Research in our group is focused on synthesizing Co3+/Ni2+coordination complexes designed to inhibit zinc finger proteins. The coordination complexes contain both a multidentate Schiff base ligand and a monodentate labile ligand. Exchange of the labile ligand for one of the histidine residues bound to the Zn2+ion in the zinc finger protein is the proposed point of inhibition. This leads to eventual Zn2+ion expulsion from the protein. This work is inspired by Doxovir, a related coordination complex undergoing clinical trial as an antiviral metallodrug. Targeted combinations of the following components were used to prepare coordination complexes in this study: the metal ions Co3+or Ni2+; the Schiff bases made from the 1:1 condensation of tris(2-aminoethyl)amine and one of the following three carbonyl compounds: acetylacetone (H[trenacac]), salicylaldehyde (H[trensal]) or orthovanillin (H[trenvan]); and the labile ligands aquo, bromido, chlorido, and 2- or 4-methylimidazole (denoted 2- or 4-MeIm). Characterization techniques employed include elemental analysis, NMR and UV-VIS spectroscopy, and x-ray crystallography. The aquo Co3+complexes of all three Schiff bases and the aquo Ni2+complex of [trensal]-were successfully prepared, the latter of which was characterized by X-ray crystallography. The chlorido Co3+complex [CoCl(trenacac)]ClO4 was also prepared, but synthesis of additional bromido or chlorido Co3+complexes of the other Schiff bases was unsuccessful. In the latter situation, aquo complexes and complexes containing a Schiff base made from the 1:2 condensation of tris(2-aminoethyl)amine and the corresponding carbonyl compound were isolated. 2- and 4-MeIm Co3+complexes of [trensal]-and [trenvan]-were synthesized. [Co(trenvan)(4-MeIm)](ClO4)2was characterized by X-ray crystallography. For these amine Co3+complexes, it was discovered that those of [trensal]-were best isolated from the reaction mixture directly; purification via ion exchange chromatography produced [Co(trensal)(OH2)](ClO4)2in both cases. This observation is significant because it demonstrates ligand exchange that is necessary for potential drug action. How labile this is appears to depend on the identity of the Schiff base ligand.

Constructing Co3+/Ni2+Schiff base zinc finger inhibitors

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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