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

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。由于含有ω-羧酸的代谢物不稳定，不能用于测定，因此将维生素K_2（甲基萘醌- 2,3和4）分子引入ω-羟基或ω-醛基团，而不是ω-羧酸。将萘醌衍生物与侧链部分偶联，合成了所需的类似物。对于侧链部分的合成，我们选择了香叶醇、法尼醇和香叶基香叶醇作为原料。以1,4 -二乙酰氧基-2-甲基萘醌为原料制备萘醌部分。偶联反应后，保护基脱保护得到ω-羟基衍生物，附加氧化反应得到ω-醛衍生物。我们重点研究了其对HL-60细胞（人白血病细胞）的诱导凋亡活性。5 μM和10 μM类似物的样品被成功地添加到HL-60细胞中。流式细胞术检测细胞凋亡活性。大多数类似物的活性以剂量依赖的方式增加。在10 μM范围内，甲基萘醌(MK)-3的活性最高，约为75%。另一方面，MK-4的效价约为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种活性。ω-氧合类似物方面，ω-氧合MK-3的效价较MK-3降低；然而，它仍然保留了大约50%的MK-3效力。有趣的是，只有ω-氧化的MK-4在10 μM时的活性比底物MK-4高。因此，我们的类似物以及天然维生素K同源物对癌细胞的诱导凋亡活性表现出细胞选择性。本研究结果表明，维生素K的代谢产物可能具有潜在的生物活性化合物，为开发基于末端烷基修饰的维生素K新药提供了有益的信息。少

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