Synthesis of the first morpholine-containing iron(II) clathrochelates: A new class of efficient functionalized transcription inhibitors

• N,N- and N,S-substituted morpholine-containing iron(II) clathrochelates were obtained.
• T7 RNA polymerase is inhibited by iron(II) clathrochelates.
• Mercaptobenzoic residue is structural fragment important for the efficient inhibition.

Nucleophilic substitution of an iron(II) dichloroclathrochelate with morpholine as a N-nucleophilic agent afforded a monomorpholine-containing cage complex, characterized by X-ray diffraction. This complex as a monochloroclathrochelate precursor easily undergoes further nucleophilic substitution with 2-ethanolamine as a N-nucleophile and with meta- and para-mercaptobenzoic acids as S-nucleophiles, giving the bifunctional N,N- and N,S-substituted macrobicyclic iron(II) complexes. In vitro testing in a transcription assay based on T7 RNA polymerase showed the efficient structure- and concentration-dependent inhibition of transcription by these heterofunctionalized cage compounds in low- and submicromolar concentration range. The proposed mode of inhibition includes a trapping of clathrochelate inhibitor molecule by the binding pocket formed by three interconnected macromolecules of the transcription complex.

Morpholine-functionalized iron(II) clathrochelates display an efficient transcription inhibition in a model in vitro system based on T7 RNA polymerase.Figure optionsDownload as PowerPoint slide