Triostin a derived cyclopeptide as architectural template for the alignment of four recognition units

Abstract

The DNA bisintercalator triostin A is structurally based on a disulfide-bridged depsipeptide scaffold that provides preorganization of two quinoxaline units in 10.5 Å distance. Triostin A analogues are synthesized with nucleobase recognition units replacing the quinoxalines and containing two additional recognition units in between. Thus, four nucleobase recognition units are organized on a rigid template, well suited for DNA double strand interactions. The new tetra-nucleobase binders are synthesized as aza-TANDEM derivatives lacking the N-methylation of triostin A and based on a cyclopeptide backbone. Synthesis of two tetra-nucleobase aza-TANDEM derivatives is established, DNA interaction analyzed by microscale thermophoresis, cytotoxic activity studied and a nucleobase sequence dependent self-aggregation investigated by mass spectrometry. Designed to match! Four nucleobases were attached to the disulfide bridged cyclopeptide scaffold derived from the DNA bisintercalator triostin. The aza-TANDEM backbone provides organization and alignment of the nucleobases, allowing for application in sequence- dependent DNA recognition and molecular architecture. © 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.