Novel taxane halogenation derivates with anti-tumor activity

An anti-tumor activity and taxane technology, applied in the field of biomedicine, can solve the problems of high systemic toxicity, multidrug resistance of tumor cells, narrow treatment threshold, etc.

Active Publication Date: 2008-11-19
ZHANGJIAGANG IND TECH RES INST CO LTD DALIAN INST OF CHEM PHYSICS CHINESE ACADEMY OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Taxane drugs currently on the market generally have defects such as low water solubility, high systemic toxicity, narrow

Method used

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  • Novel taxane halogenation derivates with anti-tumor activity
  • Novel taxane halogenation derivates with anti-tumor activity
  • Novel taxane halogenation derivates with anti-tumor activity

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0093] Example 1

[0094] Preparation of compounds DCB6101, DCB6102, DCB6103, DCB6104

[0095] Weigh 1g taxane sample (determined by HPLC external standard method, containing 17% paclitaxel, 71% cephalomannine, see the LC-MS spectrum figure 1 ) Dissolve in 4ml acetonitrile system, add 1ml deionized water, 250mg NBS, and react at room temperature for 3 hours. HPLC detection shows that the conversion of cephalomannine is complete. The product was directly dried by rotary evaporation, and then subjected to silica gel column chromatography to obtain 760 mg of 2"-bromo-3"-hydroxy-cephalomannine, with a content of about 72%. After the partial products were separated by C18 reverse phase preparative chromatography, 530 mg of 2"-bromo-3"-hydroxy-cephalomannine diastereomer mixture was obtained, the purity was about 83%, and the total yield was 55.5%. It is configured into a 10mg / ml methanol solution and passed through a reversed-phase (YMC, C18 column) high performance liquid chromatogra...

Example Embodiment

[0097] Example 2

[0098] Preparation of compounds DCB6109, DCB6110, DCB6111, DCB6112

[0099] Take 10-desacetyl-cephalomannine (content 65%, LC-MS spectrum see Figure 4 ) Is the raw material for the reaction, and the synthesis method is similar to that in Example 1, and the separation and purification steps for the preparation of the diastereoisomer mixture will not be repeated. Reversed phase (YMC, C18 column) high performance liquid chromatography system was used to complete the resolution of diastereomers. The mixture of different diastereomers was prepared into a methanol solution of 10 mg / ml, and the mobile phase of water: acetonitrile (65:35) was used to rinse at a flow rate of 1 ml / min to obtain compound DCB6109 (content 93%). Compound DCB6110 (content 91%), compound DCB6111 (content 95%), compound DCB6112 (content 95%).

Example Embodiment

[0100] Example 3

[0101] Preparation of compounds DCB6105, DCB6106, DCB6107, DCB6108

[0102]Weigh 1g taxane sample (determined by HPLC external standard method, containing 17% paclitaxel, 71% cephalomannine) and dissolve it in 5ml methanol system, add 50mg ytterbium triflate, 250mg NBS, and react at room temperature for 1 Hours, HPLC detection showed that the conversion of cephalomannine was complete. The product was directly dried by rotary evaporation, and then subjected to silica gel column chromatography to obtain 680 mg of 2"-bromo-3"-methoxy-cephalomannine, with a content of about 77%. After the partial product was separated by C18 reversed-phase preparative chromatography, 510 mg of 2"-bromo-3"-methoxy-cephalomannine diastereomer mixture was obtained, the purity was higher than 90%, and the total yield was 56 %. It is configured into a 10mg / ml methanol solution and washed with a mobile phase of water: acetonitrile (45:55) at a flow rate of 1ml / min to obtain 33mg of compou...

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Abstract

The invention relates to a novel taxus halogenated derivative with anti-tumor activity, which is characterized in that: the novel taxus halogenated derivative having a structural general formula and an anti-tumor drug with the derivative as an active component are shown in formula I, wherein R is H or Ac; R' has a structure shown in a following right formula, wherein R'' is a substituent selected from -Ome and -OH; X is a halogen selected from Cl and Br. For leukemia cells (K562), non-small cell lung cancer cells (A549), colon cancer cells (HT-29), ovarian cancer cells (OVCAR-3), human osteosarcoma cells (Saos-2), breast cancer cells (MCF-7) and a plurality of tumor cell lines, a compound shown in the invention shows the cytotoxicity similar to taxol, thereby having the value for anti-tumor drug development.

Description

technical field [0001] The invention relates to the technical field of biomedicine, and in particular provides a class of novel taxane halogenated derivatives with antitumor activity. Background technique [0002] Taxane compounds, especially paclitaxel (Paclitaxel, formula II, 1) and docetaxel (Docetaxel, formula III), are currently used as first-line clinical drugs and are widely used in the treatment of different types of tumors. [0003] [0004] Formula II paclitaxel and cephalomannine Formula III docetaxel (Docetaxel) [0005] Taxane drugs currently on the market generally have defects such as low water solubility, high systemic toxicity, narrow therapeutic threshold, and easy to cause multidrug resistance of tumor cells, which greatly restrict their curative effect. In response to the above defects, scientists from various countries have carried out a lot of structural optimization work on its structure, especially the C(3') N terminal group that directly particip...

Claims

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Application Information

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IPC IPC(8): C07D305/14A61K31/337A61P35/00
Inventor 杨凌张延延葛广波马红
Owner ZHANGJIAGANG IND TECH RES INST CO LTD DALIAN INST OF CHEM PHYSICS CHINESE ACADEMY OF SCI
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