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Prodrug with anti-tumor activity and preparation and application thereof

A technology of anti-tumor activity and prodrug, which is applied in the direction of anti-tumor drugs, organic active ingredients, medical preparations of non-active ingredients, etc., to achieve the effects of improving drug efficacy, good tumor targeting, and low toxicity

Inactive Publication Date: 2019-08-30
HUNAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Through domestic and foreign literature and patent searches, no co-modification of biotin in the form of base monomers or terminal amide bonds on the nucleic acid backbone containing gemcitabine drug molecules has been found to construct a gemcitabine prodrug system to achieve cancer-targeted drug delivery. precedent

Method used

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  • Prodrug with anti-tumor activity and preparation and application thereof
  • Prodrug with anti-tumor activity and preparation and application thereof
  • Prodrug with anti-tumor activity and preparation and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0044] The operation, deprotection and concentration determination process of embodiment 1 DNA synthesizer

[0045] 1) Operation of DNA synthesizer: Taking the synthesis of phosphoramidite oligonucleotide as an example to introduce the operation steps of the DNA synthesis instrument produced by polygen ( figure 1 ):

[0046] (1) Preparation of synthetic reagents: 5'-DMT for protecting bases, A, G, C, T phosphoramidite monomers, tetrazole coupling catalysts, acetic anhydride, N-methylimidazole blocking reagents, trichloroacetic acid ( TCA) deprotection solution, oxidation mixture, acetonitrile cleaning solvent, ammonia removal solution, etc.

[0047] (2) Carefully check the amount of reagents in all reagent bottles on the synthesizer, and replace the reagent bottles if necessary, paying special attention to the amount of anhydrous acetonitrile, because the amount of this solvent is relatively large.

[0048] (3) Put the marked clean collection bottle on the synthesizer.

[...

Embodiment 2

[0081] Embodiment 2 has the preparation of prodrug (B-3GEM-1) of antitumor activity

[0082]Put the phosphoramidite base monomer (A / T / C / G / GEM(Z) / Biotin(B)) into the corresponding anhydrous reagent bottle of the nucleic acid synthesizer, and design according to the standard procedure of the DNA synthesizer The sequence 5'-B-CTT ZZZ CCG GCG-3' is automatically synthesized. After the synthesis is completed, DMT cutting, desalting precipitation and HPLC separation and purification are carried out in sequence according to the standard procedure. The purity is greater than 95%, and the yield is not less than 75%. The mass spectrometry showed that the molecular weight was 4102.1, which was consistent with the calculated molecular weight of 4101.4, and 5'-B-CTT ZZZ CCG GCG-3' was obtained.

Embodiment 3

[0083] Embodiment 3 has the preparation of the prodrug (B-3GEM-2) of antitumor activity

[0084] Put the phosphoramidite base monomer (A / T / C / G / GEM(Z) / Biotin(B)) into the corresponding anhydrous reagent bottle of the nucleic acid synthesizer, and design according to the standard procedure of the DNA synthesizer The sequence 5'-B-TTT ZCZ CZG GCC-3' is automatically synthesized. After the synthesis is completed, DMT cutting, desalting precipitation and HPLC separation and purification are carried out in sequence according to the standard procedure. The purity is greater than 94%, and the yield is not less than 76%. The mass spectrometry showed that the molecular weight was 4102.0, which was consistent with the calculated molecular weight of 4101.4, and 5'-B-CTT ZCZ CZG GCC-3' was obtained.

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Abstract

The invention belongs to the field of target drug design and preparation, and particularly relates to a prodrug with anti-tumor activity and preparation and application thereof. The prodrug is obtained by constructing biotin and a phosphoramidite monomer of gemcitabine on 10-100 base nucleic acid skeletons through a 3',5'-phosphodiester linkage, or by cross-linking biotin on a multi-carbon chain which has NH2 and is extended from 10-100 base nucleic acid skeletons containing gemcitabine through an amido linkage. The drug has better inhibition effect on tumor cells and has lower toxicity, and the in vitro cell transport of the prodrug does not depend on the expression of nucleic acid transport vector protein, thereby being beneficial to reducing the drug resistance of GEM; and the drug canmaintain higher drug concentration and half-life period in an organism, overcomes the problems of low anticancer target selectivity, easy deamination passivation and easy drug resistance of GEM, and achieves the effect of clearing cancer cells through target antagonism tumor metabolic pathways.

Description

technical field [0001] The invention belongs to the field of targeted drug design and preparation, and in particular relates to a prodrug with antitumor activity and its preparation and application. Background technique [0002] Cancer chemotherapy, in addition to the effect of killing cancer cells / tissues, its non-target selectivity will have toxic and side effects on cells in non-cancerous parts (bone marrow hematopoietic cells, hair follicles, oral cavity, digestive tract, reproductive system cells, etc.), making The clinical maximum tolerated dose of chemotherapy drugs is very limited, which reduces the real therapeutic effect and drug economy of chemotherapy drugs on cancer. In view of this, it is of great significance to find / design safe, effective and low-toxic anticancer drugs and their systems and study their mechanism of action. [0003] As we all know, in modern cancer treatment, how to efficiently and safely deliver anti-tumor drugs to tumor organs or tissues, i...

Claims

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Application Information

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IPC IPC(8): A61K47/54A61K31/7068A61P35/00
CPCA61K31/7068A61K47/545A61K47/549A61P35/00
Inventor 谭蔚泓彭咏波刘腾李雄张水寒
Owner HUNAN UNIV
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