Identification of the Structural Determinants for Anticancer Activity of a Ruthenium Arene Peptide Conjugate

Abstract

Organometallic Ru(arene)-peptide bioconjugates with potent in vitro anticancer activity are rare. We have prepared a conjugate of a Ru(arene) complex with the neuropeptide [Leu(5)]-enkephalin. [Chlorido(η(6)-p-cymene)(5-oxo-κO-2-{(4-[(N-tyrosinyl-glycinyl-glycinyl-phenylalanyl-leucinyl-NH2)propanamido]-1H-1,2,3-triazol-1-yl)methyl}-4H-pyronato-κO)ruthenium(II)] (8) shows antiproliferative activity in human ovarian carcinoma cells with an IC50 value as low as 13 μM, whereas the peptide or the Ru moiety alone are hardly cytotoxic. The conjugation strategy for linking the Ru(cym) (cym=η(6)-p-cymene) moiety to the peptide involved N-terminal modification of an alkyne-[Leu(5)]-enkephalin with a 2-(azidomethyl)-5-hydroxy-4H-pyran-4-one linker, using Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC), and subsequent metallation with the Ru(cym) moiety. The ruthenium-bioconjugate was characterized by high resolution top-down electrospray ionization mass spectrometry (ESI-MS) with regard to peptide sequence, linker modification and metallation site. Notably, complete sequence coverage was obtained and the Ru(cym) moiety was confirmed to be coordinated to the pyronato linker. The ruthenium-bioconjugate was analyzed with respect to cytotoxicity-determining constituents, and through the bioconjugate models [{2-(azidomethyl)-5-oxo-κO-4H-pyronato-κO}chloride (η(6)-p-cymene)ruthenium(II)] (5) and [chlorido(η(6)-p-cymene){5-oxo-κO-2-([(4-(phenoxymethyl)-1H-1,2,3-triazol-1-yl]methyl)-4H-pyronato-κO}ruthenium(II)] (6) the Ru(cym) fragment with a triazole-carrying pyronato ligand was identified as the minimal unit required to achieve in vitro anticancer activity.

Exploring Ruthenium-based organometallic inhibitors against Plasmodium Calcium Dependent Kinase 2 (PfCDPK2): a combined ensemble docking, QM paramterization and molecular dynamics study

“…As an extension to the practical utility of this idea, we report the ensemble docking and dynamics of Ruthenium-based organometallic inhibitor with staurosporine moiety which can be used as kinase inhibitor against malarial CDPKs. Ruthenium is considered as most promising transition metal for drug development and pharmaceutical values (Abid, Shamsi, & Azam, 2016;Dragutan, Dragutan, & Demonceau, 2017;Meier-Menches, Gerner, Berger, Hartinger, & Keppler, 2018;Meier et al, 2013). In the context of ruthenium-based kinase inhibitor, Meggers and co-workers have pioneered the development of potent and selective kinase inhibitors through the use of octahedral pyridocarbazole complexes mimicking the pan-kinase inhibitor staurosporine (Debreczeni et al, 2006).…”

“…Various metals have been introduced in designing metal-organic framework in drug development, in which ruthenium is often considered as the most promising transition metal from the pharmaceutical viewpoint because of its safe and druggable properties (Maschke, Alborzinia, Lieb, Wölfl, & Metzler-Nolte, 2014;Meier et al, 2013). The ruthenium (Ru-based) compounds have also demonstrated promising biological activities such as antibacterial (F. Li, Collins, & Keene, 2015;Mu et al, 2018), antileishmanial (Iniguez et al, 2016;Marcusso Orsini et al, 2016), anticancer (Su, Li, & Li, 2018;Thota, Rodrigues, Crans, & Barreiro, 2018) and antiplasmodial (Ekengard et al, 2015;Rylands et al, 2019).…”

Colorimetric detection, quantification and extraction of Fe(III) in water by acrylic polymers with pendant Kojic acid motifs

“…The methacrylate sensory monomer (3) could not be conventionally prepared in a single step from Kojic acid and methacryloyl chloride but was synthesized using a two-step procedure. First, the treatment of Kojic acid with thionyl chloride led to the reaction of the primary alcohol with the formation of a Kojic acid primary chloro-derivative [19] that led to (3) by reaction with potassium methacrylate at 100ºC (no thermal initiated polymerization was observed) [20]. The reaction steps are schematically shown in Scheme 1.…”

Incorporating ruthenium into advanced drug delivery carriers – an innovative generation of chemotherapeutics

“…The Hartinger group successfully conjugated a ruthenium complex to a neuropeptide (Fig. ) . This conjugated entity shows antiproliferative activity with IC 50 values as low as 13 µmol L ‐1 , whereas the peptide or the ruthenium moiety alone are barely cytotoxic.…”