权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

新規多機能性エチニルヌクレオシド類の抗腫瘍性と作用機序

新型多功能乙炔核苷的抗肿瘤特性和作用机制

基本信息

批准号：
08266223
负责人：
佐々木琢磨
金额：
$ 2.05万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
1996
资助国家：
日本
起止时间：
1996 至无数据
项目状态：
已结题

项目摘要

核酸代謝拮抗剤はがん化学療法剤の中でも重要な位置を占め,そのほとんどはDNA合成阻害作用を主たる作用機構としている.しかし臨床における難治がんの大部分は固形腫瘍であり,静止期にある固形腫瘍に対して核酸代謝拮抗剤が十分な効果を発揮するためには,DNA合成阻害作用以外の作用機構も有する化合物の創製が必須と考えられる.本研究では,細胞の増殖に必要な核酸の代謝に関する酵素反応を複数の点で阻害するような「化学反応性を付与した多機能化構造」を念願に入れ,リボヌクレオシドの糖部の3'-β位水素原子の反応性に着目し,3'-β位に種々のアルキニル基を導入した化合物を新たに分子設計・合成し,構造活性相関を検討した.リボヌクレオシドの3'-β位に各種置換基を導入したシチジンおよびウリジン誘導体の細胞増殖抑制作用は置換基の炭素鎖長が長くなるほど,また飽和度が高くなるほど減弱する傾向が見られ,エチニル基を導入した化合物に最も強い細胞増殖抑制作用が見られた.今回見いだされた3'-エチニルシチジン(ECyd)および3'-エチニルウリジン(EUrd)は,従来の核酸代謝拮抗剤には見られない強い細胞増殖阻害作用を示すと共に,実験腫瘍に対しても優れたin vivoにおける抗腫瘍効果を示した.作用機構については検討中であるが,ECyd,EUrdの細胞増殖抑制効果は,ウリジンまたはシチジンを添加することにより競合的に阻害されたことから,ウリジン・シチジンキナーゼによるリン酸化が抗腫瘍効果発現に必須であり,ECyd,EUrdの5'-トリリン酸体がRNAポリメラーゼを直接阻害することを明らかにした.このような既存の核酸代謝拮抗剤とは異なった作用機構を持つ新規多機能性ヌクレオシドのECyd,EUrdは,抗ガン剤として今後の臨床開発が期待される化合物である.

Nucleic acid substituted antagonistic agents play an important role in the chemical method, and the main mechanism of action is the main mechanism for the inhibition of DNA synthesis. During the resting period, the nucleic acid antagonism of nucleic acid generation in the resting phase has a significant effect. In addition to the harmful effect of DNA synthesis, it is necessary to test the molecular weight of the compounds. In this study, it is necessary to reproduce nucleic acid, reverse transcriptase, enzyme reverse transcription, chemical reactionability and multi-mechanization. In this study, the necessary nucleic acid, nucleic acid, enzyme, enzyme, The production of active phase is different from that of others. In the position of 3-β, the cell colonization inhibition is affected by the growth of carbon, the growth of carbon, the weak response of carbon, and the strongest inhibition of cell colonization of the compound. In this reply, we will see that the nucleic acid generation is responsible for the antagonistic effect of nucleic acid on the inhibition of cytopathic acid (EUrd). This time, we will see that the nucleic acid generation is responsible for the antagonistic effect of nucleic acid on the inhibition of cytopathic acid. this time, we will see that the nucleic acid generation has a strong effect on the colonization of the cells. This is the first time that we can see that the nucleic acid generation has a strong effect on the colonization of the cells. This time, we will see that the nucleic acid generation is responsible for the inhibition of cellular colonization. This time, the nucleic acid generation showed that it was not harmful to the colonization of the cells, and the results showed that the nucleic acid generation was effective in antagonizing the effect of in vivo. In the mechanism of action, the cell colonization inhibition of ECyd,EUrd is effective, and the effect of the combination of cell proliferation and cell colonization must be affected, and the effect of ECyd must be achieved. EUrd 5-1-1-1-1-3-1-3-1-3-1-3-1-3-1-3-1-3-1-3-1-3-1-3-3-4-3-3-4-3-3-3-6-4-4-4-6-6-4-4-4-6-6-6-6-6-6-6-6-6-6-4-3-3-4-3-4-3-3-4-1-4-1-1-4-6-4-6-4-6-6-6-6-6-6-6-6-6-6-6-6-6-6-6-6-6-6-6-6-6-6-6-6-6-6-6-6-6-6-6 The existing nucleic acid substitutes antagonize the potency of nucleic acids, and the mechanism of action is consistent with the new regulations, multi-functional nucleotides, ECyd,EUrd, and antiviral drugs. In the future, we are looking forward to the formation of compounds.