Nukleobasen-funktionalisierte Azatriostine: Synthese und Studien zur Wechselwirkung mit DNA (English shop)

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Specific interactions of small molecules with DNA play an important role in nature. Through the synthesis of compounds that interact with DNA in a sequence-specific manner, the regulatory processes of protein synthesis can be decisively disrupted and influenced. An important class of DNA-binding natural products is represented by the members of the quinoxaline antibiotics. The cause of their cytotoxic activity is their structurally identical architecture, which results in high binding affinity and sequence specificity. A rigid peptidic scaffold, consisting of 8–10 amino acids, preorganises two aromatic quinoxaline systems in parallel at a distance of 10.5 Å. The interaction with DNA occurs via the minor groove: while the peptidic backbone forms sequence-specific hydrogen bonds and van der Waals interactions with the DNA backbone and the base pairs, the two chromophores intercalate into the DNA by bridging two base pairs. In the framework of this work, model systems were developed on the basis of triostin A, in which the aromatic quinoxaline systems are substituted by canonical nucleobases. Besides an altered binding affinity, these systems also display a potentially altered binding selectivity and can thereby provide valuable information for understanding the mechanism of interaction with DNA. Moreover, owing to their numerous hydrogen bond donors and acceptors, nucleobases can bind not only via the minor groove but also via the major groove, by intercalation, or at abasic sites.