Somatostatin subtype-2 receptor-targeted metal-based anticancer complexes.

Conjugates of a dicarba analogue of octreotide, a potent somatostatin agonist whose receptors are overexpressed on tumor cells, with [PtCl2(dap)] (dap = 1-(carboxylic acid)-1,2-diaminoethane) (3), [(eta(6)-bip)Os(4-CO2-pico)Cl] (bip = biphenyl, pico = picolinate) (4), [(eta(6)-p-cym)RuCl](dap)(+) (p-cym = p-cymene) (5), and [(eta(6)-p-cym)RuCl(imidazole-CO2H)(PPh3)](+) (6), were synthesized by using a solid-phase approach. Conjugates 3-5 readily underwent hydrolysis and DNA binding, whereas conjugate 6 was inert to ligand substitution. NMR spectroscopy and molecular dynamics calculations showed that conjugate formation does not perturb the overall peptide structure. Only 6 exhibited antiproliferative activity in human tumor cells (IC50 = 63 +/- 2 mu M in MCF-7 cells and IC50 = 26 +/- 3 mu M in DU-145 cells) with active participation of somatostatin receptors in cellular uptake. Similar cytotoxic activity was found in a normal cell line (IC50 = 45 +/- 2.6 mu M in CHO cells), which can be attributed to a similar level of expression of somatostatin subtype-2 receptor. These studies provide new insights into the effect of receptor-binding peptide conjugation on the activity of metal-based anticancer drugs, and demonstrate the potential of such hybrid compounds to target tumor cells specifically.