New trans-platinum planar amines (TPAs) represent a family of platinum-based drugs with cytotoxicity equivalent to that of cisplatin, but with negligible cross-resistance. According to the substitution pattern around the metal center, distinct DNA adducts can be formed which yield various levels of cytotoxicity in cell lines. We compared the effects of leaving groups (Cl- versus formate or acetate) and amines (NH3 versus aromatic heterocyclic planar systems) on the efficiency, kinetics, and mode of DNA platination. We show that the substitution of just a single amino group on the transplatin nucleus is optimal, with major effects on the kinetics of metal complex conversion into the reactive aquo species. Additionally, by monitoring TPA reactivity toward variable DNA structures, a lack of preference for double-stranded DNA in over single-stranded or G-quadruplex DNA was observed which is possibly related to steric effects of the planar amine groups. These properties can lead to a unique distribution of platination sites by TPA relative to the lead compound cisplatin, which may help to explain the unique cytotoxic profile of TPAs.