Synthesis and structural characterisation of novel platinum-based drug candidates with extended functionality by incorporation of bis(diphenylphosphino)ferrocene units as metal chelators

Among the metal-based anticancer drugs, cisplatin (cis-diaminedichloroplatinum(II)) is the most widely used species in therapy. Despite its clinical success, cisplatin still suffers in generating resistance, as well as being highly toxic due to poor selectivity between healthy and sick cells. By molecular design it ought to be possible to generate new cis-platinum compounds with increased selectivity and improved cellular behaviour. In this paper, we report a synthetic pathway for construction of derivatives of 1,1′-bis(diphenylphosphino)-ferrocene, together with their corresponding cis-platinum compounds with the aim testing them for their interaction capacity with respect to various DNA models. We also report a synthetic route for a nucleoside-based cis-platinum compound containing a bidentate ferrocenylphosphine derivative connected through a succinamic-based linker to the 5-position of the heterocyclic moiety of uridine. Our preliminary kinetic investigation of 5-{N-1-1′,2-bis(diphenylphosphino)ferrocenyl]ethyl]-N′-prop-2-yn-3-yl]succinamide} uridinedichloroplatinum(II) showed that this compound reacted faster with the phosphorothioate containing oligonucleotides d(T₆p(S)T₆), with an observed first-order rate constant k_obs=(1.4±0.1)×10⁻⁴ s⁻¹, compared with the G-N7 target in d(T₇GGT₇), for which the observed first-order rate constant is k_obs=(7.2±0.5)×10⁻⁴ s⁻¹.