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10-HCPT (10-hydroxycamptothecine) derivative, synthesis method and application thereof

A technology of hydroxycamptothecin and its synthesis method, which is applied in the field of camptothecin drugs, can solve the problems of slow crossing biomembrane speed, limitation of clinical application, and large tissues and organs, so as to increase the speed and quantity, and improve the utilization rate of drugs , reduce the effect of toxic and side effects

Active Publication Date: 2017-04-26
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Since the hydroxyl group in 10-HCPT is a highly polar group, the polarity of 10-HCPT is relatively high, its crossing biomembrane speed is slow, the dosage is large, and it has great toxic and side effects on normal tissues and organs. App is restricted

Method used

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  • 10-HCPT (10-hydroxycamptothecine) derivative, synthesis method and application thereof
  • 10-HCPT (10-hydroxycamptothecine) derivative, synthesis method and application thereof
  • 10-HCPT (10-hydroxycamptothecine) derivative, synthesis method and application thereof

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[0059] In a second aspect, the present invention provides a method for synthesizing 10-hydroxycamptothecin derivatives, comprising the following steps: dissolving 10-hydroxycamptothecin and a carboxylic acid with the structure RCOOH in pyridine, wherein R is any Select a substituted C1-C10 straight chain alkyl or branched chain alkyl, and / or, an optionally substituted C2-C10 alkenyl; then add EDCI and stir for 1-4 hours to obtain the 10-hydroxycamptothecin base derivatives.

[0060] Among them, EDCI is carbodiimide.

[0061] In a preferred embodiment, the synthesis method further includes: after stirring for 1-4 hours, adding dichloromethane and water, stirring for 10-50 minutes, separating the organic layer, and finally drying and concentrating the residue Purify and elute with dichloromethane and methanol at a volume ratio of (5-25):1 to obtain the 10-hydroxycamptothecin derivative.

[0062] In a preferred embodiment, the following steps are included: dissolving 1-4 mmol o...

Embodiment 1

[0068] A 10-hydroxycamptothecin derivative 1, the structural formula is as follows:

[0069]

Embodiment 2

[0071] The derivative described in embodiment 1 is synthesized by the following method:

[0072] 10-HCPT (1.00g, 2.7mmol) and 5-carbonylhexanoic acid (1.07g, 8.1mmol) were dissolved in 10mL of pyridine, EDCI (2.06g, 10.8mmol) was added at room temperature, stirred for 3h, thin-layer chromatography Monitor the response. Add 50mL of dichloromethane and 50mL of water to the reaction system, stir and react for 30 minutes, separate the organic layer, dry and concentrate under reduced pressure, and purify the obtained residue with a silica gel column, elute with dichloromethane and methanol, dichloromethane and The volume ratio of methanol was 10:1, and a yellow solid compound, namely 10-hydroxycamptothecin derivative 1 (1.25 g, yield 96%) was obtained.

[0073] The synthesis reaction is as follows:

[0074]

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Abstract

The invention relates to the field of camptothecine drugs, in particular to a 10-HCPT (10-hydroxycamptothecine) derivative, a synthesis method and an application thereof. The 10-HCPT derivative is a derivative which is formed by esterifying a hydroxyl radical at site 10 in 10-HCPT and has an ester structure. The molecular polarity of the derivative is greatly reduced, the biological membrane crossing speed is remarkably increased, the speed and the number of drugs entering tumor cells are increased, the utilization of the drugs is increased, the better anti-tumor effect can be realized, and the toxic and side effects are reduced.

Description

technical field [0001] The invention relates to the field of camptothecin drugs, in particular to a 10-hydroxycamptothecin derivative, a synthesis method and an application thereof. Background technique [0002] 10-Hydroxycamptothecine (10-HCPT) is a camptothecin alkaloid with significant anti-cancer activity extracted from the fruit and leaves of the deciduous plant Camptothecin genus Eclipta genus in the Davidiaceae family. Synthetic resin obtained. Its anticancer effect is equivalent to 30 times that of camptothecin. 10-HCPT has obvious curative effect on pancreatic cancer, prostate cancer, bladder cancer, oral squamous cell carcinoma, colorectal cancer, gastric cancer, liver cancer, non-small cell lung cancer, etc. It also has a good curative effect on oral cavity, neck and face cancer, head and neck cancer, cylindrical adenocarcinoma of the head and neck and skin cancer; it also has good curative effect on malignant mole, choriocarcinoma, lung cancer, acute and chroni...

Claims

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Application Information

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IPC IPC(8): C07D491/22A61K31/4745A61P35/00
CPCC07D491/22
Inventor 刘洋
Owner ZHENGZHOU UNIV
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