Synthesis and in vitro cytotoxicity of cis,cis,trans- diamminedichloridodisuccinatoplatinum(iv)-peptide bioconjugates

The synthesis and characterization of four Pt(iv)-peptide conjugates, containing one or two peptides in the axial position, designed for the purpose of targeted drug delivery to tumor cells, are described. The precursor cis,cis,trans-diamminedichloridodisuccinatoplatinum(iv) was coupled in the last step of standard solid-phase peptide synthesis (SSPS) with an analogue of neurotensin (pseudo-neurotensin = Lys-Lys-Pro-Tyr-Ile-Leu) and with octreotate (d-Phe-Cys-Phe-d-Trp-Lys-Thr-Cys-Thr-OH), an analogue of somatostatin, respectively. For all peptides, the SSPS reactions afforded both mono- and diconjugated Pt-peptide species, which were separated and purified by RP-HPLC. The two couples of conjugates, together with the precursor, were tested as cytotoxic agents towards different cancer cell lines. In general all conjugates are good inhibitors of cellular proliferation when compared to a nontargeting platinum(iv) parent compound, so that its relatively low cytotoxicity is greatly improved by addition of the peptides.