The Use of Novel C-Methylated Spermidine Derivatives To Investigate the Regulation of Polyamine Metabolism

详细信息    查看全文

• 作者：Mervi T. Hyvo虉nen ; Tuomo A. Keina虉nen ; Maxim Khomutov ; Alina Simonian ; Janne Weisell ; Sergey N. Kochetkov ; Jouko Vepsa虉la虉inen ; Leena Alhonen ; Alex R. Khomutov
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：July 14, 2011
• 年：2011
• 卷：54
• 期：13
• 页码：4611-4618
• 全文大小：830K
• 年卷期：v.54,no.13(July 14, 2011)
• ISSN：1520-4804

文摘

The polyamines are organic polycations present at millimolar concentrations in eukaryotic cells where they participate in the regulation of vital cellular functions including proliferation and differentiation. Biological evaluation of rationally designed polyamine analogs is one of the cornerstones of polyamine research. Here we have synthesized and characterized novel C-methylated spermidine analogs, that is, 2-methylspermidine, 3-methylspermidine, and 8-methylspermidine. 3-Methylspermidine was found to be metabolically stable in DU145 cells, while 8-methylspermidine was a substrate for spermidine/spermine N¹-acetyltransferase (SSAT) and 2-methylspermidine was a substrate for both SSAT and acetylpolyamine oxidase. All the analogs induced the splicing of the productive mRNA splice variant of SSAT, overcame growth arrest induced by 72-h treatment with ornithine decarboxylase (ODC) inhibitor 伪-difluoromethylornithine, and were transported via the polyamine transporter. Surprisingly, 2-methylspermidine was a weak downregulator of ODC activity in DU145 cells. Our data demonstrates that it is possible to radically alter the biochemical properties of a polyamine analog by changing the position of the methyl group.