Abstract
Partial and total syntheses of polyamines incorporating crown ether moieties have been effected using N-tritylated linear amino acids, like β-alanine (βAla) and γ-aminobutyric acid (γAba), to introduce the N-3-C and N-4-C polyamine structural units, respectively. The partial syntheses involve the acylation of commercially available crown bearing amino function(s) or aza-oxa crown ethers with the isolable succinimidyl esters of Trt-βAla-OH or Trt-βAla-γAba-OH, followed by LiAlH4-mediated reduction of the resulting amides, whereas in the total syntheses the crown and the aza-oxa crown ether moieties are built-up from commercially available starting materials like polyethylene glycols, epichlorohydrin and dibenzylamine.
Highlights
Linear polyamines (PAs), like spermidine (SPD) and spermine (SPM) and their conjugates (PACs) with other natural products are widely distributed in the living organisms and are associated with interesting biological functions
We decided to examine the possibility of introducing crown ethers (CEs) moieties into PA molecules and study the complexing and biological properties of this new family of organic compounds, which we collectively coin as crowned polyamines (CRPAs)
Linear amino acids and α,ω-diaminoalkanes as building blocks for the assembly of linear polyamine skeletons In a series of letters,[5,6] we have shown that the triphenylmethyl N-protected linear amino acids, like βAla and γ-aminobutyric acid (γAba), and their dipeptides, e.g. βAla-γAba, in the form of their corresponding isolable succinimidyl ‘active′ esters (SAEs) 5 and 6 can be successfully employed for the synthesis of a variety of linear and cyclic SPD and SPM analogues and conjugates of the alkaloid kukoamine A type as well as their symmetric and asymmetric dimers, bridged by linear dicarboxylic acids, of the alkaloid tenuilobine type using the ‘amide approach[4]
Summary
Linear polyamines (PAs), like spermidine (SPD) and spermine (SPM) and their conjugates (PACs) with other natural products are widely distributed in the living organisms and are associated with interesting biological functions. For this reason, they have attracted considerable interest, and a variety of PA analogues and PACs have been already synthesized in order to determine structure-activity relationship and to identify possible leads for the development of PA-based pharmaceuticals.[1] On the other hand, the cyclic oligomers of ethylene oxide, collectively known as crown ethers (CEs), and their analogues and derivatives are widely used for complexing and separating metal or organic cations, as well as in the areas of phase transfer. We used simple commercially available building blocks, like polyethylene glycols, epichlorihydrin, and dibenzylamine, in order to build-up various CE skeletons to the appropriate size and content of N atoms, and the ‘isolable′ active esters 5 and 6, readily available from the corresponding linear amino acids β-alanine (βAla) and γ-aminobutyric acid (γAba),[5] as N–3-C and N–3-C–N–4-C synthons for the assembly of various PA skeletons
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