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Application of monoketene monocarbonyl curcumin analogue in preparation of antioxidant drugs

An anti-oxidation and drug technology, applied in the direction of drug combination, ketone active ingredients, anti-toxic agents, etc., can solve the problems of no pharmacological activity and high toxicity, and achieve the effects of reduced toxicity, improved stability, and good application prospects

Active Publication Date: 2021-08-27
THE SECOND HOSPITAL AFFILIATED TO WENZHOU MEDICAL COLLEGE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, through literature research (ACS Chem.Neurosci.2019, 10, 4545) and experimental comparative studies, it is found that this type of compound actually has greater toxicity, and the stability of its molecular skeleton needs to be improved ( figure 1 )
Monoketene monocarbonyl curcumin analogs (compounds of general formula (I)) are currently mainly used as a chemical raw material for the synthesis of other curcumin analogs, and there is no relevant literature reporting its pharmacological activity

Method used

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  • Application of monoketene monocarbonyl curcumin analogue in preparation of antioxidant drugs
  • Application of monoketene monocarbonyl curcumin analogue in preparation of antioxidant drugs
  • Application of monoketene monocarbonyl curcumin analogue in preparation of antioxidant drugs

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] The synthesis of embodiment 1 compound

[0034] Using L-proline as a catalyst, monoketene monocarbonyl curcumin analogs were synthesized in one step. All compounds were obtained by reacting acetone with corresponding aldehydes at room temperature. After purification by column chromatography, as shown in Table 1, relatively high yields (40%-71%) were obtained.

[0035]

[0036] Synthesis and structure of monoketone monocarbonyl curcumin analogues. Reaction Conditioning: (I) L-Proline, DMSO, room temperature.

[0037] Table 1. Structures and yields of monoketene monocarbonyl curcumin analogues

[0038]

[0039] The structure of the compound was identified by mass spectrometry and H1-NMR, and the spectroscopic and physical and chemical data are as follows

[0040] . 1. (E)-4-phenylbut-3-en-2-one (sAc or sAc1)

[0041] Yellow powder, 70% yield, mp 34.8~36.0℃. 1 H-NMR (600MHz, CDCl 3 ),δ: 7.558-7.542(m,2H,Ar-H 2 ,β-H),7.520(d,J=16.2Hz,1H,Ar-H 6 ),7.409-7.398(m...

Embodiment 2

[0106] The monocarbonyl curcumin analog molecular skeleton (sAc or sAc1) has good stability, low toxicity, and good activity on cell protection.

[0107] In phosphate buffer, measured curcumin (Cur.), curcumin skeleton (Cur-S), diketene monocarbonyl curcumin analog molecule skeleton (Ac) and monoketene monocarbonyl curcumin of the present invention The stability of the molecular skeleton (sAc) of the analogue ( figure 1 B). The results showed that within 30 min, the light absorption of Cur., Cur-S, Ac decreased greatly in a time-dependent manner, while sAc remained unchanged. Therefore, it is suggested that sAc has a more stable structure than Cur., Cur-S, and Ac.

[0108] The effect of diketene monocarbonyl curcumin analog molecular framework (Ac) and monoketene monocarbonyl curcumin analog molecular framework (sAc) of the present invention on normal liver cells (MIHA) and kidney cells was determined by MTT method (NRK) cytotoxicity ( figure 2 ). The results showed that...

Embodiment 3

[0112] Monocarbonyl curcumin analogues (sAcs) have good antioxidant protective activity and low cytotoxicity against PC12 cells

[0113] The cytotoxicity of 32 sAc compounds to PC12 cells was measured by MTT method, and the results showed that, compared with the curcumin control group, all compounds clearly showed significant cytotoxicity to PC12 cells at the measured concentration ( Figure 4 A).

[0114] In H2O2-induced PC12 cell oxidative damage model, the antioxidant protection activity of 32 sAc compounds was determined. The results showed that cell viability increased to 70%–80% in most groups pre-incubated with compounds ( Figure 4 B). The protective activity of 20 compounds (sAc(1-5), sAc7, sAc9, sAc14, sAc(15-24), sAc27 and sAc32) was even better than that of the antioxidant TBHQ. The cell survival rate of the curcumin group was lower than that of the H2O2 group.

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Abstract

The invention belongs to the field of medicinal chemistry. Aiming at the patent medicine defects that curcumin is unstable, and mono-ketene mono-carbonyl curcumin analogues are high in toxicity and low in stability, the inventionparticularly provides application of a mono-ketene mono-carbonyl curcumin analogue which is stable in structure and good in safety in drugs, especially application of the analogue used as an antioxidant drug in treatment of diseases caused by oxidative stress. The compound has good in-vitro and in-vivo anti-oxidation effects; in vitro, the compound has an excellent anti-oxidation protection effect in a hydrogen peroxide induced cell oxidative damage model; and in a mouse body, in oxidative stress related cerebral ischemia reperfusion injury, the compound has a good anti-oxidation protection effect.

Description

technical field [0001] The invention belongs to the field of medicine use, and in particular relates to the application of a monoketene monocarbonyl curcumin analogue in the preparation of antioxidant medicines. Background technique [0002] Curcumin ( figure 1 .Cur.) is an active ingredient widely present in Zingiberaceae plants, which has a wide range of pharmacological activities such as anti-inflammatory, anti-oxidation, and anti-tumor. Due to its good pharmacological activity, there have been more than 260 clinical trials ( https: / / clinicaltrials.gov ), but most of them have failed so far, and have not been approved for clinical application for the time being. The pharmacokinetic defect caused by instability is one of the main reasons for the clinical failure of curcumin. Therefore, the study of improving its stability and retaining its pharmacological activity is a research hotspot in this field. [0003] The β-diketone structure of the molecular skeleton of curcum...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/12A61P39/06A61P25/00A61P9/00A61P1/16A61P13/12A61P9/10A61P29/00A61P25/16A61P25/28A61P3/10A61K31/33
CPCA61K31/12A61P39/06A61P25/00A61P9/00A61P1/16A61P13/12A61P9/10A61P29/00A61P25/16A61P25/28A61P3/10A61K31/33
Inventor 吴建章何文斐金琪玲王靖松张佳枫沈梦雅胡越
Owner THE SECOND HOSPITAL AFFILIATED TO WENZHOU MEDICAL COLLEGE
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