Glycosylated Antitumor Ether Lipids (GAELs) kill cancer cells by a nonapoptotic pathway which is an attractive strategy to avoid resistance. To further optimize the antitumor effect, we prepared various analogs of di-, and tri-cationic GAEL analogs differing in the nature of the sugar (D-giucose or L-glucose), the anomeric linkage as well as position of the glycerolipid moiety. The di- and tri-cationic GAELs were synthesized and their in vitro anticancer properties were evaluated against drug resistant and aggressively growing cancer cell lines derived from human breast, prostate, pancreatic and ovarian cancers. The most potent dicationic GAEL analogs were also studied against cancer stem cells obtained from breast BT 474, prostate DU145 and ovarian A2780cp cell lines. Our results indicate that the number of positive charges, the position of the amino substituents and the nature of the sugar have significant effects on the anticancer activities of these compounds. The most active analog kill 50% of the cells at concentration range of 0.5-5μΜ and 90% of the cells at the concentration of 1-10μΜ depending on type of cancer cells.
糖基化抗肿瘤醚脂质(G
AELs)通过一种非凋亡途径杀灭癌细胞,这是一种吸引人的策略,可以避免抗药性。为了进一步优化抗肿瘤效果,我们制备了不同的双-和三-阳离子G
AEL类似物,其糖的性质(
D-葡萄糖或L-
葡萄糖)、
缩醛键以及甘
油脂类团的位置不同。合成了双-和三-阳离子G
AEL类似物,并评估了它们对人类乳腺、前列腺、胰腺和卵巢癌衍生的耐药和快速生长的癌
细胞系的体外抗癌性能。最有效的双阳离子G
AEL类似物也针对从乳腺
BT 474、前列腺DU145和卵巢A2780cp
细胞系中获得的癌干细胞进行了研究。我们的结果表明,阳离子数量、
氨基取代物的位置和糖的性质对这些化合物的抗癌活性有显著影响。最活跃的类似物在浓度范围为0.5-5μΜ时杀死50%的细胞,在浓度为1-10μΜ时杀死90%的细胞,具体取决于癌细胞类型。