Reduction/pH double response adriamycin prodrug and preparation method and application thereof

A doxorubicin-responsive technology, applied in the field of biomedical polymer materials, can solve the problem of reducing the effect of drugs on cancer treatment, and achieve the effect of rapid synthesis method

Active Publication Date: 2017-09-08
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

If these problems are not addressed, the effectiveness of the drug against cancer will be greatly reduced

Method used

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  • Reduction/pH double response adriamycin prodrug and preparation method and application thereof
  • Reduction/pH double response adriamycin prodrug and preparation method and application thereof
  • Reduction/pH double response adriamycin prodrug and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] Embodiment one: doxorubicin derivative (N 3 - hyd -DOX×HCl) synthesis

[0080] Doxorubicin derivatives (N 3 - hyd -DOX×HCl) is mainly prepared through three steps. The first step is to prepare methyl 6-azidehexanoate; the second step is to prepare 6-azidehexanohydrazide; the third step is to modify doxorubicin hydrochloride (DOX×HCl) to obtain doxorubicin derivatives matter (N 3 - hyd -DOX×HCl), the specific synthesis method is as follows:

[0081] Synthesis of small molecular compound 6-azidohexanoic acid methyl ester. Take out the device previously placed in the oven at 120 °C, put it in a desiccator, wait for it to cool to room temperature, and take it out for use. Weigh 6-bromohexanoic acid methyl ester (3.54 g, 16.93 mmol) and sodium azide (NaN 3 ) (2.75 g, 42.33 mmol), and dissolved in 20 mL of DMF in a 50 mL round-bottomed flask, and reacted at 60 °C for 12 h under reflux of condensed water. Use neutral aluminum oxide (Al 2 o 3 ) short column to fi...

Embodiment 2

[0084] Example 2: Alkynyl-terminated 3,3'-dithiodiynbutyl dipropionate (B- ss -B) Synthesis of

[0085] First, 3,3'-dithiodipropionic acid and 3-butyn-1-ol were used as raw materials, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride was used as The activator uses 4-dimethylaminopyridine as a catalyst and dichloromethane as a solvent to obtain 3,3'-dithiodiynbutyl dipropionate through esterification. The specific synthesis method is as follows:

[0086]The glass instruments used were dried in an oven at 120 °C for 4 h, then taken out and cooled to room temperature in a desiccator for later use. First, add 3,3'-dithiodipropionic acid (3.66 g, 17.40 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride in sequence to the three-necked flask (EDC×HCl) (8.67 g, 45.23 mmol) and 4-dimethylaminopyridine (DMAP) (3.19 g, 2.61 mmol) in 100 mL of CH 2 Cl 2 dissolved; secondly, 3-butyn-1-ol (3.17 g, 45.23 mmol) and 15 mL of CH 2 Cl 2 Add to constant pressure...

Embodiment 3

[0088] Embodiment three: diazide ethyl diacetal polyethylene glycol (N 3 - a -PEG 21 - a -N 3 )Synthesis

[0089] Azido-terminated compound diazide ethyl diacetal polyethylene glycol (N 3 - a -PEG 21 - a -N 3 ), obtained through a two-step reaction: First, the synthesis of dichloroethyl diacetal polyethylene glycol (Cl- a -PEG 21 - a -Cl); Secondly, the synthesis of diazide ethyl diacetal polyethylene glycol (N 3 - a -PEG 21 - a -N 3 ). The specific synthesis method is as follows:

[0090] The first step is to synthesize dichloroethyl diacetal polyethylene glycol (Cl- a -PEG 21 - a -Cl). Take polyethylene glycol (HO-PEG) with a molecular weight of 1000 22 -OH) (6.01 g, 6.01 mmol) and pyridinium p-toluenesulfonate (PPTS) (0.30 g, 1.20 mmol) were placed in a 100 mL branched flask, and 50 mL of toluene was added, and the toluene at normal pressure was used twice. The method of boiling removes impurity water. After it was cooled, under nitrogen protection, ...

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Abstract

The invention discloses a reduction/pH double response adriamycin prodrug and a preparation method and application thereof. The specific preparation method comprises the steps of performing a chemical reaction by using a small molecule compound 3,3'-dithio diyne butyl dipropionate (B-ss-B) endcapped with alkynyl and a compound diazide ethyl diacetal polyethyleneglycol (N3-a-PEG-a-N3) endcapped with an azide group, so as to prepare a reduction/pH double response polymer poly(SS-alt-A)n endcapped with alkynyl; and then connecting adriamycin derivatives at two ends of a polymer chain, so as to obtain the reduction/pH double response adriamycin prodrug DOX-hyd-poly(SS-alt-A)n-hyd-DOX. The reduction/pH double response water-soluble adriamycin prodrug has good biocompatibility and characteristics of controlled-release drugs, so that the reduction/pH double response water-soluble adriamycin prodrug can be used as a stimulating sensitive antitumor prodrug.

Description

technical field [0001] The invention belongs to the field of biomedical polymer materials, and in particular relates to a polyethylene glycol-based reduction / pH dual-responsive doxorubicin prodrug, its preparation method and its application. Background technique [0002] Cancer is the result of normal cells becoming cancerous due to multiple factors, multiple stages and multiple mutations in the body, and it is also called malignant tumor in medicine. Cancer is highly lethal and easy to transfer. By destroying the functions of tissues and organs, it will eventually lead to people's death due to organ failure. According to statistics, with the growth of population, the incidence of cancer is also increasing, which seriously endangers human health. Therefore, cancer treatment methods have attracted the attention of domestic and foreign medical researchers. [0003] In the past few decades, with the advancement of medical technology, various cancer treatment methods have been ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/26C07H1/00A61K31/7056C08G65/334A61K9/107A61K47/60A61K47/69A61P35/00
CPCA61K31/704A61K47/60A61K47/6907A61P35/00C08G65/334
Inventor 倪沛红杜雪琼何金林张明祖
Owner SUZHOU UNIV
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