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) (<b>3</b>), [(η⁶-bip)­Os­(4-CO₂-pico)­Cl] (bip = biphenyl, pico = picolinate) (<b>4</b>), [(η⁶-<i>p</i>-cym)­RuCl­(dap)]⁺ (<i>p</i>-cym = <i>p</i>-cymene) (<b>5</b>), and [(η⁶-<i>p</i>-cym)­RuCl­(imidazole-CO₂H)­(PPh₃)]⁺ (<b>6</b>), were synthesized by using a solid-phase approach. Conjugates <b>3</b>–<b>5</b> readily underwent hydrolysis and DNA binding, whereas conjugate <b>6</b> was inert to ligand substitution. NMR spectroscopy and molecular dynamics calculations showed that conjugate formation does not perturb the overall peptide structure. Only <b>6</b> exhibited antiproliferative activity in human tumor cells (IC₅₀ = 63 ± 2 μM in MCF-7 cells and IC₅₀ = 26 ± 3 μM 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 μM 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