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Selenourea warhead and building method thereof

A construction method and warhead technology, applied in peptide preparation methods, chemical instruments and methods, pharmaceutical formulations, etc., can solve problems such as slowness and weakening sirtuin inhibitory effect

Inactive Publication Date: 2017-05-10
JIANGSU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, a variety of sirtuin catalytic mechanism-oriented inhibitors rely on the catalytic mechanism-oriented sirtuin inhibitory warheads that exert sirtuin inhibitory effects have been discovered[7,18]; but among all warheads, only thiourea warheads can It is catalyzed by sirtuin to form an intermediate that cannot be further catalyzed (that is, a chemically stable isothiourea intermediate); while other warheads that are catalyzed by sirtuin can still be slowly catalyzed by sirtuin to form the final product , so as to weaken the inhibitory effect on sirtuin

Method used

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  • Selenourea warhead and building method thereof
  • Selenourea warhead and building method thereof
  • Selenourea warhead and building method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] Embodiment 1. An inhibitor containing selenourea class SIRT5 inhibition warhead ( figure 1 ) chemical synthesis. The synthesis process of this compound is as follows figure 2 As shown, the specific steps are as follows:

[0080] Step 1. 3mmol H 3 COOC (CH 2 ) 2 Dissolve NHCHO in 15ml of DCM, add 3.6mmol of Burgess reagent, reflux for 2 hours to produce a yellow liquid; add 10ml of DCM to dilute, distill the water twice with 10ml, and discard the water layer; 5ml of saturated saline, keep organic layer. Anhydrous sodium sulfate was added to the organic layer to dry, filtered, and rotary evaporated to obtain product one.

[0081] Step 2. fully dissolve the product one in 30ml of tetrahydrofuran (THF), add triethylamine and 0.48g selenium powder and heat to reflux to fully react to generate a dark yellow liquid; use diatomaceous earth to filter the dark yellow liquid to obtain The filtrate, after being rotary evaporated and acidified with dilute hydrochloric acid, ...

Embodiment 2

[0084] Example 2. An inhibitor containing selenourea SIRT1 / 2 / 3 inhibitor warhead ( figure 1 ) chemical synthesis. The synthesis process of this compound is as follows image 3 As shown, the specific steps are as follows:

[0085] Step 1. 2mmol CH 3 Dissolve NHCHO in 6ml of DCM, add 3mmol of Burgess reagent, reflux for 2h; add 5ml of DCM to dilute, distill water twice with 5ml, discard the water layer; 2ml of saturated saline, keep the organic layer. Anhydrous sodium sulfate was added to the organic layer to dry, filtered, and rotary evaporated to obtain product 1.

[0086] Step 2. Fully dissolve product one in 24ml of tetrahydrofuran (THF), add triethylamine and 0.72g of selenium powder and heat to reflux for 5h to generate a crude product; use diatomaceous earth to filter the crude product to obtain the filtrate, which is spinned and diluted After acidifying with hydrochloric acid, extract twice with ethyl acetate to obtain an organic layer; continue to wash the organic l...

Embodiment 3

[0088] Embodiment 3. An inhibitor that contains selenourea class SIRT6 inhibition warhead ( figure 1 ) chemical synthesis. The synthesis process of this compound is as follows Figure 4 shown.

[0089] Step 1. By the method of solid-phase peptide synthesis (SPPS), the pentapeptide with fully protected side chains is attached to the MBHA resin.

[0090] Step 2. After being treated with 1% TFA / DMF solution, the lysine side chain at the middle position is selectively deprotected to release a free amino group.

[0091] Step 1a. 1 mmol H 3 C(CH 2 ) 11 Dissolve NHCHO in 10ml of DCM, add 1.6mmol of Burgess reagent, reflux for 3h; add 5ml of DCM to dilute, distill the aqueous solution twice with 15ml, and discard the aqueous layer; 10ml of saturated saline aqueous solution, keep the organic layer; in the organic layer Add anhydrous sodium sulfate to dry, filter, and rotary evaporate to obtain product one.

[0092] Step 1b. Fully dissolve product one in 15ml tetrahydrofuran (THF...

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Abstract

The invention discloses a selenourea warhead and a building method thereof. A thiourea sirtuin inhibition warhead is developed, a compound containing the selenourea warhead is endowed with the mechanism, of inhibiting catalytic activity of sirtuin, similar to that of the thiourea sirtuin inhibition warhead, namely, the selenourea warhead can be recognized as a substrate by the sirtuin and forms a stable isothiourea (or isoselenourea) intermediate which cannot be further converted through catalytic treatment of the sirtuin. The sirtuin inhibition warhead has a higher sirtuin inhibition effect and higher antioxidant capacity than the thiourea sirtuin inhibition warhead, and can be applied to a sirtuin inhibitor as a novel drug for treating human diseases.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a selenium-containing compound and its preparation technology. Background technique [0002] As a major post-translational modification, acylation and deacylation of lysine side chains have been shown in recent years to effectively regulate the structure and function of modified proteins in cells [1-3]. The acylation and deacylation of lysine side chains in cells is a dynamic process, in which the acyl group can be a smaller acetyl group or a larger succinyl group or myristoyl group. ). It should be pointed out that, based on current knowledge, acylation can be an enzyme-catalyzed process (such as catalyzed by members of the acetyltransferase family (protein lysine acetyltransferases)) [4] or a non-enzyme-catalyzed process [5], while Deacylation is an enzyme-catalyzed process, which is catalyzed by members of the protein acyl-lysine deacylases family (protein acyl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/08C07K7/06C07K1/16C07K1/06C07K1/04A61K38/08A61K38/06A61P35/00A61P5/00
CPCA61K38/00C07K5/0827C07K7/06Y02P20/55
Inventor 郑卫平江彦弘
Owner JIANGSU UNIV
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