Synthetic methods for polyamine linkers and their application to combinatorial chemistry

Abstract

Polyamines and polyamine conjugates display a diverse range of important biological functions, ranging from antibiotics to immunosuppressants and glutamate receptor antagonists. For these reasons, polyamines provide an excellent template/scaffold for combinatorial chemistry. In this paper we present methods for the solid-phase immobilisation of polyamines for use in synthetic and combinatorial chemistry and describe how they have been employed in the preparation of a number of important polyamine conjugates and polyamine libraries. Thus, we have designed, synthesised and utilised a number of polyamine linkers for both solution and resin screening combinatorial application.

Linkers and Cleavage Strategies in Solid-Phase Organic Synthesis and Combinatorial Chemistry

“…TFA (20%) in CH 2 Cl 2 for 2 h was sufficient to cleave 96% of a peptide ester against 42% with the HMPA linker . Aqueous TFA (95%) was used to cleave polyamines from carbamate 23.3 …”

“…99 Aqueous TFA (95%) was used to cleave polyamines from carbamate 23.3. 100 In this case, the scaffold (polyamine) was bound to the linker prior to the resin attachment. p-Nitrophenyl carbonate derivative 23.4 101 and succinimidyl carbonate 23.5 can also be employed to anchor amines directly onto the solid support.…”

Recent developments in solid-phase organic synthesis

“…The polyamine linker 162 was designed to permit selective manipulation of the two orthogonally protected primary amine groups. 170 Combinatorial modification of the two primary amino groups was used to synthesise large libraries of polyamine conjugates. A polyamine linker 163 with both primary amino groups protected with N-1-(4-nitro-1,3-dioxoindan-2-ylidene)ethyl (NDE) groups was used to synthesise trypanothione disulfide.…”

Versatile Procedure for Asymmetric and Orthogonal Protection of Symmetric Polyamines and Its Advantages for Solid Phase Synthesis

“…In the search for therapeutically active compounds, several combinatorial approaches on solid phase have been undertaken, which exploit a variety of polyamine backbones. – However, many polyamine conjugates have either amphiphilic character or are highly sensitive to acids and bases. In some approaches, hydrophilic polyamine building blocks have been cleaved from a solid support and sequentially coupled to hydrophobic moieties to overcome the difficulties (for review, see ref ).…”

“…This method is especially favorable for commercially available backbones such as spermine. However, this requires an efficient protection of the primary and secondary amino groups in a solution phase synthesis step. ,– For high throughput library productions and large-scale SPS, large quantities of highly stable and partially or fully protected polyamine building blocks are required. They should be asymmetrically protected to exclude cross-linking reactions that would severely decrease yields and purities of the solid phase synthesis.…”