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Muscone 3-position derivative, and preparation method and application thereof

A technology of musk ketone and derivatives, applied in the field of medicine, can solve few problems and achieve the effect of broad medicinal prospects

Active Publication Date: 2021-06-29
SHANGHAI UNIV OF T C M
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In recent years, a large number of research results have shown that muscone has a certain regulatory effect on angiogenesis, but there are few studies on muscone derivatives for angiogenesis

Method used

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  • Muscone 3-position derivative, and preparation method and application thereof
  • Muscone 3-position derivative, and preparation method and application thereof
  • Muscone 3-position derivative, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Embodiment 1: the preparation of formula I and formula II compound

[0063] 1.1: Preparation of compound 2

[0064]

[0065] Dissolve compound 1 (cyclopentadecanone, 6.72g, 30mmol), p-toluenesulfonic acid (570mg, 3mmol) in toluene (90mL) and ethylene glycol (83mL, 1500mmol), then reflux for 2 hours to end the reaction After the reaction solution was cooled to room temperature, it was transferred to a separatory funnel for liquid separation, and the separated toluene layer was successively washed with saturated NaHCO 3 , water, and saturated NaCl, dried over anhydrous magnesium sulfate, filtered with suction, and distilled off the solvent under reduced pressure to obtain a colorless oily substance, namely compound 2, with a yield of 99%.

[0066] Tested: 1 H NMR (400MHz, CDCl 3 ): δ3.91(s,4H), 1.66–1.53(m,4H), 1.46–1.23(m,24H).

[0067] 1.2: Preparation of Compound 3

[0068]

[0069] Compound 2 (8.05g, 30mmol) and liquid bromine (4.8g, 30mmol) were dissolved ...

Embodiment 2

[0129] Example 2: In Vitro Pharmacological Activity Screening of Muscone 3-Derivatives

[0130] Macrophages play a potentially key regulatory role in complex angiogenesis and remodeling processes, and literature research results show that macrophages are the main source of angiogenesis-related factor VEGF-A, and MMP9 produced by macrophages can also Promotes the release of VEGF from its cellular stores and regulates angiogenesis. Therefore, the present invention conducts preliminary drug screening by measuring the effect of the target compound on the expression of VEGF-A mRNA in macrophages. Table 1 shows the activity results of the muscone 3-position derivatives of the present invention acting on Raw264.7 cells for 3 hours at a concentration of 1 μM on VEGF-A mRNA.

[0131] Table 4 Preliminary Screening of the Effects of Muscone 3-Position Derivatives on Raw264.7 Cells on VEGF-A mRNA

[0132]

[0133]

[0134] It can be seen from Table 4 that the 3-position derivative...

Embodiment 3

[0135] Example 3: Toxicity screening and analysis of muskone 3-position derivatives on cancer cells

[0136] As can be seen from Table 4 in Example 2, compound: these 8 compounds of ZM-31, ZM-32, ZM-39, ZM-40, ZM-41, ZM-43, ZM-44, ZM-46 The inhibitory effect of VEGF-A mRNA expression is the most obvious. In this example, these 8 compounds were screened for MTT cytotoxicity of cancer cells. In this experiment, 6 kinds of solid tumor adherent cell lines were selected, which were human gastric cancer cell AGS, human breast Cancer cells MDA-MB-231, MDA-MB-468, human lung cancer cells A549, H1299 and human prostate cancer cell line PC-3, the results are shown in Table 5.

[0137] Table 5 The 3-position derivative of muscone acts on the IC50 value of cancer cells for 48 hours

[0138] compound AGS MDA-MB-231 MDA-MB-468 A549 H1299 PC-3 ZM-31 111.70±1.34 104.10±1.06 >128 23.33±1.34 64.81±1.21 105.10±1.07 ZM-32 8.36±1.04 4.29±1.18 9.32±1.13 8.15...

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Abstract

The invention discloses a muscone 3-position derivative, and a preparation method and application thereof. The muscone 3-position derivative is a compound with a structure as shown in formula I or formula II or a pharmaceutically acceptable salt or stereoisomer thereof, and R in the formula I or formula II is Ra and Rb and is independently selected from alkyl or aryl. The muscone 3-position derivative has obvious angiogenesis inhibiting activity and antitumor activity, can be used for preparing drugs for inhibiting angiogenesis and antitumor drugs, especially for preparing drugs for inhibiting tumor angiogenesis, and has a wide medicinal prospect.

Description

technical field [0001] The invention relates to a class of 3-position derivatives of muskone, a preparation method and application thereof, and belongs to the technical field of medicine. Background technique [0002] Angiogenesis plays a key role in the occurrence, development and spread of tumors. In the article Tumor angiogenesis: therapeutic implications published in the New England Journal of Medicine, Dr. Judah Folkman systematically proposed for the first time the vascular dependence of solid tumor growth and the idea and mechanism of anti-angiogenesis, that is, by inhibiting tumor angiogenesis, tumor cells can In a growth environment lacking oxygen and nutrients, it can effectively inhibit the growth of tumors. Therefore, targeting tumor vascular endothelial cells to find new tumor vascular specific inhibitors has gradually become a hot spot in anti-tumor angiogenesis research. [0003] Tumor-associated macrophages (TAM) are the most abundant immune cells in the tu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C235/46C07C233/31C07C233/18C07C275/18C07C275/26C07C275/28C07C275/34C07C275/30C07C275/24C07C233/76A61P35/00A61K31/166A61K31/165A61K31/164A61K31/17A61K31/16
CPCC07C235/46C07C233/31C07C233/18C07C275/18C07C275/26C07C275/28C07C275/34C07C275/30C07C275/24C07C233/76A61P35/00C07C2601/18C07C2601/14Y02P20/55
Inventor 张建革田平林国强
Owner SHANGHAI UNIV OF T C M
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