R G Stirling S M Evans
 R.G. Stirling, S.M. Evans, P. McLaughlin, M. Senthuren, J. Millar, J. Gooi, L. Irving,
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European Journal of Medicinal Chemistry
Bimetallic titanocene-gold phosphane complexes inhibit invasion, metastasis, and angiogenesis-associated signaling molecules in renal cancer
Benelita T. Elie a, b, Jacob Fernandez-Gallardo a, Natalia Curado a, Mike A. Cornejo a, Joe W. Ramos e, María Contel a, b, c, d, e, * a Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA
b Biology PhD Programs, The Graduate Center, The City University of New York, 365 Fifth Avenue, New York, NY, 10016, USA
c Chemistry PhD Programs, The Graduate Center, The City University of New York, 365 Fifth Avenue, New York, NY, 10016, USA
d Biochemistry PhD Programs, The Graduate Center, The City University of New York, 365 Fifth Avenue, New York, NY, 10016, USA
e Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, USA
Received in revised form
Following promising recent in vitro and in vivo studies of the anticancer efficacies of heterometallic titanoceneegold chemotherapeutic candidates against renal cancer, we report here on the synthesis, characterization, stability studies and biological evaluation of a new titanocene complex containing a gold-triethylphosphane fragment [(h-C5H5)2TiMe(m-mba)Au(PEt3)] (4) Titanofin. The SR 11302 is more stable in physiological fluid than those previously reported, and it is highly cytotoxic against a line of human clear cell renal carcinoma. We describe here preliminary mechanistic data for this compound and previously reported [(h-C5H5)2TiMe(m-mba)Au(PPh3)] (2) Titanocref which displayed remarkable activity in an in vivo mouse model. Mechanistic studies were carried out in the human clear cell renal carcinoma Caki-1 line for the bimetallic compounds [(h-C5H5)2TiMe(m-mba)Au(PR3)] (PR 3 ¼ PPh3 2 Titanocref and PEt3 4 Titanofin), the two monometallic gold derivatives [Au(Hmba)(PR3)] (PR3 ¼ PPh3 1 cref; PEt3 3 fin), titanocene dichloride and Auranofin as controls. These studies indicate that bimetallic compounds Titanocref (2) and Titanofin (4) are more cytotoxic than gold monometallic derivatives (1 and 3) and significantly more cytotoxic than titanocene dichloride while being quite selective. Titanocref (2) and Titanofin (4) inhibit migration, invasion, and angiogenic assembly along with molecular markers asso-ciated with these processes such as prometastatic IL(s), MMP(s), TNF-a, and proangiogenic VEGF, FGF-basic. The bimetallic compounds also strongly inhibit the mitochondrial protein TrxR often overex-pressed in cancer cells evading apoptosis and also inhibit FOXC2, PECAM-1, and HIF-1a whose over-expression is linked to resistance to genotoxic chemotherapy. In summary, bimetallic titanocene-gold phosphane complexes (Titanocref 2 and Titanofin 4) are very promising candidates for further preclinical evaluations for the treatment of renal cancer.
© 2018 Elsevier Masson SAS. All rights reserved.
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 compound 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 .