Synthesis, characterisation and influence of lipophilicity on cellular accumulation and cytotoxicity of unconventional platinum(IV) prodrugs as potent anticancer agents.

Lipophilic platinum(IV) complexes were synthesised of the type [Pt(H_L)(A_L)(OH)(R)]²⁺ and [Pt(H_L)(A_L)(R)₂]²⁺ (H_L = 5,6-dimethyl-1,10-phenanthroline or 1,10-phenanthroline; A_L = 1S,2S-diaminocyclohexane and R = increasingly lipophilic carboxylate axial ligands (C10–18)) from hydrophilic platinum(II) precursors that exhibit exceptional anticancer activity. The increased overall lipophilicity of the complexes suggested the formation of spontaneously self-assembled structures in an aqueous environment. The anti-proliferative properties were assessed against one non-cancerous and a panel of cancerous cell lines. Nanomolar levels of activity were observed against several cell lines, with the lowest GI₅₀ of 3.4 nm against the Du145 prostate cancer cell line and over 1100-fold greater activity than cisplatin against HT29 colon carcinoma. RP-HPLC was utilised to establish the relative lipophilicities of each complex. While there seemed to be an increase in cellular accumulation for the lipophilic derivatives in some instances, ICP-MS studies showed no clear correlation between increasing lipophilicity, cellular accumulation and cytotoxicity. [ABSTRACT FROM AUTHOR]