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Preparation method and anti-tumor application of conformation-locked melittin Anoplin derivative

A technology of conformation locking and melittin, which is applied in the preparation methods of peptides, antineoplastic drugs, chemical instruments and methods, etc., can solve the problems of limited clinical application, intolerance to protease hydrolysis, and the activity needs to be improved.

Pending Publication Date: 2021-07-30
SHANGHAI UNIV OF T C M
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the study also found that Anoplin has some shortcomings that limit its clinical application, such as activity still needs to be improved and intolerance to protease hydrolysis, etc.
No similar reports have been seen so far

Method used

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  • Preparation method and anti-tumor application of conformation-locked melittin Anoplin derivative
  • Preparation method and anti-tumor application of conformation-locked melittin Anoplin derivative
  • Preparation method and anti-tumor application of conformation-locked melittin Anoplin derivative

Examples

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Effect test

Embodiment 1

[0026] Example 1 Preparation of conformationally locked Anoplin derivatives Ano-1-6 of the present invention

[0027] Table 1 Amino acid sequences of the conformationally locked Anoplin derivatives Ano-1-6 of the present invention

[0028]

[0029] The conformationally locked Anoplin derivatives shown in Table 3 can be prepared by polypeptide solid-phase synthesis.

[0030] The preparation of the conformationally locked Anoplin derivative Ano-1 is described below as an example, and the preparation operations of the other conformationally locked Anoplin derivatives are the same.

[0031] synthetic route:

[0032]

[0033] Synthetic steps:

[0034] Weigh 667 mg of amino resin (degree of substitution 0.3 mmol / g) into a peptide synthesis tube, add 5 mL g of dichloromethane at room temperature to swell for 20 min, and then drain the solvent with a water pump. Add 5mL N,N-dimethylformamide to the above synthetic tube to wash the resin, add 7mL 20% piperidine / N,N-dimethylfor...

Embodiment 2

[0036] Example 2 The high-resolution mass spectrum and α-helical degree data of the conformationally locked Anoplin derivatives Ano-1-6 of the present invention

[0037] The high-resolution mass spectrum and α-helical degree data of the conformationally locked Anoplin derivatives Ano-1-6 of the present invention are shown in Table 2.

[0038] Table 2 High-resolution mass spectrum and α-helical degree data table of conformationally locked Anoplin derivatives Ano-1-6 of the present invention

[0039] It can be seen from the above table that the compounds of the present invention all increase the α-helix degree of Anoplin.

[0040]

Embodiment 3

[0041]Example 3 In vitro anti-tumor experiment of conformationally locked Anoplin derivatives of the present invention

[0042] 3.1 Experimental method: CCK-8 cell proliferation toxicity detection kit was used to test the anti-proliferation activity of conformationally locked Anoplin derivatives on melanoma cell B16F10. Prepare 200 μL of B16F10 cell suspension in a 96-well plate, and place the culture plate at 37°C, 5% CO 2 The incubator was pre-incubated for 24 hours. Add 10 μL of different concentrations of conformationally locked Anoplin derivatives to the culture plate and incubate in the incubator for 24 hours. Add 10 μL of CCK-8 solution to each well. After the culture plate was incubated in the incubator for 2 hours, the absorbance of the 96-well plate at 450 nm was measured with a microplate reader. Calculate the inhibitory rate of the drug to B16F10 cells according to the following formula: inhibitory rate=[(Ac-As)] / [(Ac-Ab)]×100%, As: experimental well (culture me...

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Abstract

The invention relates to a conformation-locked melittin Anoplin derivative, which is characterized in that a peptide chain contains a fragment shown as a formula (I), the fragment is positioned at the end part or the middle section of the Anoplin peptide chain, each x is derived from a sequence in melittin Anoplin, and a hydrocarbon bracket is formed on a side chain of the Anoplin peptide fragment to stabilize alpha-helical conformation of polypeptide, so that the purpose of conformation locking is achieved. In-vivo and in-vitro pharmacological experiments show that the compound disclosed by the invention shows very strong inhibitory activity on melanoma cells B16F10, has the advantages of high efficiency, stability and the like, and has great potential in the aspect of preparing anti-melanoma drugs.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical compounds, in particular to a preparation method and anti-tumor application of a conformation-locked melittin Anoplin derivative. Background technique [0002] Melanoma is a highly malignant solid tumor characterized by high invasiveness, high metastasis, and poor prognosis. It mainly involves the skin and is caused by genetic mutations and environmental risks. The most important external The causative factor is exposure to ultraviolet radiation. Globally, cutaneous melanoma accounts for 232,100 (1.7%) of newly diagnosed primary malignancies (excluding non-melanoma skin cancers) each year and is responsible for 55,500 annual patient deaths (accounting for all cancer deaths 0.7% of Once melanoma spreads, it will be directly related to life safety. In recent years, with the advancement of immune and targeted therapy research, the prognosis of patients has been greatly improved, but for adv...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/04C07K1/06A61K38/08A61P35/00
CPCC07K7/06A61P35/00A61K38/00Y02P20/55
Inventor 张卫东栾鑫吴也陈红专黄睿靳金美张鹤沈逸雯陈锦娇杨婷邓仪卿兰海月卢露王梦鸽
Owner SHANGHAI UNIV OF T C M
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