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Docetaxel derivative and its preparation method and application

A technology of docetaxel and derivatives, which is applied in the field of medicine, can solve the problems of non-tumor cell cytotoxicity, achieve the effects of inhibiting proliferation, increasing drug loading and encapsulation efficiency, and reducing non-specific toxicity

Active Publication Date: 2020-05-19
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

High zeta potential will interact with many proteins in plasma, and it will also produce certain cytotoxicity to non-tumor cells, so its application will be limited at certain levels

Method used

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  • Docetaxel derivative and its preparation method and application
  • Docetaxel derivative and its preparation method and application
  • Docetaxel derivative and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Synthesis of Triphenylphosphine-Docetaxel Derivatives (TD)

[0041] Dissolve an appropriate amount of docetaxel and 4-carboxybutyltriphenylphosphine bromide in anhydrous DMSO, add appropriate amount of EDC and DMAP, stir at room temperature for 3 days under nitrogen protection, and dialyze the product with distilled water to remove EDC and DMAP , extracted three times with dichloromethane, the organic phase was saturated with sodium sulfate to remove water, and after separation and purification, a white powder was obtained.

[0042] Determination by NMR 1 H-NMR hydrogen spectrum is determined the structure of TD among the embodiment 1, and the solvent selected is, deuterated DMSO, and the result is as follows figure 1 . 1.15ppm, 1.78ppm, 5.23ppm, 8.13ppm belong to the characteristic peak of docetaxel. 7.7-8.2ppm is the characteristic peak of triphenylphosphine. In the HNMR spectrum of TD, the characteristic peak of carboxylic acid in 4-carboxybutyltriphenylphosphine ...

Embodiment 2

[0045] Synthesis of pH Sensitive Polyethylene Glycol-Cholesterol Derivatives

[0046] Dissolve p-hydroxybenzaldehyde in tetrahydrofuran and add N,N-diisopropylethylamine (DIPEA) to catalyze it. Add a dichloromethane solution of cholesterol formyl chloride under ice-bath conditions and stir at room temperature for reaction. The reaction solution was poured into an appropriate amount of double-distilled water, extracted repeatedly with dichloromethane, the water layer was discarded, and the dichloromethane was distilled off under reduced pressure to obtain an intermediate product A.

[0047] The intermediate product A was dissolved in toluene, phenylenediamine was added, heated in an oil bath at 120°C for reflux reaction, the toluene was distilled off under reduced pressure, acetonitrile was added, solid was precipitated at low temperature, and solid compound B was obtained by suction filtration. The intermediate product C was obtained by separation and purification.

[0048] C...

Embodiment 3

[0051] Preparation of PEGylated liposomes

[0052] Weigh an appropriate amount of TD / DTX, phospholipids, cholesterol, and PEG derivatives into an eggplant-shaped flask, add dichloromethane to dissolve, and place on a rotary evaporator to remove organic solvents to form a uniform film. Add an appropriate amount of redistilled water to hydrate to obtain a suspension, and ultrasonically pass the suspension through the membrane to obtain PEGylated liposomes.

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Abstract

The invention relates to a docetaxel derivative, and a preparation method and application thereof, belonging to the technical field of medicine. The docetaxel derivative provided by the invention is triphenyl phosphine-docetaxel (TD) and is prepared by subjecting docetaxel and 4-carboxybutyltriphenylphosphonium bromide to an esterification reaction under the catalysis of EDC and DMAP. Docetaxel and a mitochondrion-targeted group triphenylphosphine are connected via an ester bond; and the structure of the docetaxel derivative is as shown in the specification. The docetaxel derivative provided by the invention is simple and practicable to synthesize and provides a novel idea for mitochondrion-targeted drug delivery. The docetaxel derivative is entrapped in liposome; the preparation method issimple and practicable and has good reproducibility and high stability; and the PEG-modified liposome of the docetaxel derivative is increased in circulation time in blood and can better release antitumor drugs at tumor sites due to a pH-sensitive fracture mechanism.

Description

technical field [0001] The invention belongs to the technical field of medicine and relates to a derivative of an antineoplastic drug, in particular to a docetaxel derivative and a preparation method and application thereof. Background technique [0002] Paclitaxel, as a classic anti-tumor drug, has been widely valued and applied by researchers at home and abroad. This type of drug promotes the assembly of microtubules by binding to tubulin, and at the same time prevents the dissociation of assembled microtubules, thereby Inhibit the mitosis of tumor cells to achieve anti-tumor effect. Docetaxel, as a second-generation taxane antitumor drug, has more powerful antitumor activity than paclitaxel, and has been more and more used in the research of antitumor therapy. [0003] In recent years, more and more researchers have found that the specific delivery of docetaxel to mitochondria can reduce the mitochondrial membrane potential, open the mitochondrial plastome transport chan...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/655A61K31/665A61K31/337A61K47/54A61K47/28A61K9/127A61P35/00C08G65/335
CPCA61K9/1271A61K31/337A61K31/665A61K47/28C07F9/65512C08G65/3356C08G2650/04
Inventor 赵秀丽张九龙陈大为
Owner SHENYANG PHARMA UNIVERSITY
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