アプリシアトキシン単純化アナログのがん細胞増殖抑制機構の解明

阐明海兔毒素简化类似物的癌细胞生长抑制机制

• 批准号: 13J02518
• 负责人: 菊森 将之
• 金额: $ 1.54万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for JSPS Fellows
• 财政年份: 2013
• 资助国家: 日本
• 起止时间: 2013 至 2014
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13J02518/
• 关键词: aplysiatoxin; 発がん促進物質; protein kinase C; がん細胞増殖抑制; protein kinase c

Aplog-1は, 海洋動物・アメフラシ由来の発がん促進物質であるAplysiatoxin(ATX)の構造単純化により得られた, 発がん促進活性をもたないプロテインキナーゼC(PKC)活性化剤である. 本化合物は, 数種のヒトがん細胞株に対して顕著な増殖抑制活性を有することが明らかとなっている. 昨年度までの構造一活性相関研究により, 10-Methyl-Aplog-1がAplog類の中で最も優れており, 乳がん細胞・MDA-MB-231や肺がん細胞・NCI-H460などを含む数種のがん細胞に対する増殖抑制活性は, Aplog-1よりも10倍以上高かった. 昨年度, さらに活性の高い誘導体を開発する目的で, Aplog-1の4位と10位にメチル基を有する誘導体(4, 10-Dimethyl-Aplog-1)を合成したが, 本化合物はがん細胞増殖抑制活性とともに, 弱い発がん促進活性を示すことが判明した.そこで本年度は, 10-Methyl-Aplog-1のin vivoでの抗がん試験および, さらなる作用機構解析に向けた量的供給を目的として, 合成法の改良を行なった. 当初は28段階の反応が必要であったが, 連続不斉中心の構築の簡略化および保護基を用いない官能基選択的反応を開発することにより, 5つの反応段階を減らすとともに各段階の収率を上げることに成功した. その結果, in vivoでの抗がん活性試験に適用できる高純度(98%以上)試料を数百ミリグラム調整することができた(総収率1.1%). これより, 10-Methyl-Aplog-1の移植がん動物モデルを用いた抗がん試験ならびに薬物動態の解析とともに, Aplog類高感受性がん細胞株に対する増殖抑制機構に関する研究が進展するものと期待される.

Aplog-1, the origin of the marine animal and animal products, the promoter, the Aplysiatoxin (ATX), the chemical, the active, the active. The colonization inhibitory activity of several cell strains of this compound has been shown to be sensitive to the activity of colonization inhibition. A comparative study of activity was made last year. In the 10-Methyl-Aplog-1 Aplog category, the most sensitive enzyme was found in the breast milk cell MDA-MB-231 lung cancer cell NCI-H460, which contained several kinds of cell cycle inhibition activity, and the Aplog-1 concentration was more than 10 times higher. Last year, the high level of Aplog-1 activity and the presence of (4, 10-Dimethyl-Aplog-1) at position 10 at 4 and 10 were found to synthesize the compound. The activity of inhibition of cell colonization of this compound is sensitive, while the activity of promoting activity of weak chain is determined. In the current year, 10-Methyl-Aplog-1 in vivo is effective in anti-drug treatment, and the mechanism of action is used to analyze the amount of supply to the target. The synthesis method is improved. At the beginning, it is necessary to improve the performance of the 28-paragraph system, and contact the key protection system that is selected by the functional basis of the system, and the success rate of each segment is higher than that selected by the functional basis of the system. The results showed that the anti-tumor activity of in vivo was higher than 98% (more than 98%). In this case, 10-Methyl-Aplog-1 transplant animal products were used to analyze the dynamics of anti-tumor drugs. Aplog highly sensitive cell strain colonization inhibition mechanism was studied in advance.