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Novel water-soluble polyethylene glycol link-coupled hydroxycamptothecine derivatives and application thereof

A technology of hydroxycamptothecin and polyethylene glycol, which is applied in the direction of medical preparations with non-active ingredients, medical preparations containing active ingredients, drug combinations, etc., and can solve unstable metabolism in the body, poor water solubility, and many side effects, etc. problem, to achieve the effect of inhibiting or killing tumor cells, short synthetic route and simple operation

Inactive Publication Date: 2015-07-22
TIANJIN UNIVERSITY OF SCIENCE AND TECHNOLOGY
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  • Summary
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  • Application Information

AI Technical Summary

Problems solved by technology

10-Hydroxycamptothecin is a natural analogue of camptothecin. Its anticancer activity is significantly higher than that of camptothecin, but it also has certain toxicity, many side effects, poor water solubility and unstable metabolism in the body

Method used

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  • Novel water-soluble polyethylene glycol link-coupled hydroxycamptothecine derivatives and application thereof
  • Novel water-soluble polyethylene glycol link-coupled hydroxycamptothecine derivatives and application thereof
  • Novel water-soluble polyethylene glycol link-coupled hydroxycamptothecine derivatives and application thereof

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Experimental program
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Effect test

Embodiment 1

[0045] (1) Synthesis of 10-(4-nitrophenylcarbonate)-camptothecin (1a)

[0046] Take 3g (8.23mmol) of 10-hydroxycamptothecin and dissolve it in 600mL of anhydrous tetrahydrofuran, add 11.5mL (82.3mmol) of triethylamine under ice bath, and then add 6.64g (32.9mmol) of phenyl p-nitrochloroformate , reacted at room temperature for 1h. The reaction solution was directly spin-dried under reduced pressure, subjected to ethyl acetate, 200-300 mesh silica gel column chromatography, and recrystallized from dichloromethane and n-hexane to obtain 3.59 g of a white solid, which was sent to the next step without further purification, and the crude yield was 82.3%. 1 H NMR (400MHz, DMSO-d 6 )δ (ppm): 8.74 (s, 1H), 8.40 (d, J = 9.2Hz, 2H), 8.30 (d, J = 9.2Hz, 1H), 8.20 (d, J = 2.4Hz, 1H), 7.97 –7.80(m,1H),7.78(d,2H,J=9.2Hz),7.37(s,1H),6.54(s,1H),5.44(s,2H),5.32(s,2H),1.85– 1.92(m,2H),0.89–0.92(m,3H).

[0047] (2) Synthesis of N-tert-butoxycarbonyl valine polyethylene glycol monomethyl eth...

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Abstract

The invention relates to novel water-soluble polyethylene glycol link-coupled hydroxycamptothecine derivatives and the application thereof. The general molecular formula is MPEG-X-H or H-X-PEG-X-H, wherein X refers to the linking group, such as valine, and H refers to the medicine molecule, such as hydroxycamptothecine and the like. The invention further relates to the synthesis of the prodrug and the release of the active compound under the condition of a 37-degree phosphate buffer solution. The synthetic compounds are adopted to conduct the test of tumor cells in vitro inhibitory activity against human leukemia cells (K562), human colon cancer cells (HT-29) and human hepatoma carcinoma cells (HepG2); the results show that the compounds have remarkable antitumor activity, and the data show that the release rate and in vitro activity of hydroxycamptothecine are closely related to the length of PEG connected and the connection manner. The compounds have wide prospects in development and application of antitumor drugs.

Description

technical field [0001] The invention belongs to the field of new compound synthesis and drug application, and relates to a novel water-soluble polyethylene glycol-coupled hydroxycamptothecin prodrug: polyethylene glycol monomethyl ether or polyethylene glycol and hydroxycamptothecin drugs combination (MPEG-X-H or H-X-PEG-X-H). technical background [0002] Camptothecin is a class of alkaloids extracted from the bark and fruit of Camptotheca involucrata, a species endemic to the mainland of my country. It has significant curative effect on the treatment of various malignant tumors. Studies have shown that camptothecin and its derivatives can inhibit DNA replication, transcription and mitosis by acting on DNA topoisomerase I. [0003] At present, camptothecin drugs have become one of the main varieties of anti-tumor treatment, and are known as anti-cancer drugs in the 21st century. However, in clinical use, it is also found that camptothecin has relatively large toxic and s...

Claims

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Application Information

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IPC IPC(8): C08G65/00A61K47/48A61K31/4745A61P35/00A61P35/02
Inventor 郁彭郭娜滕玉鸥江都王璐瑶吴丹
Owner TIANJIN UNIVERSITY OF SCIENCE AND TECHNOLOGY
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