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Synthesis method for dopa-containing oligopeptide and application of dopa-containing oligopeptide in antiparkinsonian prodrugs

A liquid-phase synthesis and synthetic route technology, which is applied in the preparation methods of peptides, medical preparations containing active ingredients, dipeptide ingredients, etc., can solve the problems of no inhibitory ability data, difficult to purchase, expensive and other problems, and achieves Good universality, improved bioavailability and low cost

Pending Publication Date: 2019-10-01
HAINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In 2008, Zhang Chongjing et al. tried to synthesize cyclo (DOPA-Pro) as a new peptidomimetic inhibitor of the peptide prolyl isomerase Pin1, but finally did not give the specific inhibitory data of the cyclic dipeptide on Pin1
The compound is expensive, selling for up to 10,000 yuan per gram, and it is not easy to buy

Method used

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  • Synthesis method for dopa-containing oligopeptide and application of dopa-containing oligopeptide in antiparkinsonian prodrugs
  • Synthesis method for dopa-containing oligopeptide and application of dopa-containing oligopeptide in antiparkinsonian prodrugs
  • Synthesis method for dopa-containing oligopeptide and application of dopa-containing oligopeptide in antiparkinsonian prodrugs

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0040] R 5 is an amino protecting group, R 6 For carboxyl protecting group; Synthetic method comprises the following steps:

[0041] Will Dissolve in organic solvent A, add condensing agent, liquid phase condensation reaction to obtain linear dipeptide R 5 -AA 1 -AA 2 -OR 6 ;

[0042] linear dipeptide R 5 -AA 1 -AA 2 -OR 6 Deprotection to obtain a linear dipeptide; or the linear dipeptide R 5 -AA 1 -AA 2 -OR 6 Dissolved in an alkaline deprotection solution for reaction, the liquid phase reaction removes the amino protecting group, and the protected dipeptide containing dopa ring is obtained

[0043] Amino acid side chains can be protected or not protected by general methods according to their reactivity. There is no special requirement for the type of amino acid, and it can be selected according to its specific use. Considering the wide range of raw material sources, easy availability and product safety, the amino acid side chain is preferably L-type or D-ty...

Embodiment 1

[0071] Embodiment 1, the synthesis of Cyclo (DOPA-Ala) (with the cyclic dipeptide that contains simple side chain amino acid formation)

[0072]

[0073] Dissolve Fmoc-DOPA(Acetonide)-OH (2.5mmol, 1.15g) and H-Ala-OMe HCl (2.5mmol, 0.35g) and HBTU (2.5mmol, 0.95g) in DMF (20ml), add DIEA (5mmol, 0.83ml), the solution was stirred at room temperature for 24 hours, then the solvent was evaporated in vacuo to a small amount. The resulting residue was added to saturated NaHCO 3 aqueous solution and ethyl acetate (1:1), with saturated NaHCO 3 Wash with aqueous solution 5 times. Then, the organic phase was washed with anhydrous Na 2 SO 4 dried, filtered to remove Na 2 SO 4 , the solvent was removed in vacuo, and recrystallized from a small amount of ethyl acetate and n-hexane to obtain the linear dipeptide Fmoc-DOPA(Acetonide)-Ala-OMe (1.07g, 79%). Fmoc-DOPA(Acetonide)-Ala-OMe(M:C 31 h 32 N 2 o 7 )([M+H] + :Calc.544.2210Found 544.2230).

[0074] The linear dipeptide F...

Embodiment 2

[0076] Embodiment 2, the synthesis of Cyclo (DOPA-Ser) (with the cyclic dipeptide that contains polar side chain amino acid formation)

[0077]

[0078] (1) Synthesis of compound Fmoc-DOPA(Acetonide)-Ser(tBu)-OMe

[0079] Dissolve Fmoc-DOPA(Acetonide)-OH (2.5mmol, 1.15g) and H-Ser(tBu)-OMe HCl (2.5mmol, 0.45g) and HBTU (2.5mmol, 0.95g) in DMF (100ml) , DIEA (5 mmol, 0.83 ml) was added and the solution was stirred at room temperature for 24 hours, then the solvent was evaporated in vacuo to a small amount. The resulting residue was added to saturated NaHCO 3 aqueous solution and ethyl acetate (1:1), with saturated NaHCO 3 Wash with aqueous solution 5 times. Then, the organic phase was washed with anhydrous Na 2 SO 4 dried, filtered to remove Na 2 SO 4 , the solvent was removed in vacuo, washed with a small amount of ethyl acetate, and filtered to give the linear dipeptide Fmoc-DOPA(Acetonide)-Ser(tBu)-OMe (1.03 g, 67%). Fmoc-DOPA(Acetonide)-Ser(tBu)-OMe(M:C 35 h 40...

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Abstract

The invention discloses a synthesis method for dopa-containing oligopeptide and application of the dopa-containing oligopeptide in antiparkinsonian prodrugs. According to the synthesis route, in the synthesis process, a prepared dopa-containing dipeptide intermediate protected by actonide has good stability and can be stably stored for a long time, and the dopa-containing dipeptide can be converted only in one step, which overcomes the defects that the dopa-containing dipeptide structure is not stable and cannot be stored for a long time. The method has the advantages that the universality isgood, the defect that a reflux reaction is needed in the prior art is overcome, the reaction condition is mild, side reactions are fewer, the cost of raw materials is lower, and the product has higherpurity and is easy to separate; the prepared dopa-containing dipeptide has good stability in liver homogenate and strong degradation resistance, is expected to be developed into a high-bioavailability and long-acting Parkinson's disease treatment drug, and is expected to significantly reduce the side effects of L-DOPA in treating the Parkinson's disease due to the fact that the bioavailability isgreatly improved.

Description

technical field [0001] The invention relates to a synthesis method and application of a peptide, in particular to a synthesis method and application of a dopa-containing oligopeptide. Background technique [0002] Parkinson's disease is a worldwide disease that seriously threatens the life and health of middle-aged and elderly people. L-DOPA has always been the most effective and widely used drug in the treatment of Parkinson's disease, and it is the gold standard among similar drugs. Under physiological conditions, a large proportion of levodopa exists in the form of uncharged neutral molecules, so it can cross the blood brain barrier (Blood Brain Barrier, BBB) into the brain, and then degrade into dopamine under the action of aromatic decarboxylase , so as to restore the dopamine concentration in the brain that is reduced due to the disease. After oral administration, levodopa passes through the strongly acidic stomach and the small intestine rich in digestive and degrad...

Claims

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Application Information

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IPC IPC(8): C07K5/065C07K1/06C07K1/02A61K38/05A61P25/16
CPCC07K5/06078A61P25/16A61K38/00Y02P20/55
Inventor 刘中强任毅何延淼张小燕孟明民
Owner HAINAN UNIVERSITY
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