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Targeted traceless release drug conjugate as well as preparation method and application thereof

A technology of conjugates and drugs, which can be used in drug combinations, pharmaceutical formulations, anti-tumor drugs, etc., can solve the problems of low release efficiency of enzyme cleavage response complexes and the need to improve tumor-inhibitory activity, and achieve novel linker structure and reduce toxicity. , enhance the effect of treatment

Active Publication Date: 2022-05-27
SHENZHEN INST OF ADVANCED TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the low release efficiency of the enzyme cleavage response complex, the antitumor activity needs to be improved

Method used

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  • Targeted traceless release drug conjugate as well as preparation method and application thereof
  • Targeted traceless release drug conjugate as well as preparation method and application thereof
  • Targeted traceless release drug conjugate as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1R

[0059] Example 1 Synthesis of RGD-SS-CA (2)

[0060]

[0061] Step 1. Synthesis of Compound 5. A solution of bis(2-hydroxyethyl)disulfide (2.28 g, 15 mmol) and triethylamine (3.06 mL, 22 mmol) in tetrahydrofuran (THF) (10 mL) was added dropwise 5 mL of methanesulfonyl chloride (1.22 mmol) under an ice bath mL, 15.7 mmol) THF solution, stirred at room temperature for 30 min. The reaction solution was concentrated under reduced pressure to remove THF. The residue was dissolved in 10 mL of N,N-dimethylformamide (DMF), followed by the addition of NaN 3 (2.93 g, 45 mmol), stirred at 60°C. After 6 h, the reaction solution was diluted with 80 mL of water and extracted three times with ethyl acetate (3×25 mL). The organic phase was collected and washed with anhydrous Na 2 SO 4 dry. The solvent was removed by concentration under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate=6:1) to obtain compound 5 (1.32 g, 4...

Embodiment 2

[0065] Example 2 In vitro drug release studies

[0066] RGD-SS-CA was dissolved in 10% DMF in PBS buffer (50 μM, 500 μL, pH=7.4), and dithiothreitol (DTT) was added to the solution at a final concentration of 250 μM, and incubated at 37°C, respectively. At 30, 60, and 90 min, 50 μL of samples were taken out for HPLC analysis.

[0067] In vitro drug release studies of RGD-VC-CA(3) were performed in the same way. RGD-VC-CA was dissolved in 10% DMF in PBS buffer (50 μM, 500 μL, pH=7.4), cathepsin B was added to the solution, the final concentration was 250 μM, and incubated at 37°C for 4, 12, and 24 h, respectively. A 50 μL sample was withdrawn for HPLC analysis.

[0068] Compared with the cleavage-responsive complex RGD-VC-CA (3), the in vitro release results of RGD-SS-CA showed that ( Figure 8 ), in the presence of the reducing agent DTT, RGD-SS-CA can release 1a quickly and without trace, and at 90 min, RGD-SS-CA can be completely cleaved by DTT, achieving 100% release. W...

Embodiment 3

[0070] Example 3 In vitro study of antiproliferative activity

[0071] 3000 to 4000 human non-small cell lung cancer A549 were seeded in 96-well plates. After 24 hours of inoculation, the medium was removed, new medium was added, and then new medium containing RGD-SS-CA complexes of different concentrations was added to the cells, and blank solvent was used as a control. cells in 5% CO 2 in an incubator at 37°C. After 48h, CCK8 reagent was added and the incubation was continued for 1h. Absorbance at 450 nm was then measured with a full wavelength reader (Thermol Multiskan GO). Each experiment was independently replicated three times. Obtain the value of a in the table below.

[0072] 3000 to 4000 human non-small cell lung cancer A549 were seeded in 96-well plates. 24h after inoculation, remove the medium, add a new medium, first add 1mM GSH-OEt and incubate with the cells, and the cells are incubated in 5% CO. 2 in an incubator at 37°C. Then, after adding RGD-SS-CA con...

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Abstract

The invention relates to a targeted traceless release drug conjugate as well as a preparation method and application thereof, the targeted traceless release drug conjugate has a structural formula as shown in a formula I. In the formula I, R1 is selected from RGD peptide and cyclic RGD peptide, R2 is selected from one or more cyclic RGD peptides, and R3 is selected from one or more cyclic RGD peptides. An RGDyK cyclic peptide, an RGD peptide derivative or a cyclic RGD peptide derivative, and lysine side chain amino groups of the RGD peptide, the cyclic RGD peptide, the RGDyK cyclic peptide, the RGD peptide derivative or the cyclic RGD peptide derivative form amido bonds in the structural formula shown in the formula I for coupling; r < 2 > is-CH3,-CH2OH (CH3) 3 or-CH2OH; r3 is-CH3 or-CH2OC (CH3) 3; a <-> is CF3CO2 <->, Cl <-> or CH3COO <->. According to the drug conjugate, the specific linker is adopted, and after the specific linker is split, the self-elimination reaction is carried out on aminobenzyl, so that the active drug is released in a traceless manner, the toxicity of the drug is reduced, and the treatment effect is enhanced.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a targeted traceless release drug conjugate and a preparation method and application thereof. Background technique [0002] Coibamide A (Coibamide A, CA) is a marine natural product isolated from the Panama marine cyanobacteria Leptolyngbya sp. by McPhail et al. in 2008. It is a cyclolipopeptide rich in multiple N-methylated amino acids with low nanomolar cytostatic activity against various cancer cells, and is a potentially advantageous anticancer lead compound. In the previous study, the inventors completed the total synthesis of CA for the first time by using the solid-phase synthesis method, and revised the structure of CA. Through structure-activity relationship study, the inventors found a CA analog with a relatively simple structure, [MeAla3-MeAla6]-coibamide(1a), which has the same anti-proliferative activity as CA. The specific structure is as follows: [0003] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/64A61K38/12A61P35/00C07C323/48
CPCA61K47/64A61K38/12A61P35/00C07C323/48Y02A50/30
Inventor 房丽晶武春雷粟武成哲弘杨用
Owner SHENZHEN INST OF ADVANCED TECH
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