Somatostatin Subtype-2 Receptor-Targeted Metal-Based Anticancer Complexes

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• 作者：Flavia Barrag谩n ; Dolors Carrion-Salip ; Irene G贸mez-Pinto ; Alejandro Gonz谩lez-Cant贸 ; Peter J. Sadler ; Rafael de Llorens ; Virtudes Moreno ; Carlos Gonz谩lez ; Anna Massaguer ; Vicente March谩n
• 刊名：Bioconjugate Chemistry
• 出版年：2012
• 出版时间：September 19, 2012
• 年：2012
• 卷：23
• 期：9
• 页码：1838-1855
• 全文大小：746K
• 年卷期：v.23,no.9(September 19, 2012)
• ISSN：1520-4812

文摘

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), [(畏⁶-bip)Os(4-CO₂-pico)Cl] (bip = biphenyl, pico = picolinate) (4), [(畏⁶-p-cym)RuCl(dap)]⁺ (p-cym = p-cymene) (5), and [(畏⁶-p-cym)RuCl(imidazole-CO₂H)(PPh₃)]⁺ (6), were synthesized by using a solid-phase approach. Conjugates 3鈥?b>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 卤 2 渭M in MCF-7 cells and IC₅₀ = 26 卤 3 渭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 卤 2.6 渭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.