Gauthier Charles, Legault Jean, Girard-Lalancette Karl, Mshvildadze Vakhtang, Pichette André
Laboratoire LASEVE, Chaire de Recherche sur les Agents Anticancéreux d'Origine Naturelle, Université du Québec à Chicoutimi, Chicoutimi, Québec, Canada.
Bioorg Med Chem. 2009 Mar 1;17(5):2002-8. doi: 10.1016/j.bmc.2009.01.022. Epub 2009 Jan 15.
The haemolysis of red blood cells inducing toxicity in most animals including humans is a major drawback for the clinical development of saponins as antitumour agents. In this study, the haemolytic and cytotoxic activities as well as the membrane cell permeabilization property of a library of 31 semi-synthetic and natural lupane- and oleanane-type saponins were evaluated and the structure-activity relationships were established. It was shown that lupane-type saponins do not exhibit any haemolytic activity and membrane cell permeabilization property at the maximum concentration tested (100 microM) independently of the nature of the sugar moieties. While oleanane-type saponins such as beta-hederin (25) and hederacolchiside A(1) (27) cause the death of cancer cell lines by permeabilizing the cellular membranes, lupane-type saponins seem to proceed via another mechanism, which could be related to the induction of apoptosis. Altogether, the results indicate that the cytotoxic lupane-type glycosides 10 and 22 bearing an alpha-l-rhamnopyranose moiety at the C-3 position represent promising antitumour agents for further studies on tumour-bearing mice since they are devoid of toxicity associated with the haemolysis of red blood cells.
对包括人类在内的大多数动物而言，红细胞溶血引发毒性是皂苷作为抗肿瘤药物临床开发的一个主要障碍。在本研究中，评估了31种半合成和天然羽扇豆烷型及齐墩果烷型皂苷的溶血活性、细胞毒性活性以及膜细胞通透化特性，并建立了构效关系。结果表明，在所测试的最大浓度（100微摩尔）下，羽扇豆烷型皂苷无论糖基部分的性质如何，均未表现出任何溶血活性和膜细胞通透化特性。虽然齐墩果烷型皂苷如β-常春藤皂苷元（25）和常春藤秋水仙苷A（1）（27）通过使细胞膜通透化导致癌细胞系死亡，但羽扇豆烷型皂苷似乎通过另一种机制起作用，这可能与诱导细胞凋亡有关。总体而言，结果表明，在C-3位带有α-L-鼠李糖基部分的细胞毒性羽扇豆烷型糖苷10和22是有前景的抗肿瘤药物，可用于对荷瘤小鼠的进一步研究，因为它们没有与红细胞溶血相关的毒性。
