A drug conjugate for targeted traceless release and its preparation method and application

A conjugate and drug technology, applied in the field of medicine, can solve the problems of difficult to obtain quantitative and efficient drug loading rate, limited use of drug conjugates, high price, etc., to reduce the difficulty of preparation, reduce toxicity, and simple preparation Effect

Active Publication Date: 2022-03-08
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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  • A drug conjugate for targeted traceless release and its preparation method and application
  • A drug conjugate for targeted traceless release and its preparation method and application
  • A drug conjugate for targeted traceless release and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1 Synthesis of Ring RGDYK

[0045] The synthetic route of the ring RGDYK is shown in the route:

[0046]

[0047] Step 1, the synthesis of linear peptides

[0048] TCP resin (1 mmol / g, 2G, 2 mmol) and CH were added to a 50 ml solid phase reactor. 2 CL 2 (6 ml), swelling resin for 30 min. Pumped CH 2 CL 2 The resin was washed with anhydrous DMF (2 × 6 mL). FMOC-Gly-OH ((297 mg, 1 mmol, 0.5 eq.) Was dissolved in anhydrous DMF (4 mL), and DIEA was added to the resin (520 μL, 3 mmol, 1.5 eq.), N 2 Bubbles are mixed, and the condensation reaction is 2 h. The reaction mixture was removed, the resin was washed with DMF (4 × 6 mL), and then the resin was washed with anhydrous DMF (6 mL). A acetic acid (230 μl, 4 mmol, 2 eq.) And DMF (4 ml, 12 mmol, 6 Eq.) Of DMF (4 ml, 12 mmol, 6 Eq.) Were added to the resin, and the reaction solution was removed, the reaction solution was removed, and the resin was washed with DMF (4 × 6 mL) to give a resin. The degree of substitution ...

Embodiment 2

[0061] Example 2 Synthesis of the joint MC-VAL-CIT-PAB-CL

[0062]

[0063] MC-VAL-CIT-PAB-Cl-Cit-Pab-Cl-Cit-Pab-OH was obtained from chlorine. Synthesis of MC-VAL-CIT-PAB-OH See Patent "Antibody Drug Conjugates, WO2014 / 191578 A1". HRMS (ESI) M / Z: Calcd FORC 28 Hide 41 N 6 O 7 [M + h] + 573.3073, Found 573.3044; Calcd for c 28 Hide 40 N 6 O 7 Na [M + NA] + 595.2856, Found595.2849.

[0064] The obtained Mc-Val-Cit-Pab-OH was dissolved in anhydrous DMF, and Dichloride (2 eq.) Was added under an ice bath, and the ice bath was stirred for 2 h. The DMF was removed under reduced pressure, and the reaction product was separated by 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 = 6.8 Hz, 3H), 1.16-1.25 (m, 2H), 1.28-1.40 (m, 1h ), 1.40-1.54 (m, 5H), 1.54-1.02 (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 = 5.6 Hz, 1H), 7.01 (s, 2h), 7.16-7....

Embodiment 3C

[0065] Example 3COI A3 drug synthesis

[0066]

[0067]COI A3 is an analog of natural product Coibamide A, which is to replace N-Me-Ser (ME) -OH in Coibamide A with N-ME-ALA-OH, and the synthesis method see "YAO, Gy; PAN, ZY; Wu, cl; wang, w.; W.effect Synthesis and StereoChemical Revision of Coibamidea.j.am.chem. Soc., 2015, 137, 13488-13491. "HRMS (ESI) M / Z : Calcd for C 63 Hide 107 N 10 O 14 [M + h] + 1227.7968, Found 1227.7971; Calcd for c 63 Hide 106 N 10 O 14 Na [M + NA] + 1249.7788, Found1249.7751.

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Abstract

The invention relates to a drug conjugate for targeted traceless release, a preparation method and application thereof. Specifically disclosed is a targeted traceless release drug conjugate, the structure of which is T-L-D, T represents a targeting group, L represents a linker, and D represents an active ingredient, wherein T is selected from RGD peptide, cyclic RGD Peptides, RGD peptide derivatives, RGD cyclic peptide derivatives, folic acid, membrane-penetrating peptides, nucleic acid aptamers, fluorescent dyes; D is a pharmaceutical active ingredient with a tertiary amino group, preferably coyba peptide A, coyba peptide A Derivatives; L is A-BC-E, BC represents the enzyme cleavage site. The present invention uses cyclic RGD which has targeting effect and is easy to synthesize and modify instead of expensive and difficult-to-synthesize antibody as the targeting molecule, which is simpler to prepare and achieves high specific targeting effect. Under the action, through the self-elimination of p-aminobenzyl quaternary ammonium salt, the traceless release of the active ingredient of the drug is realized.

Description

Technical field [0001] The present invention relates to the field of medicine, and more particularly to a targeted seamless release pharmaceutical conjugate and a preparation method thereof. Background technique [0002] Coibamide A, COI A) is a highly N-methylated natural cytosperide peptide, and cells having neurotrophic cells such as lung cancer, breast cancer, melanoma, leukemia, and central neural cancer. Toxicity, while having better tissue selectivity for breast, central nervous, ovarian cancer cells. However, since COI A is water soluble, it is not easy to modify, and in vitro experiments have shown that COI A has a large toxicity to normal cells, so COI A is greatly limited as a drug application in vivo studies. Studies have shown that self-elimination reactions, non-margin release tertiary amine or aromatic amine drugs, non-retainable release tertiary amine or aromatic amine drugs. The study of this topic group shows that COIA's analogs COI A3 and COI A have the same cy...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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