinical antitumor drugs, its toxicological safety and antitumor mechanism.

[0103] 1. Compound A inhibits and kills human cancer cells in vitro:

[0104] In vitro anti-tumor test method: Compound A was dissolved in analytically pure DMSO at a final concentration of 0, 1, 2, 4, 8, 16 µg / ml (or 0, 2.5, 5, 10, 20, ...

Embodiment 3

[0142] Example 3: Compound 3-ethoxy-10-aldehyde-9-hydroxy-4,7-dimethyl-6,12-dioxo-6,12-dihydroxydibenzo represented by formula (1) Anticancer mechanism of [b,f][1,5]dioxane-1-carboxylic acid

[0143] 1. Promotes apoptosis of cancer cells

[0144] It was found by Western Blot that compound A of formula (1) could significantly promote the formation of Cleaved PARP, a marker of cancer cell apoptosis. The results are shown in Figure 22 .

[0145] 2. Effects on the growth cycle of cancer cells

[0146] Experimental methods: HepG2 hepatoma cells were treated with compound A of formula (1) for 48 hours, and the cell cycle and apoptosis were detected by flow cytometry (FACS). The results are shown in Table 5.

[0147] Results: Compound A of formula (1) could significantly affect the differentiation and cycle of cancer cells, block cells in G1 phase, and reduce cells in S phase of division.

[0148] Table 3. Effects on cell cycle (FCM, HepG2)

[0149]

[0150] 3. Effect on ge...

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Abstract

The invention relates to a dihydroxydibenzo[b,f][1,5]dioxocane compound, a preparation method, a pharmaceutical composition and an application thereof, and belongs to the technical field of chemistry and medicine. The structure of the compound is shown in formula (I): formula (I). The compound is isolated from lichen red snow tea, and can significantly kill and / or inhibit various human cancer cells in vitro. In vivo, it has a significant inhibitory effect on the growth of transplanted tumors in mice. It has synergistic or additive combined anti-tumor effect with clinical anti-tumor drugs. The anticancer effect in vitro has obvious targeting and selectivity. It can affect the cycle distribution, gene expression, signaling pathway and function of cancer cells, and promote the apoptosis of cancer cells. It has no obvious toxicity to animals, and can significantly reduce the toxicity of cisplatin to animals. The compound of formula (I) can be used as a chemotherapeutic drug for human cancer, as a combination drug of other anticancer drugs, a toxicity antagonist drug or a health product for adjuvant cancer treatment.

Description

technical field [0001] The invention belongs to the technical field of chemistry and medicine, and relates to dihydroxydibenzo[b,f][1,5]dioxane compounds, preparation methods, medicinal compositions and applications thereof, in particular to 3-ethyl acetate Oxy-10-aldehyde-9-hydroxy-4,7-dimethyl-6,12-dioxo-6,12-dihydroxydibenzo[b,f][1,5]dioxoctane Cyclic-1-carboxylic acid, preparation method, pharmaceutical composition and antitumor application thereof. Background technique [0002] Cancer is a major disease that seriously threatens human health and life safety, and has become the main cause of human death. According to Globocan 2012 data, in 2012, the number of global malignant tumor incidences reached 14.1 million, with 8.2 million deaths; and cancer cases showed an increasing trend year by year. By 2035, the number of new cancer cases worldwide will reach 24 million. According to the 2012 China Cancer Registration Annual Report, there were 3.12 million new cancer cases ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D321/12A61K31/357A61P35/00A23L33/105
Inventor 贺小琼
Owner KUNMING MEDICAL UNIVERSITY
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