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Preparation and application of curcumin analogs capable of inhibiting activity of 11beta-hydroxysteroid dehydrogenase type II (11beta-HSD2) of human

A technology of hydroxysteroids and dehydrogenase inhibitors, which is applied in the field of medicine and can solve problems such as low bioavailability and poor human absorption efficiency

Active Publication Date: 2014-08-13
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although curcumin has the potential to treat colorectal cancer, its low bioavailability, poor absorption efficiency and instability in the body greatly limit its clinical application in the treatment of colorectal cancer (Shehzad, A etc., Drugs Today 2010,46,523; Villegas, I etc., Mol.Nutr.Food Res.2008,52,1040; Wichitnithad, W etc., Molecules 2011,16,1888), for this reason, need to develop better Curcumin derivatives that inhibit 11β-HSD2 enzyme activity provide experimental and clinical basis for the future development of drugs for the prevention and treatment of colorectal cancer

Method used

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  • Preparation and application of curcumin analogs capable of inhibiting activity of 11beta-hydroxysteroid dehydrogenase type II (11beta-HSD2) of human
  • Preparation and application of curcumin analogs capable of inhibiting activity of 11beta-hydroxysteroid dehydrogenase type II (11beta-HSD2) of human
  • Preparation and application of curcumin analogs capable of inhibiting activity of 11beta-hydroxysteroid dehydrogenase type II (11beta-HSD2) of human

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1: Preparation and identification of 7 curcumin analogues

[0056] (1) 3,5-bis[4-(fluoro)benzylidene]piperidin-4-one, namely YD1

[0057]

[0058] Weigh 1.0g (7.5mM) of piperidone hydrochloride and 1.8g (15mM) of p-fluorobenzaldehyde in a round bottom flask, add 10ml of absolute ethanol to dissolve, then slowly add 5ml of concentrated hydrochloric acid dropwise under ice bath conditions, magnetically Stir and heat to reflux for 6 hours. The separation and purification refer to cooling the filtrate obtained after heating to reflux to room temperature, and simultaneously, a yellow solid is precipitated. After filtering the suspension with a sand core funnel, the solid matter was collected, washed 3 times with absolute ethanol, and vacuum-dried overnight at 30° C. to obtain 1.83 g of a yellow powder product, which was purified by silica gel column chromatography to obtain 98% of the yellow compound. The yield is 65.2%. 1 H NMR (500MHz, DMSO) δ: 10.23(s, 2H), ...

Embodiment 2

[0078] Example 2: Detection of 7 kinds of curcumin analogues inhibiting human kidney cell type 2 11β-hydroxysteroid dehydrogenase activity

[0079] Type 2 11β-hydroxysteroid dehydrogenase (11β-hydroxysteroid dehydrogenase type II, 11β-HSD2) is an enzyme with nicotinamide adenine dinucleotide as a coenzyme, mainly in tissues such as kidney, large intestine, placenta and testis expressed in microsomes. Microsomes containing 11β-HSD2 can be prepared according to conventional methods (Brennan, J. et al., Genes Dev, 2003.17, 800), and can also be purchased from reagent companies.

[0080] 11β-HSD2 enzyme activity was detected according to the existing research method (Haider, S.G.Int.Rev.Cytol., 2004, 233, 181). Briefly, reaction tubes were first labeled, and 40 μg of human kidney cell microsomal protein and 1 mM curcumin analog (dissolved in dimethylphenylsulfone, DMSO) were added to each tube, and then PBS was added to 100 μl. Then prepare steroid detection mixture: 2 μl [1,2- ...

Embodiment 3

[0088] Embodiment three: 7 kinds of curcumin analog preparations for the treatment of human colorectal cancer

[0089] Compounds YD1-YD7 prepared according to the method of Example 1 were respectively added with excipients according to the weight ratio of the excipients at a ratio of 5:1, and then granulated and compressed into tablets. For liquid preparations, compound YD1-YD7 can be prepared according to the method of Example 1, then add water for injection according to the conventional injection preparation method, and then make injection after fine filtration, potting and sterilization.

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Abstract

The present invention relates to curcumin analogs of formula (I), and their pharmaceutical salts, enantiomers, diastereomers and racemates. A preparation method of the compounds and application of the compounds as 11beta-hydroxysteroid dehydrogenase type II (11beta-HSD2) inhibitor in preventing or treating colorectal cancer of human are disclosed.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically, the invention relates to the preparation of seven compounds capable of inhibiting type 2 11β-hydroxysteroid dehydrogenase activity and their application in anti-colorectal cancer. Background technique [0002] Colorectal cancer is one of the malignant tumors with high migration rate. According to cancer statistics in 2011, the incidence of colorectal cancer ranks third among malignant tumors in both men and women worldwide, while in Western developed countries, the incidence of colorectal cancer in men has risen to the second (Jemal, A. et al., CA Cancer J. Clin.. 2011, 61, 69). Each year, more than 1.2 million new cases are detected and approximately 600,000 patients die from the disease. In my country, in addition to the obvious increase in the incidence rate, the average age at onset of colorectal cancer also has a downward trend. According to statistics, the median age o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/68A61K31/4412A61P35/00A61P1/00
Inventor 黄亚东葛仁山苏志坚项琪张齐好
Owner JINAN UNIVERSITY
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