Engineering the rhenium metalation of phenanthroline imino complexes for variable structure activity relationships.

There are marked advantages for incorporating multiple metal atoms into a single entity specifically for theranostic and radiopharmaceutical development for the treatment and imaging of cancer. To this end, we have synthetically manipulated a series of rhenium tricarbonyl complexes based on a 1,10-phenanthroline imino bifunctional ligand system to allow for the formation of mononuclear, dinuclear and mixed di-metal rhenium tricarbonyl complexes. Thus, diverse protein bio-chemical interactions are in principle possible by harnessing the chemical versatility of the the phenanthroline scaffold together with strategic metal substitution to advance drug development. The structure-activity relationships for these complexes are described indicating covalent and non-covalent interactions which are explored through the lens of macromolecular interactions and metallo-inorganic drug design. Complex characterisation was conducted with IR, 1H and 13C NMR, EA and detailed structural investigations using SC-XRD. Hirshfeld surface analysis indicated that halogen, hydrogen and oxygen-based hydrogen interactions play dominant roles in crystal packing and are significant to consider for drug design. In silico drug likeness analysis of the compounds using Swiss ADME had predicted good potential bioactivity. HeLa and MCF-7 cell SRB assay was used to identify the cytotoxic properties of the fac-tricarbonyl-(1,10-phenanthroline-N,N')-(bromido)-rhenium(I), fac-tricarbonyl-{2-([1,10-phenanthrolin-5-ylimino]methyl)phenol-N,N'}-(bromido)-rhenium(I), fac-tricarbonyl-{2-([1,10-phenanthrolin-5-ylimino]methyl)phenol-N,N'}-(chlorido)-rhenium(I), fac-{2-([1,10-phenanthrolin-5-ylimino]methyl)phenolato-N,N'}-(methanol)(bromido)-hexacarbonyl-di-rhenium(I), and fac-bis{2-([1,10-phenanthrolin-5-ylimino]methyl)phenol-N,N'}-hexacarbonyl-di-rhenium(I). Excellent activity was shown for the free ligand and 1,10-phenanthroline with IC50 values of 9 ± 3 μM, 11 ± 2 μM (HeLa) and 8 ± 2 μM, 6 ± 2 μM (MCF-7) respectively. Rhenium complexes showed IC50 values ranging between 15 ± 2 μM and 35 ± 2 μM against HeLa cells and between 68 ± 2 μM and >100 μM against MCF-7 cells. A correlation is observed between good to moderate cytotoxicity and a balanced spread of H-bond interactions showing amphiphilic character.