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Novel application of 5-bit modified 2'deoxycytidine derivative or phosphate thereof in the preparation of medicaments

A technology of deoxycytidine and phosphate, applied in the new application field of 2'deoxycytidine derivatives or its phosphate in pharmaceuticals, which can solve the problems of limited application prospects and high toxicity

Active Publication Date: 2011-07-20
GUANGZHOU RIBOBIO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the 5-modified 2'deoxycytidine derivatives have a strong inhibitory effect on tumor cell proliferation, they are also very toxic to normal cells, which limits their application prospects as clinical drugs

Method used

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  • Novel application of 5-bit modified 2'deoxycytidine derivative or phosphate thereof in the preparation of medicaments
  • Novel application of 5-bit modified 2'deoxycytidine derivative or phosphate thereof in the preparation of medicaments
  • Novel application of 5-bit modified 2'deoxycytidine derivative or phosphate thereof in the preparation of medicaments

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053]Human lung cancer cells (A549), human embryonic lung fibroblasts (HLF) were incubated with 10μM XdC, 10nM XdCMP, 10μM XdC+10μM thymidine, 10μM XdC+10nM dTMP, 10nM XdCMP+10μM thymidine, 10nM XdCMP+10nM dTMP, respectively, for 96h (The structures of XdC, XdCMP, thymidine, and dTMP are shown in the following structural formula, and XdC is 5-fluoro-2'-deoxycytidine). Then fixed with PBS solution containing 4% paraformaldehyde and stained with DAPI. High-content screening instrument photographing analysis.

[0054]

[0055] As shown in Fig. 1, when X is a fluorine atom, compared with the control group, the pharmaceutical composition of XdC or its monophosphate XdCMP and thymidine (thymidine) or its monophosphate (dTMP) has a stronger effect on cancer cell A549 Inhibition of proliferation and promotion of apoptosis. However, this drug combination showed much lower cytotoxicity to the corresponding normal cell HLF, and almost no obvious effect of inhibiting the proliferati...

Embodiment 2

[0057] Human lung cancer cells (A549), human embryonic lung fibroblasts (HLF) were incubated with 50μM XdC, 50nM XdCMP, 50μM XdC+10μM thymidine, 50μM XdC+10nM dTMP, 50nM XdCMP+10μM thymidine, 50nM XdCMP+10nM dTMP, respectively, for 96h (The structures of XdC, XdCMP, thymidine, and dTMP are shown in the following structural formula, and XdC is 5-iodo-2'-deoxycytidine). Then fixed with PBS solution containing 4% paraformaldehyde and stained with DAPI. High-content screening instrument photographing analysis.

[0058]

[0059] As shown in Fig. 2, when X is an iodine atom, compared with the control group, the pharmaceutical composition of XdC or its monophosphate XdCMP and thymidine (thymidine) or its monophosphate (dTMP) has a stronger effect on cancer cell A549 Inhibition of proliferation and promotion of apoptosis. But compared with Fig. 1, when X is an iodine atom, the tumor suppressor effect of XdC is significantly weaker than that of XdC when X is a fluorine atom (when ...

Embodiment 3

[0062] Human lung cancer cells (A549), human embryonic lung fibroblasts (HLF) were incubated with 10μM XdC, 10nM XdCMP, 10μM XdC+10μM thymidine, 10μM XdC+10nM dTMP, 10nM XdCMP+10μM thymidine, 10nM XdCMP+10nM dTMP, respectively, for 96h (The structures of XdC, XdCMP, thymidine, and dTMP are shown in the following structural formula, and XdC is 5-ethynyl-2'-deoxycytidine). Then fixed with PBS solution containing 4% paraformaldehyde and stained with DAPI. High-content screening instrument photographing analysis.

[0063]

[0064] As shown in Fig. 3, when X is an ethynyl substituent, relative to the control group, the pharmaceutical composition of XdC or its monophosphate XdCMP and thymidine (thymidine) or its monophosphate (dTMP) has an effect on cancer cell A549 Strong inhibition of proliferation and promotion of apoptosis. However, this drug combination showed much lower cytotoxicity to the corresponding normal cell HLF, and almost no obvious effect of inhibiting the proli...

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Abstract

The invention discloses application of a 5-bit modified 2'deoxycytidine analogue or phosphate thereof in the preparation of medicaments for treating cancers. The 5-bit modified 2' deoxycytidine analogue or the phosphate thereof can also be used in combination with deoxythymidine or phosphate thereof to form a medicinal composition for treating tumors. A 5-bit modified 2' deoxycytidine derivative is added with an appropriate amount of thymidine or 5' monophosphate when administrated, so that the toxicity to normal cells is greatly reduced to keep the effect of inhibiting tumor cell proliferation.

Description

technical field [0001] The invention belongs to the field of medicine and biology, in particular to the new application of 5-position modified 2'deoxycytidine derivatives or their phosphates in pharmacy. Background technique [0002] 5-modified 2'deoxycytidine derivatives are a class of thymidine synthase inhibitors with better selectivity than 5-modified 2'deoxyuridine derivatives, and their antiviral activities have been widely studied, such as their It can selectively inhibit the replication of herpes simplex virus (HSV). The present invention finds that the 5-modified 2'deoxycytidine derivative or its monophosphate not only has good antiviral activity, but also has obvious inhibitory effect on the proliferation of cancer cells. [0003] The present invention finds that the 5-position modified 2' deoxycytidine derivatives can be phosphorylated by deoxypyrimidine nucleoside kinase (thymidine kinase 2, deoxycytidine kinase) into 5' monophosphate 5-modified 2' deoxycytidine...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/7068A61P35/00
Inventor 张必良渠德忠
Owner GUANGZHOU RIBOBIO
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