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  • br Preliminary mechanistic studies indicated that these com

    2020-08-18


    Preliminary mechanistic studies indicated that these com-pounds achieve toxicity through mechanisms different than that of cisplatin as is the case for many other metallodrugs [25,26,30]. The TieAu derivatives studied did not bind to DNA, however they were excellent inhibitors of protein kinases such as p90-RSK, AKT, and MAPKAPK [26], and thioredoxin reductase [26,27] (the inhibition occurred for both isolated kinases and in renal or prostate cancer cell lines). We report here on the synthesis and characterization of a new bimetallic titanocene containing a gold-phosphane fragment (AuPEt3) that is also present in the drug Auranofin (AF). AF has been used in the clinic for the treatment of rheumatoid arthritis [34] but it is currently being investigated in clinical trials in cancer as a potential anticancer chemotherapeutic [35e38]. It has been
    described recently that human serum albumin adducts of [AuPEt3]þ have inhibited T cell proliferation at nanomolar doses [39]. It has also been reported that the cytotoxic properties of AF on colorectal cancer cells and the inhibition of purified TrxR depend solely on the [AuPEt3]þ fragment, and that the presence of the thiosugar moiety does not contribute to the pharmacologic efficacy of AF [33]. We have named the new TieAu compound [(h-C5H5)2TiMe(m-mba) Au(PR3)] (4) Titanofin (Equation (1)).
    Here we report comparative in vitro mechanistic evaluation of
     the efficacy of two bimetallic [(h-C5H5)2TiMe(m-mba)Au(PR3)] compounds (PR3 ¼ PPh3 2 [26], PEt3 4) with that of AF and the monometallic gold compounds [Au(Hmba)PR3] (PR3 ¼ PPh3 1 cref [26], PEt3 3 fin). All compounds are depicted in Chart 1 or in Equation 1. We studied their cytotoxicity, type of cell death in-duction, SR-11302 disruption as well as anti-migratory and anti-angiogenic properties along with inhibitory effects on 84 markers of oncological interest. We have recently reported on the in vitro (caki-1 cancer cells) mechanism of action of a ruthenium-gold derivative in which we also used AF as control in a number of similar experiments [30].
    2. Results and discussion
    2.1. Synthesis and characterization
    Crystals suitable for X-diffraction were obtained for new com-pound [Au(Hmba)(PEt3)] (3) fin. As for previously described phos-phane [Au(Hmba)(DPPF)] [27] and N-heterocyclic carbene [Au(Hmba)(IMes)] [27] compounds with the Hmba ligand, the in-dividual dimeric units (SI, figure S19) form chains which show hydrogen bonding at one end (Fig. 1). Bond distances and angles are depicted in Table 1.
    Chart. 1. Select heterometallic Ti-Au (2, a) and Ru-Au (b) compounds with relevant in vitro and in vivo activity reported by our group [26,27,29,30]. Structure of monometallic [Au(Hmba)(PPh3)] (1), Auranofin (AF) and Titanocene dichloride (TDC) also employed in this work.
    Fig. 1. ORTEP view of the polymeric structure of 3 showing hydrogen bonds (blue dotted line) and the Au-Au interactions. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
    Table 1
    Selected Structural Parameters of complex 3 obtained from X-ray single crystal diffraction studies. Bond lengths in Å and angles in .
    In this case, the monomeric molecules are linked by intermo-lecular gold-gold interactions (3.0678 (4) Å) not present in similar compounds described by us and others (S19) [25,26]. Such in-teractions giving rise to oligomers (AueAu distances at 2.8e3.3 Å, well below the sum of the van der Waals radii of ca. 3.6 Å) are common in gold chemistry and are due to the effect of aurophilicity [40,41]. The resulting dimeric units are linked by OeH intermo-lecular contacts (with the corresponding O or H from a second dimeric unit). The environment of the gold atoms is close to linear [PeAueS 177.32 (3)] (Fig. 1). The ORTEP drawing and crystal and refinement data for this structure are provided in the SI.
    The structure of bimetallic complex 4 depicted in Equation 1 has been proposed on the basis of NMR, IR and UVevis spectroscopy, mass spectrometry, and elemental analysis (see experimental sec-tion and SI). The difference between the symmetric and antisym-metric stretching bands in the solid-state IR spectra of compound 4 (Titanofin) is 377 cm 1, i.e. larger than 200 cm 1, which points out that the carboxylate group is bonded to the titanium center in a monodentate fashion as we found previously for Titanocref (2) [26] and derivatives where the phosphane is replaced by heterocyclic (NHC) carbenes [27].
    The stability of Titanofin 4 was evaluated by 31P 1H and 1H NMR spectroscopy in DMSO‑d6, 3:2 DMSO‑d6/PBS-D2O and UVevis spectroscopy in a 1:99 DMSO/PBS solution (NMR and UVeVis spectra corresponding to stabilities studies are included in the SI). Titanofin (4) resulted more soluble than Titanocref (2) in mixtures DMSO/PBS. While the half-life for Titanocref (2) was in neat DMSO‑d6 was 8 h, the half-life of new Titanofin (4) was 24 h (three times higher). In addition, Titanofin resulted soluble in mixtures