Gemcitabine prodrug with tumor targeting properties and preparation method and application thereof

A tumor-targeted, gemcitabine technology, which can be used in anti-tumor drugs, preparation of sugar derivatives, medical preparations containing active ingredients, etc. Selectivity, excellent tumor targeting selectivity, and good solubility

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

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Problems solved by technology

[0008] Through domestic and foreign literature and patent searches, no precedents have been found for the

Method used

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  • Gemcitabine prodrug with tumor targeting properties and preparation method and application thereof
  • Gemcitabine prodrug with tumor targeting properties and preparation method and application thereof
  • Gemcitabine prodrug with tumor targeting properties and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1: Preparation of Biotin-Gemcitabine Prodrug

[0040] Dissolve biotin (0.18 mmol) in 60 ml of DMSO, stir at 0°C for 6 h under the action of dehydrating agent DCC (4.0 mmol) and catalyst DMAP (4.0 mmol); then add gemcitabine dissolved in DMSO dropwise, biotin and The molar ratio of gemcitabine is 1:3; raise the temperature from the ice bath to room temperature 25°C, and stir overnight in the dark; filter to remove by-products, concentrate the filtrate, recrystallize from ice ether or isopropanol, and purify by chromatography or preparative liquid phase , lyophilized to obtain tumor-targeted gemcitabine prodrug GEM-B, C 19 H 25 F 2 N 5 O 6 S, the theoretical MW is 489.5 (the yield is about 70%), the ion peak MS is identified by mass spectrometry + is 490.6. The structural characterization data is as follows, and its structure is determined as shown in formula (I):

[0041] 1 H-NMR (300MHz, DMSO): δ1.25-1.28 (m, CH 2 ,2H), 1.55-1.60(m, 2CH 2 ,4H), 2.35-2....

Embodiment 2

[0042] Example 2: Preparation of Biotin-Gemcitabine Prodrug

[0043] 1) Preparation of biotin active ester (B-NHS): take biotin (0.62 g, 2.5 mmol) and dissolve it in 40 ml of anhydrous DMF, add 0.5 ml of TEA triethylamine and mix and stir at room temperature in an anhydrous environment in the dark Uniform; then mixed 0.51g (2.5mmol) of DCC and 0.28g (2.5mmol) of NHS, stirred in the dark for 24h, filtered to remove by-product dicyclohexylurea, dried under low temperature vacuum to remove DMF and TEA, and the product was precipitated with ether to obtain biotin Active ester B-NHS.

[0044] 2) Preparation of biotin-gemcitabine prodrug: take biotin active ester B-NHS (0.15mmol) and dissolve it in 50ml of anhydrous DMSO / TEA (volume ratio 2:1), take an equimolar amount of B-NHS. The gemcitabine was added to the mixed solution and reacted overnight under anhydrous conditions in the dark. The reaction solution was vacuum-dried, recrystallized with glacial ether or isopropanol, purifi...

Embodiment 3

[0046] Example 3: Cytotoxicity detection and evaluation experiment

[0047] Comparison of in vitro anticancer effect evaluation of GEM and GEM-B. In view of the fact that gemcitabine nucleoside drugs are broad-spectrum anti-cancer cell poisons, a variety of cancer tissue-derived biotin receptor-positive tumor cells (HeLa, HepG2, BXPC-3, MDA-MB-231 and SK) were used in this example. -OV-3) Evaluate the efficacy of the corresponding conjugated product GEM-BIOTIN prepared in Example 2 and its prototype compound, and conduct the LO2 liver cell toxicity test to normal cells.

[0048] Take the cells in the logarithmic growth phase and inoculate 2-10×10 cells according to the size of the cells 3 After 24 hours of growth, the supernatant was discarded, and then the drugs were divided into groups as follows: cancer cells were divided into a drug-free group and a drug-added group (concentration 0.05-50 μM for cancer cells, 0.5-100 μM for LO2 cells) ; wherein the biotin concentration i...

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Abstract

The invention belongs to the field of targeted drug therapy, and discloses a gemcitabine prodrug with tumor targeting properties and a preparation method and application thereof. The structural formula of the prodrug is GEM-B, wherein GEM represents gemcitabine, B represents biotin, and NH2 of GEM is coupled with COOH of B through an amide bond; the prodrug has better inhibiting effects on varioustumor cell strains, the IC50 value of the prodrug is 5-7 times lower than that of GEM, but the toxicity of the prodrug on normal hepatocytes is 3-4 times or more lower, in-vitro cell transport of theprodrug does not rely on expression of nucleic acid transport carrier proteins, and thus drug resistance of GEM can be reduced. Compared with the drug prototype, the prodrug can maintain higher in-vivo gemcitabine concentration, larger AUC and longer half-life after being injected. The prodrug has the advantage of tumor targeting mediated by biotin receptors, and the defects can be overcome thatgemcitabine is low in targeting and easy to deaminize and passivate and easily causes drug resistance; and effects of eliminating tumor cells by targeting metabolic pathways antagonistic to the tumorcells are achieved.

Description

technical field [0001] The invention belongs to the field of targeted drugs and drug therapy, in particular to a gemcitabine prodrug with tumor targeting and a preparation method and application thereof. Background technique [0002] Cancer is a major stubborn disease that seriously endangers human health, and it has become the second largest 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] Chemotherapy, which is a traditional treatment for cancer, in addition to killing cancer cells / tissues, its non-targeted selectivity will have toxic side effects on cells in non-cancer sites, such as bone marrow hematopoietic cells, hair follicles, oral cavity, digestive tract, and reproductive system. Cells, etc.; the maximum tolerated dose of chemotherapeutic drugs in clinical practice is very limited, which reduces the real therapeutic ...

Claims

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Application Information

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IPC IPC(8): C07H19/073C07H1/00A61P35/00A61K31/7068
CPCC07H19/073C07H1/00A61P35/00Y02P20/55
Inventor 谭蔚泓彭咏波刘腾周融融李雄符婷万丹陈慧
Owner HUNAN UNIV
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