Prodrug with tumor targeting and preparation method and application of prodrug

A technology of tumor-targeting and prodrugs, which is applied in the field of tumor-targeting prodrugs and their preparation, can solve the problems that no precedents for cancer-targeted drug regimens have been found, and achieve increased tumor cell selectivity, Good tumor targeting and low toxicity

Pending Publication Date: 2019-08-09
HUNAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Through domestic and foreign literature and patent searches, no precedents have been found for folic a

Method used

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  • Prodrug with tumor targeting and preparation method and application of prodrug
  • Prodrug with tumor targeting and preparation method and application of prodrug
  • Prodrug with tumor targeting and preparation method and application of prodrug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1: Preparation of folic acid-gemcitabine prodrug

[0040] Take folic acid (0.15mmol) and dissolve it in 60ml DMSO. Under the action of dehydrating agent DCC (3.0mmol) and catalyst DMAP (3.0mmol), the reaction is stirred at 0℃ for 6h; then gemcitabine is added according to the molar ratio of folic acid 1:3 (Gemcitabine is Dissolved in DMSO), raise the temperature from an ice bath to room temperature 25℃, stir overnight in the dark, filter to remove by-products, concentrate the filtrate, recrystallize with ice ether or isopropanol, and purify by chromatography or preparative liquid phase , Freeze-drying can obtain tumor-targeting prodrug GEM-FA, C 28 H 28 F 2 N 10 O 9 , The theoretical MW is 686.5 (the yield is about 70%), and the ion peak MS is identified by mass spectrometry + Is 687.6. The structure characterization data are as follows, and the structure is determined as shown in formula (I):

[0041] 1 H-NMR (300MHz, DMSO): δ 2.05-2.14 (m, 4H), 3.55-3.61 (m, 2H), ...

Embodiment 2

[0042] Example 2: Preparation of folic acid-gemcitabine prodrug

[0043] 1) Preparation of folic acid active ester (γ-NHS-FA): Dissolve folic acid (1.0g, 2.3mmol) in 40ml anhydrous DMSO, add 0.5ml TEA triethylamine and mix and stir in anhydrous environment at room temperature and avoid light Overnight; then mix 0.47g (2.3mmol) of DCC and 0.26g (2.3mmol) of NHS, stir for 24h in the dark, filter to remove by-product dicyclohexylurea, and vacuum dry at low temperature to remove DMSO and TEA to obtain active folate.

[0044] 2) Preparation of folic acid-gemcitabine prodrug: Dissolve folic acid active ester γ-NHS-FA (0.15mmol) in 60ml of anhydrous DMSO / TEA (volume ratio 2:1), take it with γ-NHS-FA, etc. Add moles of gemcitabine to the mixed solution and react overnight in the absence of light under anhydrous conditions. The reaction solution is vacuum dried, recrystallized with ice ether or isopropanol, purified by chromatography or liquid phase preparation, and lyophilized to obtain tu...

Embodiment 3

[0046] Example 3: Cytotoxicity detection and evaluation experiment

[0047] Evaluation and comparison of in vitro anticancer effects of GEM and GEM-FA. In view of the fact that gemcitabine nucleoside drugs are broad-spectrum anti-cancer toxicants, tumor cells (HeLa, HepG2, BXPC-3, MDA-MB-231 and SK- OV-3) The pharmacodynamic evaluation of the corresponding conjugate product prodrug GEM-FA and its prototype compound prepared in Example 1 was carried out, and the LO2 liver cells were subjected to the normal cell toxicity test.

[0048] Take the cells in the logarithmic growth phase and inoculate 2~10×10 according to the cell size 3 After growing on a 96-well plate, discard the supernatant, and then administer according to the following groups: cancer cells are divided into non-drug group and drug-added group (concentration of 0.05-50μM for cancer cells, concentration of 0.5-100μM for LO2 cells ; Where the concentration of folic acid is set to 0.5-100 μM), gemcitabine is used as a po...

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Abstract

The invention belongs to the field of treatment by targeting drugs, and discloses a prodrug with tumor targeting and a preparation method and application of the prodrug. The structural formula of theprodrug is GEM-FA, GEM is gemcitabine, FA is folic acid or an analogue of the folic acid, and the GEM and the FA are coupled through an amido bond; the inhibiting effect of the prodrug on multiple kinds of tumor cells is 3-5 times better than that of the original drug, the toxicity of the prodrug to a normal liver cell LO2 is lowered by about three times, and the in-vitro cell transport of the prodrug does not depend on expression of nucleic acid transport carrier protein, which is beneficial for reducing drug resistance of the gemcitabine. Compared with the original drug, the prodrug GEM-FA after intravenous injection can maintain higher concentration, higher AUC content and longer half-life period of the gemcitabine medicine in a body. The prodrug has the characteristic of folate receptor-mediated tumor cell targeting, can solve the problems that the gemcitabine is low in anticancer targeting, and the phenomena of deamination and passivating and drug resistance easily occur, and hasan effect of removing cancer cells through metabolism of targeting antagonistic tumor cells and the like.

Description

Technical field [0001] The invention belongs to the field of targeted drugs and drug therapy, and in particular relates to a prodrug with tumor targeting and a preparation method and application thereof. Background technique [0002] Cancer is a major chronic disease that seriously endangers human health. It has become the second killer after cardiovascular disease. Therefore, it is of great significance to find safe, effective, and low-toxic anti-tumor drugs and their systems and to study their mechanism of action. . [0003] In addition to the effect of killing cancer cells / tissues, the traditional chemotherapy of cancer treatment has non-targeted selectivity that can produce toxic side effects on cells in non-cancerous areas, such as bone marrow hematopoietic cells, hair follicles, oral cavity, digestive tract, and reproductive system. Cells, etc.; make the maximum clinically tolerated dose of chemotherapeutic drugs very limited, reducing the true therapeutic effect and drug ec...

Claims

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Application Information

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IPC IPC(8): A61K47/54A61K31/7068A61P35/00
CPCA61K47/545A61K31/7068A61P35/00
Inventor 谭蔚泓彭咏波刘腾李雄符婷张水寒万丹陈慧吴萍
Owner HUNAN UNIV
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