On-Resin Conjugation of the Ruthenium Anticancer Agent Plecstatin-1 to Peptide Vectors

Saawan Kumar, Mie Riisom, Stephen M.F. Jamieson, Iman Kavianinia, Paul W.R. Harris, Nils Metzler-Nolte, Margaret A. Brimble, Christian G. Hartinger

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Ruthenium piano-stool complexes have been explored for their anticancer activity and some promising compounds have been reported. Herein, we conjugated a derivative of plecstatin-1 to peptides in order to increase their cancer cell targeting ability. For this purpose, plecstatin-1 was modified at the arene ligand to introduce a functional amine handle (3), which resulted in a compound that showed similar activity in an in vitro anticancer activity assay. The cell-penetrating peptide TAT48-60, tumor-targeting neurotensin8-13, and plectin-targeting peptide were functionalized with succinyl or β-Ala-succinyl linkers under standard solid-phase peptide synthesis (SPPS) conditions to spatially separate the peptide backbones from the bioactive metal complexes. These modifications allowed for conjugating precursor 3 to the peptides on resin yielding the desired metal-peptide conjugates (MPCs), as confirmed by high-performance liquid chromatography (HPLC), NMR spectroscopy, and mass spectrometry (MS). The MPCs were studied for their behavior in aqueous solution and under acidic conditions and resembled that of the parent compound plecstatin-1. In in vitro anticancer activity studies in a small panel of cancer cell lines, the TAT-based MPCs showed the highest activity, while the other MPCs were virtually inactive. However, the MPCs were significantly less active than the small molecules plecstatin-1 and 3, which can be explained by the reduced cell uptake as determined by inductively coupled plasma MS (ICP-MS). Although the MPCs did not display potent anticancer activities, the developed conjugation strategy can be extended toward other metal complexes, which may be able to utilize the targeting properties of peptides.

Original languageEnglish
Pages (from-to)14310-14317
Number of pages8
JournalInorganic Chemistry
Volume62
Issue number35
DOIs
StatePublished - 4 Sep 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023 American Chemical Society.

Funding

The authors thank the University of Auckland and the Maurice Wilkins Centre for Molecular Biodiscovery for financial support. N.M-N. is grateful to the Royal Society of New Zealand for a Julius von Haast Fellowship. M.R. would like to thank Eva & Henry Frænkels Mindefond, Knud Højgaards Fond, Dagmar Marshalls Fond, Carl og Ellen Hertz’ legat til Dansk Læge-og Naturvidenskab, Viet-Jacobsen Fonden, Christian og Ottilia Brorsons Rejselegat for yngre videnskabsmænd-og kvinder, and Direktør Jacob Madsens og Hustru Olga Madsens Fond for financial support. They thank Mansa Nair and Githal Arachchige for collecting ESI-QToF-MS data, Stuart Morrow for ICP-MS support, and Natalia Abrego, for their help with elemental analysis.

FundersFunder number
Carl og Ellen Hertz’ legat til Dansk Læge-og Naturvidenskab
Christian og Ottilia Brorsons Rejselegat
Natalia Abrego
Viet-Jacobsen Fonden
Royal Society Te Apārangi
University of Auckland
Direktør Jacob Madsen og Hustru Olga Madsens Fond

    Fingerprint

    Dive into the research topics of 'On-Resin Conjugation of the Ruthenium Anticancer Agent Plecstatin-1 to Peptide Vectors'. Together they form a unique fingerprint.

    Cite this