发现鲨鱼肝油(SLO)混合物中的活性成分是一组被称为烷基甘油(AKGs)的醚连接的甘油。在上个世纪,SLO混合物的初始临床应用是用于治疗白血病,后来用于预防癌症X线治疗引起的放射病.Selachyl醇是SLO混合物中最丰富的AKG之一,在小鼠移植肿瘤模型(Lewis肺癌细胞)上,它在减少肺转移数量方面表现出很强的活性。
在这项研究中,含甲氧基(7)的自醇类似物,宝石-二氟化(8),合成了位于烷基链12位的叠氮化物(9)和羟基(10)基团,并比较了它们对人脐静脉内皮细胞系的细胞毒性和抗迁移作用。
根据文献程序合成AKG7-10。通过MTT测试评估所研究的AKG的细胞毒性,并使用人脐静脉内皮细胞系(HUVEC)作为体外模型来评估其抗迁移作用。
四个AKG具有基本相同的毒性阈值(≥12μM),而它们对内皮细胞具有明显不同的抗迁移活性。AKG9和10显著降低VEGF诱导的趋化迁移,但在烷基链12位含羟基的类似物(10)是最有效的抗VEGF抑制剂.
我们在这里介绍了一系列的四种合成的自醇类似物,其中AKG9和AKG10表现出抑制内皮细胞迁移的能力。还评估和讨论了这些类似物的关系结构和抗VEGF作用。非天然合成的AKGs可以作为一种新的抗癌剂来源。
The active ingredients in the shark liver oil (SLO) mixture were found to be a group of etherlinked glycerol known as
alkylglycerols (AKGs). During the last century, initial clinical use of the SLO mixture was for treating leukemias and later preventing radiation sickness from cancer x-ray therapy. Selachyl alcohol is one of the most abundant AKGs in the SLO mixture and it displayed strong activity in reducing lung metastasis number on a model of grafted tumor in mice (Lewis lung carcinoma cells).
In this study, selachyl alcohol analogue containing methoxyl (7), gem-difluorinated (8), azide (9) and hydroxyl (10) group at the 12 position in the alkyl chain were synthesized and compared regarding their cytotoxicity and anti-migratory effects on Human Umbilical Vein Endothelial Cell line.
AKGs 7-10 were synthesized according to the literature procedure. The cytotoxicity of the studied AKGs was evaluated by the MTT test and Human Umbilical Vein Endothelial Cell line (HUVEC) was used as an in vitro model to evaluate their anti-migratory effects.
The four AKGs have substantially the same toxicity threshold (≥ 12 μM), whereas they have an anti-migratory activity significantly different on endothelial cells. AKGs 9 and 10 significantly reduce the chemotactic migration induced by VEGF, but analogue (10) containing the hydroxyl group at the 12 position in the alkyl chain was the most potent anti-VEGF inhibitor.
We presented here a series of four synthetic selachyl alcohol analogues, among which AKGs 9 and 10 showed the ability to inhibit endothelial cell migration. The relationship structures and anti-VEGF effects of these analogues were also evaluated and discussed. Unnatural synthesized AKGs could be explored as one new source of anticancer agents.