title: Somatostatin subtype-2 receptor-targeted metal-based anticancer complexes.
abstract: Conjugates of a dicarba analogue of octreotide, a potent somatostatin agonist whose receptors are overexpressed on tumor cells, with [PtCl(2)(dap)] (dap = 1-(carboxylic acid)-1,2-diaminoethane) (3), [(η(6)-bip)Os(4-CO(2)-pico)Cl] (bip = biphenyl, pico = picolinate) (4), [(η(6)-p-cym)RuCl(dap)](+) (p-cym = p-cymene) (5), and [(η(6)-p-cym)RuCl(imidazole-CO(2)H)(PPh(3))](+) (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 (IC(50) = 63 ± 2 μM in MCF-7 cells and IC(50) = 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 (IC(50) = 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.
authors.affiliation: Departament de Química Orgànica and IBUB, Universitat de Barcelona, Martí i Franquès 1-11, E-08028 Barcelona, Spain.
authors.forename: Flavia
authors.initials: F
authors.lastname: Barragán
authors.forename: Dolors
authors.initials: D
authors.lastname: Carrion-Salip
authors.forename: Irene
authors.initials: I
authors.lastname: Gómez-Pinto
authors.forename: Alejandro
authors.initials: A
authors.lastname: González-Cantó
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sadler
authors.forename: Rafael
authors.initials: R
authors.lastname: de Llorens
authors.forename: Virtudes
authors.initials: V
authors.lastname: Moreno
authors.forename: Carlos
authors.initials: C
authors.lastname: González
authors.forename: Anna
authors.initials: A
authors.lastname: Massaguer
authors.forename: Vicente
authors.initials: V
authors.lastname: Marchán
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007150:Immunohistochemistry; D009682:Magnetic Resonance Spectroscopy; D008670:Metals / Q000737:chemistry*; D017481:Receptors, Somatostatin / Q000187:drug effects*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D000970:Antineoplastic Agents; D008670:Metals; D017481:Receptors, Somatostatin; C093733:somatostatin receptor 2