蛋白激酶B(Akt)的N-羟胺酸酰胺类似物的合成,靶向阴离子糖甘油脂,并评估其对人类卵巢癌细胞的抗增殖活性。
Synthesis of N-oxyamide analogues of protein kinase B (Akt) targeting anionic glycoglycerolipids and their antiproliferative activity on human ovarian carcinoma cells.
发表日期:2023 Aug 01
作者:
Marco Zuccolo, Giulia Orsini, Martina Quaglia, Luca Mirra, Cristina Corno, Nives Carenini, Paola Perego, Diego Colombo
来源:
Cellular & Molecular Immunology
摘要:
基于2-0-β-D-葡萄糖甘油基的具有生物活性的阴离子糖甘油脂的N-活化酰胺衍生物已经高效制备。然而,在N-活化酰胺基团的存在下,葡萄糖单元的羟基氧化步骤似乎是一个困难的任务,然而通过采用化学酶蓝酶/TEMPO程序,首次可以方便地实现。所得的N-活化酰胺显示出较高的抑制卵巢癌IGROV-1细胞在无血清培养基中的增殖,与对应的生物活性酯类类似。稳定性和血清结合研究表明,化合物在完整培养基中观察到的活性降低可能主要是由于血清蛋白的结合效应,而不是葡萄糖甘油脂酰基链的水解降解。此外,在无血清条件下的细胞研究结果表明,N-活化酰胺基团可以独立于阴离子羧基的存在增加糖甘油脂的抗增殖活性。除了IGROV-1之外的其他细胞系的细胞研究也支持这一系列化合物对Akt高活化肿瘤细胞具有一定程度的选择性。
N-Oxyamides of bioactive anionic glycoglycerolipids based on 2-O-β-D-glucosylglycerol were efficiently prepared. However, the oxidation step of the primary hydroxyl group of the glucose moiety in the presence of the N-oxyamide function appeared to be a difficult task that was nevertheless conveniently achieved for the first time by employing a chemoenzymatic laccase/TEMPO procedure. The obtained N-oxyamides exhibited a higher inhibition of proliferation of ovarian carcinoma IGROV-1 cells in serum-free medium than in complete medium, similarly to the corresponding bioactive esters. Stability and serum binding studies indicated that the observed reduced activity of the compounds in complete medium could be mainly due to a binding effect of serum proteins rather than the hydrolytic degradation of glycoglycerolipid acyl chains. Furthermore, the results of the cellular studies under serum-free conditions suggested that the N-oxyamide group could increase the antiproliferative activity of a glycoglycerolipid independently of the presence of the anionic carboxylic group. Cellular studies in other cell lines besides IGROV-1 also support a certain degree of selectivity of this series of compounds for tumor cells with Akt hyperactivation.