ABSTRACT
Biogenic amines spermine and spermidine are essential factors of cellular growth. Polyamine analogues are widely used to investigate and to regulate the enzymes of polyamine metabolism and functions of spermine and spermidine in vitro and in vivo. Recently, it was demonstrated that alpha-methylated derivatives of spermine and spermidine are capable to fulfill key cellular functions of polyamines, moreover in some cases of (R)- and (S)-isomers are actually different. Using these alpha-methylated spermine and spermidine analogues it turned possible to prevent the development of acute pancreatitis of SSAT-transgenic rats and to demostrate for the first time that polyamine oxidase, spermine oxidase and deoxyhypusine synthase have dormant stereospecificity. An original approach to regulate the stereospecificity of polyamine oxidase was suggested. It was also demonstrated that the depletion of the intracellular polyamine pool has both hypusine-related consequences and also the consequences unrelated to the posttranslational modification of eukaryotic initiation translation factor eIF5A. Possible applications of a new family of C-methylated polyamine analogues for the investigation and regulation of polyamine metabolism in vitro and in vivo are discussed.
Subject(s)
Enzymes/metabolism , Spermidine/analogs & derivatives , Spermidine/metabolism , Spermine/analogs & derivatives , Spermine/metabolism , Animals , Humans , Methylation , Peptide Initiation Factors/metabolism , Protein Processing, Post-Translational/physiology , RNA-Binding Proteins/metabolism , Rats , Rats, Transgenic , Spermidine/chemistry , Spermine/chemistry , Eukaryotic Translation Initiation Factor 5AABSTRACT
The design and synthesis of SpmTrien (1,12-diamino-3,6,9-triazadodecane), an isosteric and charge-deficient analogue of spermine with excellent chelating properties towards Cu(2+) ions, as well as novel N(1)- and N(12)-Ac-SpmTriens and bis-Et-SpmTrien (N(1),N(12)-diethyl-1,12-diamino-3,6,9-triazadodecane) are described. Possible applications of SpmTrien and its derivatives to the investigation of the enzymes of polyamine metabolism and spermine cellular functions, including interaction with DNA, are discussed.
Subject(s)
Spermine/analogs & derivatives , Spermine/chemical synthesis , Amines/analysis , Chelating Agents/chemical synthesis , Chelating Agents/pharmacology , Drug Design , Hydrogen-Ion Concentration , Models, Molecular , Spermidine/analogs & derivatives , Spermidine/chemical synthesis , Spermidine/pharmacology , Spermine/pharmacologyABSTRACT
N,N'-Di-Boc-N"-triflylguanidine was demonstrated to be an efficient guanidinylation reagent for O-substituted hydroxylamines. N-(3-Aminooxypropyl)- and N-(3-aminopropoxy)guanidines, previously unknown isosteric and charge-deficient agmatine analogues, have been synthesized. The possibilities of using these compounds in studying polyamine metabolism are discussed. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2005, vol. 31, no. 6; see also http://www.maik.ru.
Subject(s)
Agmatine/analogs & derivatives , Agmatine/chemical synthesis , Agmatine/chemistryABSTRACT
1,12-Diamino-3,6,9-triazadodecane, a new isosteric and charge-deficient analogue of spermine, is synthesized. Unlike spermine, the new analogue is an excellent chelator of Cu2+ ions. Possible applications of this compound for studying enzymes of polyamine metabolism and cellular functions of spermine are discussed. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2005, vol. 31, no. 3; see also http://www.maik.ru.
Subject(s)
Chelating Agents/chemistry , Copper/chemistry , Spermine/analogs & derivatives , Spermine/chemistry , Chelating Agents/chemical synthesis , Spermine/chemical synthesisABSTRACT
alpha-Methylspermine and alpha,alpha'-dimethylspermine were synthesized in high overall yields starting from N-(benzyloxycarbonyl)-3-aminobutanol in order to study polyamine biochemistry in vitro and in vivo.
Subject(s)
Spermine/analogs & derivatives , Spermine/chemical synthesis , Magnetic Resonance Spectroscopy/methods , Spermine/chemistry , StereoisomerismABSTRACT
A five-step synthesis of alpha-methylspermidine (1,8-diamino-5-azanonane), the first polyamine analogue preventing pathological consequences of spermidine depletion in transgenic rats overproducing spermine/spermidine N'-acetyltransferase, from ethyl 3-aminobutyrate was achieved in a high overall yield.