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Isaridin cyclic ester peptide derivative as well as preparation method and application thereof

The technology of cyclic lipopeptide and its derivatives is applied in the field of isaridin-like cyclic lipopeptide derivatives and its preparation, which can solve the problems of adverse reactions of antithrombotic drugs, complicated preparation method and high preparation cost, and achieve good antithrombotic activity and cytotoxicity. The effect of low, low product cost

Active Publication Date: 2022-02-25
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The technical problem to be solved by the present invention is to overcome the defects and deficiencies of existing antithrombotic drugs such as adverse reactions, no anti-inflammatory effect, unsatisfactory effect, complicated preparation method and high preparation cost, and provide a drug with significant anti-inflammatory and anti-thrombotic effects. , a safe and reliable isaridin-like cyclic lipopeptide derivative

Method used

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  • Isaridin cyclic ester peptide derivative as well as preparation method and application thereof
  • Isaridin cyclic ester peptide derivative as well as preparation method and application thereof
  • Isaridin cyclic ester peptide derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1 A method for preparing isaridin-like cyclic ester peptide derivatives

[0056] ascidian symbiotic fungal strains Beauveria felina SYSU-MS7908 (preserved in Guangdong Microbial Culture Collection Center on June 28, 2018, with the preservation number GDMCC No: 61059, and preservation address: 5th Floor, Building 59, Compound, No. 100 Xianlie Middle Road, Guangzhou City) was fermented, and the fermentation liquid for separation and extraction to obtain compound I-1 to compound I-15.

[0057] The specific fermentation, separation and extraction process is as follows:

[0058] 1. Seed culture:

[0059] 1.1 Seed culture medium: 10 g of yeast extract, 20 g of peptone, 20 g of glucose, and 1 L of tap water were evenly distributed in five 500 mL Erlenmeyer flasks, and sterilized at 121°C for 15 minutes.

[0060] 1.2 Cultivation of seeds: Inoculate the ascidian symbiotic fungus strains into the seed culture medium, place them on a shaker at 180 rpm at a temperature ...

Embodiment 2

[0113] Example 2 Anti-inflammatory activity test of isaridin cyclic ester peptide

[0114] Taking the 12 compounds (compounds I-1~I-9 and I-13~I-15) prepared in Example 1 as research objects, their effects on intracellular NO in mouse macrophage RAW264.7 cells induced by lipopolysaccharide LPS were tested. Release amount to evaluate the anti-inflammatory activity of the compound, the specific process is as follows:

[0115] 1.1 Experimental materials: lipopolysaccharide (LPS), indomethacin (Indomethacin, Indo, positive control), mouse mononuclear macrophages (RAW264.7), DMSO, tetrazolium (MTT, 5 mg / mL), Griess method NO kit (Beiyuntian Company).

[0116] 1.2 Experimental method

[0117] The compound was dissolved in DMSO and made into a 10 mM stock solution, which was diluted with DMEM medium to the required concentration (the content of DMSO was less than 2%).

[0118] RAW264.7 cells (1×10 5 cells / mL) 100 μL per well were cultured in a 96-well plate at 37°C, 5% CO 2 Inc...

Embodiment 3

[0125] Example 3 In vitro antithrombotic experiment of isaridin cyclic ester peptide

[0126] Taking the 12 compounds (compounds I-1~I-9 and I-13~I-15) prepared in Example 1 as research objects, their inhibitory effect on the aggregation of platelets induced by adenosine diphosphate ADP was tested in vitro to evaluate The antithrombotic activity of compound, specific process is as follows:

[0127] Kunming mice were taken, and blood was collected from the celiac artery after pentobarbital sodium anesthesia, and 3.2% sodium citrate was added to the syringe for anticoagulation (the volume ratio of whole blood to anticoagulant was 9:1), mixed gently, and 1000 r centrifuge at 3000 r / min for 10 min, and take the supernatant, which is platelet-rich plasma (PRP); centrifuge the remaining part at 3000 r / min for 10 min to obtain platelet-poor plasma (PPP), and use PPP to adjust the PRP to a platelet count of 3×10 8 / mL.

[0128] 295 μL of PRP was taken for each test, 1% DMSO was mixe...

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Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to an isaridin cyclic ester peptide derivative as well as a preparation method and application thereof. Tests prove that the derivative shows good anti-inflammatory and antithrombotic activity, even the activity is higher than that of a positive control drug, in addition, a natural compound derived from marine microorganisms has the characteristics of difficulty in resistance generation, high safety and the like, and tests also prove that the cytotoxicity of the compound disclosed by the invention is low. Meanwhile, the isaridin cyclic depsipeptide derivative disclosed by the invention is extracted from sea squirt-associated epiphytic fungi, can be fermented on a large scale by utilizing microorganisms, has the characteristics of simple production process, short period, low product cost and the like, and has a wide application prospect.

Description

technical field [0001] The invention belongs to the technical field of biomedicine. More specifically, it relates to an isaridin-like cyclic lipopeptide derivative and its preparation method and application. Background technique [0002] Thrombotic disease is a dangerous pathological process with high morbidity and mortality, which is a major threat to human health and life. Thrombosis can lead to various cardiovascular diseases, including coronary heart disease, myocardial infarction, ischemic stroke, pulmonary embolism, etc. [0003] At present, the most commonly used antithrombotic drugs clinically mainly include anticoagulants and antiplatelet drugs, which treat thrombotic diseases by directly hindering thrombus formation. However, most drugs, such as warfarin and aspirin, have serious adverse effects and are not effective. Those skilled in the art have also developed many antithrombotic compounds. For example, Chinese patent application CN1228701A discloses a heteroc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/64C07K7/06C07K7/02C12P21/02C12P21/04A61K38/12A61K38/08A61P29/00A61P7/02C12R1/645
CPCC07K7/64C07K7/02C07K7/06C12P21/02A61P29/00A61P7/02A61K38/00
Inventor 陈森华刘岚姜明华
Owner SUN YAT SEN UNIV
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