Polyethylene glycol modified cardiac glycoside compound prodrug and anti-tumor application thereof

A technology of polyethylene glycol and cardiac glycosides, which is applied in the field of medicine and can solve problems such as the application of cardiac glycosides that have not been seen

Active Publication Date: 2020-02-11
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] At present, there are reports about preparing prodrugs with PEG-modified paclitaxel, camptothecin or scutellarin, etc. Application of Glycosides

Method used

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  • Polyethylene glycol modified cardiac glycoside compound prodrug and anti-tumor application thereof
  • Polyethylene glycol modified cardiac glycoside compound prodrug and anti-tumor application thereof
  • Polyethylene glycol modified cardiac glycoside compound prodrug and anti-tumor application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Embodiment 1: the preparation of compound I

[0058]

[0059] Weigh 10g mPEG 5000 , 1.56mg TEMPO, 24mg KBr (molar ratio 10:0.05:1) was dissolved in 15mL water; another 8% NaClO solution was adjusted to pH 10 with 4M HCl. The above solution was adjusted to 0° C. with an ice bath, and mixed for reaction. During the whole reaction process, the reaction temperature was kept at 0°C, and the pH of the solution was kept at 10 with 0.5M NaOH. After reacting for 5 h, ethanol was added to terminate the reaction, the pH was adjusted to 3 with 4M HCl, and then extracted three times with dichloromethane, and the dichloromethane layer was collected and washed with saturated NaCl solution, anhydrous MgSO 4 Dry for 4 hours, filter to remove the desiccant, concentrate the filtrate to a certain amount, slowly add to an appropriate amount of ice ether, crystallize overnight at 4°C, filter with suction, recrystallize the product once with anhydrous ether, weigh it after vacuum drying,...

Embodiment 2

[0062] Embodiment 2: the preparation of compound II

[0063]

[0064] Weigh 2mmol mPEG 5000 , add 200mL of toluene to dissolve, heat and reflux in an oil bath at 120°C for 2h, evaporate the solvent to dryness under reduced pressure at 75°C, then add 150mL of anhydrous dichloromethane into the round-bottomed flask to dissolve, weigh succinic anhydride (20mmol), pyridine (0.4 mmol) was added to the above system, after the reaction vessel was airtight, stirred in an oil bath at 37°C for 24h, and was detected by TLC (I 2 Color development) after the completion of the reaction, evaporate the solvent to dryness under reduced pressure, add saturated NaHCO 3 Dissolve, adjust the pH to 2 with concentrated hydrochloric acid, extract 3 times with dichloromethane, collect the dichloromethane layer, and wash with saturated NaCl solution, anhydrous MgSO 4 Dry for 4 hours, filter to remove the desiccant, concentrate the filtrate to a certain amount, slowly add to an appropriate amount o...

Embodiment 3

[0067] Embodiment 3: the preparation of compound III

[0068]

[0069] Accurately weigh mPEG (1.00mmol), phenyl p-nitrochloroformate (5.00mmol), and DMAP (2.00mmol) in a 100mL round bottom flask, add 60mL of anhydrous dichloromethane, and react at 25°C for 12h. TLC detected that the reaction was complete, and the reaction solution was extracted three times with an equal volume of 10% citric acid aqueous solution and saturated sodium chloride aqueous solution three times, and the organic layer was dried with anhydrous sodium sulfate for 4 hours, filtered and concentrated, and the product was purified by silica gel column chromatography , a white powdery solid, ie, mPEG-pNP, was obtained with a yield of 82%. 1 H NMR (600MHz, CDCl 3 )δ8.29(d,J=9.2Hz,2H),7.40(d,J=9.2Hz,2H),4.45-4.44(m,2H),3.82-3.81(m,2H),3.65(br.s ),3.38(s,3H).

[0070]Accurately weigh the mPEG-pNP (0.19mmol) prepared above, add 30mL of toluene, stir, reflux at 115°C for 2h, evaporate the solvent under reduc...

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Abstract

The invention belongs to the technical field of medicine, and relates to a polyethylene glycol modified cardiac glycoside compound prodrug and a preparation method thereof, a drug composition including the compound prodrug, and application of the compound prodrug and the drug composition to preparation of an anti-tumor drug. The water solubility of a prototype drug is significantly improved by theprodrug, and the problem of difficult drug administration of the prototype drug is solved. An in-vitro cell experiment shows that the prodrug has the good effect of inhibiting growth of tumor cells.In-vivo pharmacokinetic property study shows that the prodrug can prolong the in-vivo half-life period. In-vivo pharmaceutical effect evaluation of nude mice shows that the prodrug had a good growth inhibition effect on a transplanted tumor of a human lung cancer A549 cell strain inoculated in the nude mice, the inhibition intensity of the prodrug is significantly better than that of the prototypedrug, and the better antitumor effect is achieved. The structure of the prodrug is as follows (please see the specifications for the structure), wherein R1, R2, R3 and R4 are as described in the claims and the specification.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a cardiac glycoside compound prodrug modified by polyethylene glycol and its preparation and application. Specifically, it relates to a polyethylene glycol prodrug of a cardiac glycoside compound isolated from the vine, a preparation method thereof, and an antitumor application. Background technique [0002] Cardiac glycosides are steroidal glycosides that exist in plants and have cardiotonic effects. At present, it is known that there are mainly a dozen families and hundreds of species of plants containing cardiac glycosides, especially Scrophulariaceae and Apocynaceae plants are the most common, others such as Liliaceae, Romoaceae, Brassicaceae, Euonymus, Fabaceae, Moraceae, etc. are also more common. According to statistics, only from 1976 to 1995, more than 250 cardiac glycosides were newly discovered (Liselotte K, et al. Phytochemistry, 1998, 48(1): 1-29), which mainly exis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/60A61K31/7048A61P35/00C08G65/338C08G65/331C08G65/332C08G65/337C08G65/333
CPCA61K47/60A61K31/7048A61P35/00C08G65/338C08G65/3318C08G65/3324C08G65/337C08G65/33396
Inventor 殷军韩娜李怡雯叶纯刘志惠翟健秀李嗣凯
Owner SHENYANG PHARMA UNIVERSITY
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