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Teixobactin analogs, and preparation method and application thereof

A technology of analogues and products, applied in the field of TEIXOBACTIN analogues and its preparation, can solve the problems of many synthesis steps and low efficiency, and achieve the effect of reducing synthesis steps

Active Publication Date: 2017-05-10
SHENZHEN INST OF ADVANCED TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In prior art 7, the tetracyclic fragment of Teixobactin was synthesized by a liquid-phase synthesis method, which has many synthetic steps and low efficiency

Method used

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  • Teixobactin analogs, and preparation method and application thereof
  • Teixobactin analogs, and preparation method and application thereof
  • Teixobactin analogs, and preparation method and application thereof

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Experimental program
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Effect test

Embodiment 1

[0070] The preparation method of embodiment 1 compound 1a

[0071] (1) Preparation of linear peptide:

[0072] In a 50mL solid phase reactor, add hydrazine resin (0.61mmol / g, 800mg, 0.488mmol) and CH 2 Cl 2 (3ml), swell the resin for 30min. Extract CH 2 Cl 2, 20% piperidine / DMF solution (3ml) was used to remove the Fmoc protecting group. After 10min, the resin was washed with DMF (4x3mL) and then with anhydrous DMF (2x3mL) for later use. At the same time, Fmoc-Ala-OH ((76mg, 0.244mmol) and HATU (91mg, 0.23mmol) were dissolved in anhydrous DMF (2ml), and DIEA (120μL, 0.732mmol) was added to the solution, mixed, and the reaction Liquid transfer to hydrazine resin for Fmoc removal, N 2 Bubbling and mixing, condensation reaction 2h. The reaction solution was pumped off, the resin was washed with DMF (4x3 mL), and then with anhydrous DMF (3 mL). Add a DMF (2mL) solution of pivalic anhydride (186 μL, 0.96mmol) and DIEA (500 μL, 2.88mmol) to the resin, react for 15min, remove...

Embodiment 2

[0091] The preparation method of embodiment 2 compound 1b

[0092] The preparation method of Example 2 is the same as that of Example 1, except that in the second step, Fmoc-Lys(Boc)-OH is used to replace Fmoc-Arg(Pbf)-OH. Other steps are the same.

[0093] Lys 10 -teixobactin(1b): 1 H NMR (DMSO-d 6 ,400MHz):δ0.52-0.64(m,6H),0.68-0.97(m,19H),0.97-1.20(m,7H),1.20-1.47(m,8H),1.47-1.95(m,10H) ,1.95-2.19(m,2H),2.46(s,3H),2.62-2.89(m,2H),2.89-3.01(m,1H),3.02-3.18(m,1H),3.49-3.78(m, 4H),3.87-4.08(m,2H),4.08-4.50(m,9H),4.50-4.70(s,1H),4.87-5.13(s,1H),5.20-5.45(m,2H),6.70- 6.88(s,1H),7.11-7.38(m,5H),7.50-7.85(m,6H),7.88-8.20(m,5H),8.30-8.59(m,2H),8.92-9.30(m,2H ) ppm; HRMS (ESI) m / z: calcd for C 58 h 98 N 13 o 15 [M+H] + 1216.7305,found 1216.7280.

Embodiment 3

[0094] The preparation method of embodiment 3 compound 1c

[0095] The preparation method of Example 3 is the same as that of Example 1, except that in the second step, Fmoc-His(Trt)-OH is used to replace Fmoc-Arg(Pbf)-OH. Other steps are the same.

[0096] His 10 -teixobactin(1c): 1 H NMR (DMSO-d 6 ,400MHz):δ0.50-0.69(m,6H),0.69-0.91(m,16H),0.95-1.35(m,11H),1.35-1.59(m,3H),1.61-2.00(m,5H) ,1.95-2.20(m,2H),2.46(s,3H),2.90-3.20(m,4H),3.49-3.77(m,5H),3.82-3.92(m,1H),3.95-4.03(m, 1H),4.09-4.28(m,3H),4.28-4.43(m,3H),4.51-4.78(m,2H),4.90-5.10(m,1H),5.15-5.40(m,2H),6.71- 6.85(m,1H),7.15-7.37(m,5H),7.70-7.90(m,2H),7.90-8.19(m,5H),8.32-8.57(m,2H),8.87-8.79(s,1H ) ppm; HRMS (ESI) m / z: calcd for C 58 h 92 N 14 o 15 [M+H] + 1225.6945,found 1225.6944.

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Abstract

The invention discloses Teixobactin analogs, and a preparation method and application thereof. The preparation method comprises the following steps: 1) sequentially coupling 6-12 amino acids onto a solid-phase synthetic resin with amino groups or diazanyl groups to obtain a straight-chain peptide AA1-AA2-...-AAn-1-AAn-solid-phase synthetic resin, wherein AAn-1 is selected from amino acids with hydroxyl on the side chain; 2) coupling 2 amino acids onto the AAn-1 side chain by condensation to obtain a precursor AA1-AA2-...-AAn-1(OCOAAi-AAii)-AAn-solid-phase synthetic resin; and 3) cracking the solid-phase synthetic resin, and carrying out condensation coupling on AAii and AAn to obtain the cyclization products. The preparation method can be used for preparing the compounds from the simple and cheap raw material amino acids in a simple and fast way.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to TEIXOBACTIN analogues and their preparation methods and applications. Background technique [0002] Teixobactin is a new type of antibacterial compound discovered by American scientists through iChip technology in 2015. The compound kills certain bacteria in the mouse body at a speed comparable to that of existing antibiotics, and has no toxic side effects, is safe and effective. Most importantly, Teixobactin destroys bacteria mainly by destroying their cell walls, without inducing bacterial resistance. However, it takes a long time to separate and screen Teixobactin by iChip technology, and the process is complicated, so it is very difficult to quickly evaluate its related pharmacodynamics. Therefore, it is a technical problem to be solved in the present invention to develop an efficient, simple and fast method for synthesizing Teixobactin analogs and obtain a series of Teixobactin ...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/06C07K1/04A61K38/08A61P31/04A61P31/10A61P31/12
CPCA61K38/00C07K7/06Y02P20/55
Inventor 粟武武春雷房丽晶潘正银姚贵阳王伟
Owner SHENZHEN INST OF ADVANCED TECH
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