School of Medicine, University of Western Sydney, Locked Bag 1797, Penrith South DC, NSW, 2751, Australia.
Metallomics. 2012 Aug;4(9):950-9. doi: 10.1039/c2mt20102j.
Platinum(II) metallointercalators of the type Pt(I(L))(A(L)), such as (5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)platinum(II) (56MESS), are structurally different from cisplatin. This study, using a comparative transcriptomics approach, uncovered genomic expression patterns and molecular pathways that distinctively differentiated 56MESS and cisplatin in the eukaryote model organism Saccharomyces cerevisiae (yeast). Down-regulation of sulfur assimilation, cellular respiration, and energy metabolism were characteristics of 56MESS while up-regulation of these pathways and genes in cell cycle was the action of cisplatin. Furthermore, de novo purine biosynthesis and glycine metabolism were induced by 56MESS but suppressed by cisplatin. Different effects on intracellular concentrations of iron and copper were evident, with 56MESS more profoundly inducing genes controlling uptake of these ions than cisplatin. Finally, apart from 56MESS, additional metallointercalators including 56MEEN, 5MERR and 5MESS were subsequently identified to be more active in a cisplatin-resistant mouse leukaemia L1210cisR cell line than cisplatin, which provides multiple lead compounds for future drug development.
Pt(I(L))(A(L))型铂(II)金属嵌入剂，如(5,6-二甲基-1,10-菲咯啉)(1S,2S-二氨基环己烷)铂(II) (56MESS)，在结构上与顺铂不同。本研究采用比较转录组学方法，揭示了在真核生物模式生物酿酒酵母中，56MESS 和顺铂明显区分的基因组表达模式和分子途径。56MESS 下调硫同化、细胞呼吸和能量代谢，而顺铂则上调这些途径和细胞周期中的基因。此外，56MESS 诱导从头嘌呤生物合成和甘氨酸代谢，而顺铂则抑制这些途径。56MESS 对细胞内铁和铜浓度的影响明显不同，其诱导控制这些离子摄取的基因的能力比顺铂更强。最后，除了 56MESS 之外，其他金属嵌入剂，包括 56MEEN、5MERR 和 5MESS，随后被确定在顺铂耐药的小鼠白血病 L1210cisR 细胞系中比顺铂更具活性，这为未来的药物开发提供了多种先导化合物。
