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Targeted traceless release drug conjugate and preparation method and application thereof

A technology for conjugates and drugs, applied in the field of medicine, can solve the problems such as difficulty in obtaining quantitative and efficient drug loading rate, limited use of drug conjugates, and reduced drug efficacy, and achieves reduced preparation difficulty, reduced toxicity, and high efficiency. The effect of specific targeting

Active Publication Date: 2019-06-21
SHENZHEN INST OF ADVANCED TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the prior art, there are certain short-term and long-term toxicity problems whether it is drug delivery through embedding methods such as liposomes, polymers, polypeptides, nanomaterials, or covalently coupled drug delivery systems, and Difficult to achieve quantitative, efficient drug loading
In addition, when using nanomaterials, polypeptides, etc. as carriers to deliver drugs through covalent bonding, the drugs need to be modified to facilitate covalent coupling between the drugs and the carrier. The drugs released by this method are modified drugs, not The drug itself, which may be less effective
Although Nature Chemistry has reported a method for the traceless release of drugs from antibody-drug conjugates, this method uses expensive, small sample amount, and difficult-to-synthesize antibodies as targeting molecules, which makes the use of the drug conjugates extremely limited. big limit

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] The synthesis of embodiment 1 ring RGDYK

[0044] The synthetic route of ring RGDYK is shown in the following route:

[0045]

[0046] Step 1. Synthesis of linear peptides

[0047] In a 50mL solid phase reactor, add TCP resin (1mmol / g, 2g, 2mmol) and CH 2 Cl 2 (6ml), swell the resin for 30min. Extract CH 2 Cl 2 , and the resin was washed with anhydrous DMF (2 x 6 mL). At the same time Fmoc-Gly-OH ((297mg, 1mmol, 0.5eq.) dissolved in anhydrous DMF (4ml) was added to the resin, and DIEA (520μL, 3mmol, 1.5eq.) was added to the resin, N 2 Bubbling and mixing, condensation reaction 2h. The reaction solution was pumped off, the resin was washed with DMF (4×6 mL), and then with anhydrous DMF (6 mL). Add acetic acid (230μL, 4mmol, 2eq.) and DMF (4mL) solution of DIEA (2ml, 12mmol, 6eq.) to the resin, react for 30min, remove the reaction solution, wash the resin with DMF (4×6mL) to obtain the resin The degree of substitution is 0.50mmol / g (2g, 1mmol, 1eq.).

[0048]...

Embodiment 2

[0060] Synthesis of Example 2 linker MC-Val-Cit-PAB-Cl

[0061]

[0062] MC-Val-Cit-PAB-Cl is obtained by chlorination of MC-Val-Cit-PAB-OH. For the synthesis of MC-Val-Cit-PAB-OH, refer to the patent "Antibody drug conjugates, WO2014 / 191578A1". HRMS(ESI)m / z: calcd for C 28 h 41 N 6 o 7 [M+H] + 573.3073, found 573.3044; calcd for C 28 h 40 N 6 o 7 Na[M+Na] + 595.2856, found 595.2849.

[0063] The obtained MC-Val-Cit-PAB-OH was dissolved in anhydrous DMF, and thionyl chloride (2eq.) was added under ice-cooling, and stirred for 2h in ice-cooling. DMF was removed under reduced pressure, and the reaction product was separated through a silica gel column to obtain MC-Val-Cit-PAB-Cl. 1 H NMR (400MHz, DMSO-d6) δ0.82(d, J=60Hz, 3H), 0.85(d, J=6.8Hz, 3H), 1.16-1.25(m, 2H), 1.28-1.40(m, 1H ),1.40-1.54(m,5H),1.54-1.78(m,1H),1.81-2.02(m,1H),2.05-2.31(m,2H),2.86-3.09(m,3H),4.11-4.22 (m,1H),4.29-4.45(m,2H),4.71(s,2H),5.42(s,2H),5.91-6.04(t,J=5.6Hz,1H),7.01(s,2H), 7.16-7.25...

Embodiment 3C

[0064] The synthesis of embodiment 3Coi A3 medicine

[0065]

[0066]Coi A3 is an analog of the natural product Coibamide A, which replaces N-Me-Ser(Me)-OH in Coibamide A with N-Me-Ala-OH. For its synthesis method, see the literature "Yao, G.Y.; Pan, Z.Y.; Wu, C.L.; Wang, W.; Fang, L.J.; Su, W. Efficient synthesis and stereochemical revision of coibamide A.J.Am.Chem.Soc., 2015, 137, 13488-13491." HRMS(ESI) m / z: calcd for C 63 h 107 N 10 o 14 [M+H] + 1227.7968, found 1227.7971; calcd for C 63 h 106 N 10 o 14 Na[M+Na] + 1249.7788, found 1249.7751.

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Abstract

The invention relates to a targeted traceless release drug conjugate and a preparation method and application thereof. The invention specifically discloses a targeted traceless release drug conjugate.The targeted traceless release drug conjugate has a structure of T-L-D, wherein T represents a targeting group, L represents a linker and D represents an active ingredient, T is selected from an RGDpeptide, a cyclic RGD peptide, an RGD peptide derivative, an RGD cyclic peptide derivative, folic acid, a transmembrane peptide, a nucleic acid aptamer and a fluorescent dye; D is a pharmaceutical active ingredient with a tertiary amine group, is preferably Coibamide A and a Coibamide A derivative; and L is A-BC-E and BC represents a cleavage site. According to the invention, the cyclic RGD whichhas a targeting effect and is easy to synthesize and modify is used for replacing an antibody which is expensive and difficult to synthesize as the targeting molecule, the preparation is simple, a quite high specific targeting effect is also achieved, and meanwhile, and under the specific cutting effect of enzyme, traceless release of a pharmaceutical active ingredient is realized through self-elimination of aminobenzyl quaternary ammonium salt.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a drug conjugate for targeted traceless release and its preparation method and application. Background technique [0002] Coiba peptide A (Coibamide A, Coi A) is a highly N-methylated natural cyclic lipopeptide, which has nanomolar effects on cells such as lung cancer, breast cancer, melanoma, leukemia and central nervous system cancer Toxicity, and good tissue selectivity for breast, central nervous system and ovarian cancer cells. However, because Coi A has poor water solubility and is not easy to modify, and in vitro experiments show that Coi A is also highly toxic to normal cells, the application of Coi A as a drug in vivo research is greatly limited. Studies have shown that p-aminobenzyl quaternary ammonium salt can undergo self-elimination reaction when the enzyme specifically cuts the amide bond or the reducing agent reduces the disulfide bond, and releases tertiary amine or aroma...

Claims

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Application Information

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IPC IPC(8): A61K47/64A61K38/08A61P35/00
Inventor 粟武武春雷房丽晶王伟成哲弘
Owner SHENZHEN INST OF ADVANCED TECH
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