Water soluble camptothecin derivative and medicinal composition containing same

A technology of camptothecin and derivatives, applied in the field of medicine based on camptothecin, can solve the problem of not being used as a CPT prodrug and the like, and achieve the effects of improving stability and reducing drug toxicity

Active Publication Date: 2011-08-17
HUNAN FANGSHENG PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it has been experimentally verified that 20(S)-O-phosphate or simple phosphonate cannot be converted into CPT under physiological conditions, so they cannot be used as CPT prodrugs (Organic Lett., 2004, 6(3), pp321 -324)

Method used

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  • Water soluble camptothecin derivative and medicinal composition containing same
  • Water soluble camptothecin derivative and medicinal composition containing same
  • Water soluble camptothecin derivative and medicinal composition containing same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0135] Example 1: Synthesis and anticancer evaluation of Dix-905

[0136] Compounds of formula I of the present invention include compounds Dix-905 having the structure

[0137]

[0138] (a) Synthesis of Dix-905

[0139] Under nitrogen protection, CPT (174 mg, 1 equivalent) was dissolved in anhydrous solvent (10 ml DMF), stirred and cooled to 0-4 ° C, and 4-dimethylaminopyridine (6.7 mg, 0.11 equivalent), di Isopropylethylamine (258mg, 2eq) and 2-cyanoethyl N,N-diisopropylphosphoramidite chloride (236mg, 2eq). The mixture was stirred for 1 hour, then cooled to room temperature. After confirming complete consumption of CPT (about 4 hours), a small amount of water (1 ml) was added to stop the reaction. The reaction solvent was removed by evaporation and the residue was resuspended in dichloromethane (10ml), extracted with ice-cold 10% sodium carbonate solution, brine and dried over sodium sulfate. Dichloromethane was evaporated to dryness under reduced pressure to obtain ...

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Abstract

The invention relates to a water soluble derivative of camptothecin and a preparation method thereof. The derivative has a structure shown in a formula (I). The derivative of the camptothecin has improved anticancer activity.

Description

technical field [0001] The present invention relates to the field of medicine, more specifically to the field of anticancer drugs, and more specifically to camptothecin-based drugs. Background technique [0002] Camptothecin (CPT), a cytotoxic alkaloid, was first isolated by Wall and colleagues from the leaves and bark of a plant native to China, Camptotheca accuminata, Nyssaceae Validation (J. Am. Chem. Soc. 88, 3888, 1966). The major cellular target of CPT is topoisomerase I (topo I), an enzyme involved in the relaxation of supercoiled chromosomal DNA by transient single-strand cleavage, unwinding, and religation of double DNA during DNA replication. CPT binds at the interface of the covalent binary topo I-DNA complex, forming a stable ternary complex that prevents religation, thus leading to replication-mediated double-strand breaks and DNA damage. Because CPT inhibition can lead to cell death in the S phase of the cell cycle, CPT has become a focus of intensive researc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/10C07H19/207C07H19/23C07H1/00C07D491/22A61K31/7072A61K31/4745A61K31/708A61K31/7056A61K31/7068A61K31/7076A61P35/00A61P35/02
CPCY02P20/55
Inventor 周文强邓静张庆华
Owner HUNAN FANGSHENG PHARMACEUTICAL CO LTD
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