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    © 2018 Elsevier Masson SAS. All rights reserved.
    1. Introduction
    The potential of heterometallic compounds in medicinal chemistry and most particularly in cancer therapy has been recently described [1]. A single molecule with two or more distinct biologically active metallic centers can potentiate oncotherapeutic
    * Corresponding author. Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA. E-mail address: [email protected] (M. Contel).
    efficacy [2]. This may derive from synergism (combined Givinostat action of the different metals) or cooperation (beneficial change in the physicochemical properties) between the two metal entities. In the past eight years a number of heterometallic compounds have been reported as anticancer agents [1e30]. However there are very few publications reporting the comparison of anticancer properties of heteronuclear compounds to that of their monometallic fragments (alone or in combination) [1,3,15,25e30]. Our group has focused on heterometallic compounds with gold fragments as one of the metallic centers. Gold(I) compounds bearing lipophilic ligands such as phosphanes (PR3) and N-heterocyclic carbenes (NHC) have
    displayed significant antitumor, antimicrobial and antiparasitic effects mostly by inhibition of the thioredoxin/thioredoxin reduc-tase Trx/TrxR systems [31e33]. In this context, we have recently reported on the preparation of complexes containing titanocenes [24e28] [TiCp2] or ruthenium (II) arene derivatives [29,30] [Ru (p-cymene)Cl2 (dppm)] and gold(I)-phosphane or gold(I)eNHC frag-ments (2, a and b in Chart 1) and their potential as chemothera-peutics against renal, colorectal and prostate cancers. Titanocene-gold derivatives containing gold-phosphane fragments (such as Givinostat 2, Titanocref) shrank tumors by 67% in a xenograft mouse model of renal carcinoma after 21 days of treatment, and that with low systemic toxicity [26].
    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, cell cycle 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].