Ruthenium(III) complexes with monodentate 5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one: Structural characterization, interaction with DNA and proteins Marzena Fandzloch a , Andrzej Wojtczak b , Joanna Wis´ niewska b , Krystian Stefan´ czak a , Juan M. Salas c , Iwona Lakomska a,⇑ a Bioinorganic Chemistry Research Group, Faculty of Chemistry, Nicolaus Copernicus University in Torun´, Gagarina 7, 87-100 Torun´, Poland b Faculty of Chemistry, Nicolaus Copernicus University in Torun´, Gagarina 7, 87-100 Torun´, Poland c Department of Inorganic Chemistry, University of Granada, Severo Ochoa s/n, 18071 Granada, Spain article info Article history: Received 10 August 2015 Received in revised form 22 December 2015 Accepted 28 December 2015 Available online 4 January 2016 Keywords: Ruthenium(III) complex Triazolopyrimidine X-ray Apotransferrin Albumin abstract X-ray structures of two Ru(III) complexes of the ‘‘Keppler-type”, [(CH 3 ) 2 NH 2 ]trans-[RuCl 4 (HmtpO) 2 ](1a) and [H 2 mtpO]trans-[RuCl 4 (HmtpO) 2 ]3H 2 O(1b), have been determined. The structures of both com- pounds established two monodentate heterocycle ligands (HmtpO) via N3 in axial positions and four equatorial chloride ions. The complexes differ only in the counter ion, which is a protonated dimethy- lamine [(CH 3 ) 2 NH 2 ] + for (1a) and a protonated [H 2 mtpO] + for (1b). Additionally, (1a) was characterized by EPR spectroscopy, and the effective magnetic moment measurement supports the paramagnetic char- acter, corresponding to the expected 4d 5 (S = 1/2) electron configuration for a Ru(III) core. CD studies on hydrophilic (1a) (logP = 1.28) suggested Ru(III) mechanisms of biological action that involve activation by reduction (with E red = 0.053 V versus NHE) and selective delivery by apotransferrin. Furthermore, it is suggested that the described (1a)-BSA adducts might form in vivo and might be relevant for the biolog- ical properties of this complex, and thus adducts may be tested as specific carriers of the ruthenium com- plex to cancer cells. Ó 2016 Elsevier B.V. All rights reserved. 1. Introduction Amongst the transition metals, ruthenium displays an espe- cially diverse coordination and organometallic chemistry, includ- ing a vast array of stable complexes with every conceivable type of ligand [1–3]. An ideal combination of relatively high stability and synthetic accessibility has underpinned the development of this field. Of the range of formal oxidation states available to this metal, the +2 and +3 ions are especially widely studied. In addition to their pure chemical interest and fundamental scientific value, ruthenium complexes have attracted attention for practical appli- cations in a number of important areas, including catalysis [4–7], medicine [8–15], and technologies that exploit the photophysical/ chemical properties of Ru(II)-based chromophores [16–19], such as organic light-emitting diodes [20,21] and dye-sensitized solar cells [22,23]. In medical applications, ruthenium(III) compounds represent a new family of promising metal-based anticancer drugs [24]. Cur- rently, some of them are being tested as drug candidates in clinical trials. For instance, NAMI-A, a sulfoxide ruthenium(III) complex with outstanding antimetastatic properties, has successfully com- pleted phase I clinical trials [25]. Similarly, KP1019, a representa- tive of the so-called ‘‘Keppler-type” complexes, of the general formula trans-[RuCl 4 L 2 ]  , where L is a N-heterocycle, showed an encouraging preclinical profile and is now undergoing phase I studies [26]. Despite the numerous in vitro and preclinical investi- gations, the final targets and the mechanisms through which ruthenium(III) complexes exert their antitumor effects remain poorly understood. A number of studies note that the interactions of these ruthenium(III) complexes with DNA are weaker than in the case of related platinum(II) complexes, suggesting the exis- tence of different biomolecular targets [27]. Thus, the paradigm of the cisplatin mechanism, i.e., ‘‘direct DNA damage – cytotoxic effect – cell death through apoptosis”, barely applies to ruthe- nium(III) complexes, whose cytotoxic effects are generally rather modest [28]. On the other hand, significant interactions of http://dx.doi.org/10.1016/j.ica.2015.12.036 0020-1693/Ó 2016 Elsevier B.V. All rights reserved. ⇑ Corresponding author. E-mail address: iwolak@chem.umk.pl (I. Lakomska). Inorganica Chimica Acta 443 (2016) 170–178 Contents lists available at ScienceDirect Inorganica Chimica Acta journal homepage: www.elsevier.com/locate/ica