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Development of new anti-cancer drugs constructed with unsaturated alkyl chain

不饱和烷基链构建的新型抗癌药物的开发

基本信息

批准号：
18590112
负责人：
SUHARA Yoshitomo
金额：
$ 1.52万
依托单位：
Kobe Pharmaceutical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590112/
关键词：
anti-tumour unsaturated alkyl chain genomic drug discovery synthetic chemistry isonrenoid fat-soluble vitamins vitamin K コンビナトリアルケミストリー

项目摘要

Our research aim is development of candidates for new anti-cancer drugs based on unsaturated alkyl chain. In this study, we synthesized six kinds of “predictable" vitamin K metabolites. They were introduced vitamin K_2 (menaquinone-2, 3, and 4) molecule to ω-hydroxyl or ω-aldehyde group instead of ω-carboxylic acid becauw the metabolites including ω-carboxylic acid were unstable and unable to use for assay. The requisite analogues were synthesized by coupling the naphthoquinone derivative and side-chain moiety. For the synthesis of side-chain part, we chose geraniol, farnesol and geranylgeraniol as the starting material. While the naphthoquinone part was prepared from 1, 4-diacetoxy-2-methylnaphthoquimne. After coupling reaction, deprotection of protective group gave ω-hydroxyl derivative, and additional oxidative reaction yielded ω-aldehyde derivative. We focused on the apoptosis-inducing activity against HL-60 cells (human leukemia cells). Samples of 5 and 10 μM analogues were succes … More sively added to HL-60 cells. The apoptosis activity was determined with a flow cytemetry. The activity of most analogues increased in a dose-dependent manner. Menaquinone (MK)-3 particularly showed the most potent activity around 75% among vitamin K_2 homologues at 10 μM. On the other hand, the potency of MK-4 was approximately 15%, which equaled 20% of MK-3 at the same dose; however, MK-2 and ω-aldehyde analogues did not exhibit such activity. In terms of ω-oxygenated analogues, ω-oxygenated MK-3 decreased the potency compared to MK-3; however it still preserved about 50% potency of MK-3. Interestingly, only ω-oxygenated MK-4 increased the activity more than substrate MK-4 at 10 μM. Thus, the apoptosis-inducing activity of our analogues as well as natural vitamin K homologues exhibited cell selectivity against cancer cells. Our results indicated that metabolites of vitamin K might have potential as biologically active compounds and can provide useful information to develop new drugs based on vitamin K with modification of terminal alkyl group. Less

我们的研究目标是开发基于不饱和烷基链的新型抗癌药物候选物。在这项研究中，我们合成了六种“可预测的”维生素 K 代谢物。他们将维生素K_2（menaquinone-2、3和4）分子引入到ω-羟基或ω-醛基而不是ω-羧酸，因为包括ω-羧酸在内的代谢物不稳定且无法用于测定。通过偶联萘醌衍生物和侧链部分合成所需的类似物。对于侧链部分的合成，我们选择香叶醇、金合欢醇和香叶基香叶醇作为起始原料。而萘醌部分则由1,4-二乙酰氧基-2-甲基萘醌制备。偶联反应后，保护基脱保护得到ω-羟基衍生物，再进行氧化反应得到ω-醛衍生物。我们重点关注针对 HL-60 细胞（人类白血病细胞）的细胞凋亡诱导活性。 5 和 10 μM 类似物的样品成功地添加到 HL-60 细胞中。用流式细胞术测定细胞凋亡活性。大多数类似物的活性以剂量依赖性方式增加。在 10 μM 的维生素 K_2 同系物中，甲萘醌 (MK)-3 尤其表现出最有效的活性，约为 75%。另一方面，MK-4 的效力约为 15%，相当于相同剂量下 MK-3 的 20%；然而，MK-2 和 ω-醛类似物没有表现出这样的活性。就ω-氧化类似物而言，与MK-3相比，ω-氧化MK-3的效力降低；然而它仍然保留了 MK-3 约 50% 的效力。有趣的是，只有 ω-氧化的 MK-4 比 10 μM 的底物 MK-4 的活性增加更多。因此，我们的类似物以及天然维生素 K 同系物的细胞凋亡诱导活性表现出针对癌细胞的细胞选择性。我们的结果表明，维生素 K 的代谢物可能具有作为生物活性化合物的潜力，并且可以为开发基于末端烷基修饰的维生素 K 的新药物提供有用的信息。较少的