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A class of alkaloid dimers and their application in the preparation of pd-1/pd-l1 pathway inhibitors

An alkaloid dimer and compound technology, applied in the field of medicine, can solve the problems of blocking PD-1/PD-L1 interaction, which have not yet been seen, and achieve sustainable industrial production, good research and development prospects, high yield effect

Active Publication Date: 2022-07-19
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The research on the biological activity of alkaloids in Corydalis extract mainly focuses on analgesia and anti-inflammation, and there is no report on blocking the interaction of PD-1 / PD-L1

Method used

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  • A class of alkaloid dimers and their application in the preparation of pd-1/pd-l1 pathway inhibitors
  • A class of alkaloid dimers and their application in the preparation of pd-1/pd-l1 pathway inhibitors
  • A class of alkaloid dimers and their application in the preparation of pd-1/pd-l1 pathway inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] The preparation of Corydalis Corydalis extract includes the following steps:

[0031] (1) Acetic acid processing: 50 kg of tubers of Corydalis yanhusuo W.T. Wang, a traditional Chinese medicine, were soaked in 10L 6% acetic acid solution, and then dried at 40°C.

[0032] (2) Extract: The medicinal materials prepared with acetic acid were crushed and soaked in water, and then extracted by ultrasonic for 3 times, each time using 50 L of water for 1 hour, and the extracts were combined and concentrated under reduced pressure to obtain the plant extract.

Embodiment 2

[0034] The preparation of alkaloid dimer compound comprises the following steps:

[0035] The extract obtained in Example 1 was subjected to macroporous adsorption resin column chromatography, eluted with water, 50% ethanol, and 95% ethanol respectively, and the eluent was concentrated under reduced pressure; the 95% ethanol extract was concentrated to no alcohol, and distilled water was added. 2L, extracted 5 times with an equal volume of ethyl acetate to obtain an ethyl acetate phase and an aqueous phase. The ethyl acetate fraction E is obtained after the organic solvent is recovered under reduced pressure. Sample E was eluted by silica gel column chromatography (dichloromethane-methanol 200:1, 150:1, 100:1, 50:1, 25:1, 10:1, 5:1, 3:1, 0:1) , to get components A-I. Component H was selected and subjected to Sephadex LH-20 column chromatography (petroleum ether-dichloromethane-methanol 5:5:1) to obtain H-2. H-2 was separated by preparative liquid chromatography (Rp C18) to ...

experiment example 1

[0043] Experimental Example 1: Evaluation of PD-1 / PD-L1 Interaction Inhibitory Activity of the Plant Extract of Example 1 of the Invention and the Alkaloid Dimer Compounds Obtained in Example 2

[0044] Experimental principle: Homogeneous Time-resolved Fluorescence (HTRF) uses the chelate and label of Europium with a crypt structure as an energy donor (Donor) and XL665 as an energy acceptor (Acceptor) to form fluorescence resonance energy. Transfer (FRET), the absorbance value at 665nm wavelength increases, and the absorbance value at 620nm wavelength decreases. Two tag antibodies, anti-Tag1-Europium and anti-Tag2-XL665, bind to Tag1-PD-L1 and Tag2-PD1, respectively. When PD-1 / PD-L1 binds, the distance between the two antibodies is just enough for energy Transfer, excitation causes fluorescence resonance energy transfer (FRET), and the absorbance value increases at 665 nm wavelength. When the PD-1 / PD-L1 interaction is interfered by compounds or antibodies, the energy transfer...

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Abstract

The invention discloses an alkaloid dimer compound with PD-1 / PD-L1 binding inhibitory effect, and the alkaloid dimer compound has the structure shown in the following formula: The polymer compounds have a significant inhibitory effect on PD-1 / PD-L1 binding, suggesting that these alkaloid dimer compounds can be used as PD-1 / PD-L1 binding inhibitors in tumors, inflammatory diseases, autologous Treatment of immune diseases, bacterial infections, viral infections, fungal infections and other diseases.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular, the invention relates to a novel alkaloid dimer compound with the function of inhibiting the interaction of PD-1 / PD-L1 and the use thereof. Background technique [0002] The human immune system can not only defend against invading bacteria and viruses, but also remove self-damaged or senescent cells, as well as monitor mutated cells to protect the human body. Immune checkpoints are a series of inhibitory signaling pathways that regulate the immune system. Under normal physiological conditions, immune checkpoints can increase or decrease signaling in immune cells (eg, cytokine secretion by effector T cells), thereby reducing immune responses and mitigating collateral tissue damage, which are important for maintaining immune tolerance and regulating immune responses, preventing Self-tissue damage is of great significance. Immune checkpoint proteins that have been discovered so...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/4745A61P35/00A61P29/00A61P37/02A61P31/04A61P31/10A61P31/12
CPCC07D471/04A61P35/00A61P29/00A61P37/02A61P31/04A61P31/10A61P31/12
Inventor 林生夏桂阳肖标兵钟万超夏欢
Owner INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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