14th World Congress on Medicinal Chemistry and Drug Design
Alex R. Khomutov
Russian Academy of Sciences, Russia
Title: Isomers and diastereomers of C-methylated spermidine and spermine: Synthesis and biochemical application
Biography: Alex R. Khomutov
Statement of the Problem: The polyamines, spermidine (1,8-diamino-4-azaoctane, Spd) and spermine (1,12- diamino-4,9-diazadodecane, Spm) are ubiquitous organic polycations present in all eukaryotic cells in µM-mM concentrations and involved in the regulation of numerous vital processes including the differentiation and growth of cells1. Disturbances of polyamines metabolism are associated with the development of many diseases, including malignant tumors, decreased immune response, some types of pancreatitis, Snyder-Robinson's syndrome, and even type 2 diabetes1. Biological evaluation of rationally designed polyamine analogs is one of the cornerstones of polyamine research having obvious basic and practical values. Here we synthesized and characterized C-methylated Spm and Spd analogues possessing a biochemically useful set of properties. Methodology & Theoretical Orientation: The synthesis of title compounds was performed using known methods starting from amino alcohols by subsequent elongation of polyamine backbone, or using convergent synthesis in the case of bis-methylated Spm derivatives2. Findings: Obtained data demonstrated that the biochemical properties of C-methylated polyamine analogs can be regulated by changing the position of the methyl substituent, and at more precise level by changing the configuration of chiral center2-4. Hidden stereospecificity (natural substrates are achiral) was shown for the enzymes of polyamine metabolism using title compounds2. An original approach to alter stereospecificity of FAD-dependent N-acetylpolyamine oxidase (APAO) and to alter stereospecificity and regioselectivity of yeast polyamine oxidase (Fms1) was suggested2,4. Conclusion & Significance: The first metabolically stable functionally active mimetics of Spd, i.e. (R)-1,8-diamino-3-methyl-4-azaoctane and Spm, i.e. (R,R)-2,13-diamino-5,10- diazatetradecane, being suitable for the investigation of the individual cellular functions of partly interchangeable and easily interconvertible Spm and Spd were found2,3.