Dihydroxydibenzo[b,f][1,5]dioxocine compound, and 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 limited application and effect of cancer chemical drug treatment, poor selectivity, and drug resistance of cancer cells.

Inactive Publication Date: 2019-06-11
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 select

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Example 1: Compound 3-ethoxy-10-formyl-9-hydroxy-4,7-dimethyl-6,12-dioxo-6,12-dihydroxydibenzo [b,f][1,5]Dioxocane-1-carboxylic acid extraction, separation and structure identification.

[0084] 1. Extraction and Isolation from Lichen Plants

[0085] Step (1): Naturally dry lichen hongxue tea, crush it, extract with ethanol with a volume concentration of 60%-70% as the extraction solvent, and concentrate the extract to obtain a paste-like AMH primary extract

[0086] Step (2), mix the initial AMH extract and distilled water at a volume ratio of 1:1 to obtain the first suspension; then mix the first suspension with ethanol or absolute ethanol with a volume concentration of 95% to ethanol The final volume concentration is greater than 80%. After shaking, let it stand for alcohol precipitation, separate the ethanol extract from the upper layer, and concentrate the ethanol extract to obtain the paste-like primary anticancer efficacy part AMH-A;

[0087] Step (3), mix AMH-...

Embodiment 2

[0101] Example 2: Compound 3-ethoxy-10-formyl-9-hydroxy-4,7-dimethyl-6,12-dioxo-6,12-dihydroxydibenzo Biological experimental results of [b,f][1,5]dioxocane-1-carboxylic acid's antitumor effect, combined antitumor effect, toxicological safety and antitumor mechanism

[0102] The following are some specific experimental examples to illustrate the formula (1) compound 3-ethoxy-10-formyl-9-hydroxyl-4,7-dimethyl-6,12-dioxo-6,12- Dihydroxydibenzo[b,f][1,5]dioxocane-1-carboxylic acid (indicated by A in the chart below, the same below) has significant, selective, cell-targeted anti-tumor effects , as well as the combined anti-tumor effect with clinical anti-tumor drugs, its toxicological safety and anti-tumor mechanism.

[0103] 1. The effect of compound A on inhibiting and killing human cancer cells in vitro:

[0104] In vitro anti-tumor test method: Compound A is dissolved in analytically pure DMSO, and the final concentration is 0, 1, 2, 4, 8, 16 µg / ml (or 0, 2.5, 5, 10, 20, 30,...

Embodiment 3

[0142] Example 3: Compound 3-ethoxy-10-formyl-9-hydroxy-4,7-dimethyl-6,12-dioxo-6,12-dihydroxydibenzo [b,f][1,5]dioxocane-1-carboxylic acid anticancer mechanism

[0143] 1. Promote the apoptosis of cancer cells

[0144] Using Western Blot detection, it was found that compound A of formula (1) can significantly promote the formation of CleavedPARP, a marker of cancer cell apoptosis, and the results are shown in Figure 22 .

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

[0146] Experimental method: after liver cancer cell HepG2 was treated with compound A of formula (1) for 48 hours, 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) can significantly affect the differentiation and cycle of cancer cells, arrest cells in G1 phase, and reduce cells in S phase during division.

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

[0149]

[0150] 3. Effect on gene exp...

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Abstract

The invention relates to a dihydroxydibenzo[b,f][1,5]dioxocine compound, and a preparation method, pharmaceutical composition and application thereof, and belongs to the technical field of chemistry and medicaments. The structure of the compound is shown in a fomula (I). The compound is separated from lichen lethariella cladonioides, can be used for remarkably killing and/or inhibiting various human cancer cells in vitro, and has a significant inhibition effect on growth of mouse transplanted tumors. The compound has a synergistic or additive combined anti-tumor effect with clinical anti-tumordrugs. The in-vitro anticancer effect has obvious target ability and selectivity. Periodic distribution, gene expression, signal passages and functions of cancer cells can be influenced, and apoptosis of the cancer cells is promoted. The compound has no obvious toxicity to animals, and can remarkably reduce toxicity of cis-platinum to animals. The compound shown in the formula (I) can be used asa chemical treatment drug for human cancers, and can be used as a combined drug, toxic antagonist drug or health care product for other anticancer drugs for cancer adjuvant therapy.

Description

technical field [0001] The present invention belongs to the technical field of chemistry and medicine, and relates to dihydroxydibenzo[b,f][1,5]dioxocane compounds, their preparation method and their pharmaceutical compositions and applications, in particular to 3-ethanediol Oxy-10-formyl-9-hydroxy-4,7-dimethyl-6,12-dioxo-6,12-dihydroxydibenzo[b,f][1,5]dioxacine Cyclo-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 death for human beings. According to the data of Globocan 2012, the number of malignant tumors in the world reached 14.1 million in 2012, and 8.2 million died; "2012 China Tumor Registration Annual Report" revealed that there were 3.12 million new cancer cases in China in 2012, and an average of 6 people were diagnosed with malignant tumors every minute. Cancer has be...

Claims

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Application Information

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IPC IPC(8): C07D321/12A61K31/357A61P35/00A23L33/105
Inventor 贺小琼
Owner KUNMING MEDICAL UNIVERSITY
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