Half-sandwich Ru(II) N-heterocyclic carbene complexes in anticancer drug design

Cancer is a pandemic with >18,000,000 diagnosed cases, [1] being considered the second cause of death worldwide [2]. Chemotherapy, along with surgery and radiotherapy, is widely used in treatments against different types of cancer. Platinum complexes such as cisplatin, carboplatin and oxaliplatin occupy a prominent place within chemotherapy, as they are widely used [3,4]. However, these treatments are associated with important side effects such as nephrotoxicity, neurotoxicity, and ototoxicity [5]. Besides all this, some tumors develop resistance to platinum-based treatments [6].

One of the most important objectives in the field of applied inorganic chemistry consists of the development of novel metallo-complexes that can overcome these limitations [7]. In this context, not only several platinum analogs have been designed [6], but also complexes with metal centers other than platinum have also been developed. Among all of them, ruthenium (Ru) complexes stand out due to their relevant anticancer activity associated with low toxicity. In addition, ruthenium complexes have also been shown to have antimetastatic properties. [[8], [9], [10], [11]]. In fact, several ruthenium complexes such as NAMI-A [12], NKP1339 [13], KP1019 [14] and TDL1433 [15] (Fig. 1) were studied as part of a clinical trial [16] and, NKP1339 is currently developed for clinical investigation. Within ruthenium complexes, those based on Ru(II)-η6-arene fragment represented by RAPTA [17,18] and RAED families [19,20], are considered as a classes of remarkable complexes with high potential as anticancer agents.

The arene group in the Ru complexes have a significant effect due to the coordination to the ruthenium is established by the donation (σ and π) from the arene (η6-donor) to the empty ruthenium orbitals, and for the subsequent back-donation from the filled metal orbitals to the empty arene orbitals (π-acceptor). As result the active oxidation state + II is stabilized. On the other hand, the coordination of arene system provides a hydrophobic face in the complex, resulting in enhanced transport of Ru across cell membranes. In addition to that arene fragment can interact with DNA through intramolecular π-π arene-nucleobase stacking [21]. Also, the anticancer activity is influenced significantly by the co-ligand(s) [21]. These co-ligands are generally bidentate N-N [22] chelating ligands, homobidentate O-O [23], heterobidentate N-O [24], N-S [25] and P-P ligands [11]. However, examples with N-heterocyclic carbene (NHC) ligands are scarce, despite the already established anticancer activities of Au, Ag, and Pd complexes with NHCs [26]. Metal-NHCs have become very well-known systems to organometallic chemists in catalysis applications [27] due to their strong and stable metal–ligand bond, which is dominated mainly by σ-donation. The same feature along with the feasible chemical derivatizations made the NHC Ru(II) η6-arene an important scaffold for drug design [28].

It is possible to differentiate between normal and abnormal NHCs since normal or classical N-heterocycle carbene (nNHCs) happens when the coordination to the metal occurs via the C2 carbon of the imidazole structure (Scheme 1), what encompasses imidazole and benzimidazole based half-sandwich (Ru(II) N-heterocyclic carbene complexes). In the case of the abnormal based half-sandwich (Ru(II) N-heterocyclic carbene complexes) the coordination of the abnormal N-heterocycle carbene (aNHC) to the metal center is through the positions C4/C5 of the imidazole ring (Scheme 1) [29,30].

The imidazole, benzimidazole, and abnormal-based half-sandwich Ru(II) NHC complexes are the kind of complexes of this type reported with anticancer properties to date, and precisely this review aims to overview the potential for these types of complexes focusing on their structure-activity (biological) relationship, providing, when it was possible, the anticancer activity of the co-ligands, metal precursors and the known anticancer complexes. All of this with the aim of reporting the impact on the anticancer activity after carbene coordination, complementing in this way, the work developed by Tasha R. Stee et al. [31] and Wukun Liu et al. [32]. Additionally, due to the fact that the topic of Tasha R. Stee et al. work is not centered on the NHC ligands we included the abnormal NHC complexes. Besides, we have included valuable information about the potential application of nanotechnology in the half-sandwich Ru(II) NHC and important aspects about the mechanism of action of the complexes.

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