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Camptothecin-based dimer compound as well as preparation and application thereof

A dimer, camptothecin technology, applied in the field of medicine, can solve the problems of difficult systemic administration, many adverse reactions, hindering application, etc., and achieve the effects of enhancing solubility, reducing toxicity, and inhibiting activity improvement.

Active Publication Date: 2021-02-05
HUAZHONG UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Camptothecin has significant anticancer properties, but the π-π interaction between the planar five-membered ring and the aromatic ring in its structure makes it less soluble, difficult to administer systemically, has many adverse reactions, and has severe bone marrow suppression Toxicity hinders its clinical application

Method used

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  • Camptothecin-based dimer compound as well as preparation and application thereof
  • Camptothecin-based dimer compound as well as preparation and application thereof
  • Camptothecin-based dimer compound as well as preparation and application thereof

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preparation example Construction

[0043] The present invention also provides a method for preparing the dimer compound, comprising the following steps:

[0044] (1) The hydroxyl group in the camptothecin structural formula is converted into a carbonyl chloride compound by a substitution reaction; then the carbonyl chloride compound is esterified with an alkyl diol containing a disulfide bond, so that the camptothecin and the disulfide-containing The alkyl diols of bonds are connected by carbonate bonds to obtain intermediate products;

[0045] (2) After the intermediate product described in step (1) is separated and purified, the hydroxyl contained in its structure undergoes a substitution reaction and is converted into an activated product, which is a carbonyl chloride compound; then the carbonyl chloride compound is substituted with NLG919 Reaction, so that the intermediate product and NLG919 are connected through a carbonate bond, and the obtained product is separated and purified to obtain the dimer compou...

Embodiment 1

[0060] as per figure 1 The preparation of the compound CN shown in the formula (2) according to the schematic flow diagram is carried out according to the following steps:

[0061] (1) Reaction of camptothecin with 2,2'-dithiodiethanol: dissolve camptothecin (1mmol, 348.34mg), triphosgene (1 / 3mmol, 98.91mg) in 20ml of dichloromethane, add 4-di Aminopyridine (1 mmol, 122.17 mg) was reacted on ice in the dark for 30 minutes, and 2,2'-dithiodiethanol (1 mmol, 154.25 mg) was added to react at room temperature in the dark for 12 h.

[0062] (2) Extract the product obtained in (1) with 0.1M hydrochloric acid aqueous solution, saturated saline, and ultrapure water, separate the organic phase, and dry in a vacuum oven at 37°C to remove the organic solvent and dry.

[0063] (3) Dissolve the product (1eq) and triphosgene (1 / 3eq) obtained in (2) in dichloromethane, add 4-dimethylaminopyridine (1eq) and react for 30 minutes, then add NLG919 (1eq) to react.

[0064] (4) Extract the produ...

Embodiment 2

[0067] Reduction-responsive studies of compounds.

[0068] Take a small amount of compound CN in 100 mM GSH aqueous solution and stir for 12 h. The stirred solution was analyzed by mass spectrometry, and the mass spectrometry results were as follows: Figure 4 shown. The results of mass spectrometry showed that compound CN could be degraded to the original camptothecin and NLG919 under reducing conditions.

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a camptothecin-based dimer compound as well as preparation and application thereof. The dimer compound has a structure represented by a formula (I), wherein in the formula (I), m is an integer of 1-4, and n is an integer of 1-4. The dimer compound is connected with camptothecin and immunomodulatory small molecules NLG919 through reductive disulfide bonds, so that combination of tumor chemotherapy and immunotherapy is realized, and the anti-tumor curative effect is enhanced. The compound prepared by the invention can be reduced into original camptothecin and NLG919 under a reducing condition, has good anti-tumor activity in tumors such as liver cancer, breast cancer, colon cancer, melanoma, ovarian cancerand the like, and can be used for inhibiting the activity of indoleamine 2,3-oxygenase, increasing DC cell maturation and reducing the number of immunosuppressive Treg cells; the drug resistance of tumor stem cells to camptothecin is reduced, and the tumor immune response is enhanced.

Description

technical field [0001] The invention belongs to the technical field of medicine, and more specifically relates to a camptothecin-based dimer compound, its preparation and application. Background technique [0002] Tumor is the most important factor threatening human health. Chemotherapy drugs are currently one of the main means of treating various tumors, which mainly exert anti-tumor effects by inhibiting cell growth and / or by cytotoxicity. The immune response elicited by chemotherapeutic drugs can also significantly enhance the overall antitumor effect. However, the immune response induced by chemotherapy is usually limited by various negative feedback regulatory mechanisms that are upregulated during tumor development or tumor treatment. Blocking these negative feedback regulatory pathways with immune drugs is currently the main strategy for reactivating anti-tumor immune responses. . [0003] Camptothecin (CPT), a cytotoxic quinoline alkaloid, can form a relatively st...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/00A61P35/00A61K31/4745
CPCA61P35/00C07D519/00
Inventor 李子福杨祥良万江陵官建坤
Owner HUAZHONG UNIV OF SCI & TECH
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