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The potential of heterometallic compounds in medicinal chemistry and most particularly in cancer therapy has been recently described . 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 . This may derive from synergism (combined 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 .
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 , 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  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 . 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 . 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 , PEt3 4) with that of AF and the monometallic gold compounds [Au(Hmba)PR3] (PR3 ¼ PPh3 1 cref , 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 .