A convenient route towards deoxygalactosyl-functionalised ortho-carbaborane: Synthesis of a building block for peptide conjugation

• ortho-Carbaborane (1,2-closo-C2B10H12) was asymmetrically functionalised with a deoxy-galactosyl and carboxyl ethyl moiety.
• The key intermediate Deoxygalactose-functionalised ortho-carbaborane was synthesised by two independent synthetic routes in similar yield.
• The direct synthesis of the key intermediate gave comparable (or better) yield than the recommended silyl protection.
• The carboxyl group was formed under mild conditions employing ruthenium catalysts and periodate as a gentle oxidant.

In the treatment of cancer, boron neutron capture therapy (BNCT) is a mild and promising alternative to established harsh therapeutic methods such as chemo- and radiation therapy. However, successful BNCT procedures strongly depend on efficient, tumour-selective boron-delivery systems, and recently we have demonstrated that the breast tumour-selective peptide [F7,P34]-NPY is a promising boron-shuttle system after conjugation with three ortho-carbaborane clusters (1,2-closo-C2B10H10). The extreme hydrophobicity of the latter, however, causes problems in medicinal applications in vivo. Therefore, we have elaborated a synthetic protocol towards a deoxygalactosyl-modified (and thus more hydrophilic) building block that can readily be conjugated with the shuttle peptide. A key intermediate, i.e., ortho-carbaborane functionalised with a bis-isopropylidene-protected deoxygalactosyl moiety, was synthesised by both a silyl protection strategy (which is generally recommended for monosubstitution) and direct reaction of metallated ortho-carbaborane in acceptable yield.

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