title: Heterometallic titanium-gold complexes inhibit renal cancer cellsin vitroandin vivo.
abstract: Following recent work on heterometallic titanocene-gold complexes as potential chemotherapeutics for renal cancer, we report here on the synthesis, characterization and stability studies of new titanocene complexes containing a methyl group and a carboxylate ligand (mba = S-C6H4-COO-) bound to gold(I)-phosphane fragments through a thiolate group ([(η-C5H5)2TiMe(μ-mba)Au(PR3)]. The compounds are more stable in physiological media than those previously reported and are highly cytotoxic against human cancer renal cell lines. We describe here preliminary mechanistic data involving studies on the interaction of selected compounds with plasmid (pBR322) DNA used as a model nucleic acid, and with selected protein kinases from a panel of 35 protein kinases having oncological interest. Preliminary mechanistic studies in Caki-1 renal cells indicate that the cytotoxic and anti-migration effects of the most active compound5([(η-C5H5)2TiMe(μ-mba)Au(PPh3)] involve inhibition of thioredoxin reductase and loss of expression of protein kinases that drive cell migration (AKT, p90-RSK, and MAPKAPK3). The co-localization of both titanium and gold metals (1:1 ratio) in Caki-1 renal cells was demonstrated for5indicating the robustness of the heterometallic compoundin vitro. Two compounds were selected for furtherin vivostudies on mice based on their selectivityin vitroagainst renal cancer cell lines when compared to non-tumorigenic human kidney cell lines (HEK-293T and RPTC) and the favourable preliminary toxicity profile in C57BL/6 mice. Evaluation of Caki-1 xenografts in NOD.CB17-Prkdc SCID/J mice showed an impressive tumor reduction (67%) after treatment for 28 days (3 mg/kg/every other day) with heterometallic compound5as compared with the previously described [(η-C5H5)2Ti{OC(O)-4-C6H4-P(Ph2)AuCI}2]3which was non-inhibitory. These findings indicate that structural modifications on the ligand scaffold affect thein vivoefficacy of this class of compounds.
authors.affiliation: Department of Chemistry, Brooklyn College and The Graduate Center, The City University of New York, Brooklyn, NY, 11210, US.
authors.forename: Jacob
authors.initials: J
authors.lastname: Fernández-Gallardo
authors.affiliation: Department of Chemistry, Brooklyn College and The Graduate Center, The City University of New York, Brooklyn, NY, 11210, US.|Biology PhD Program, The Graduate Center, The City University of New York, 365 Fifth Avenue, New York, NY, 10016, US.
authors.forename: Benelita T
authors.initials: BT
authors.lastname: Elie
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Minnesota, MN, 55455, US.
authors.forename: Tanmoy
authors.initials: T
authors.lastname: Sadhukha
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Minnesota, MN, 55455, US.|Center for Translational Drug Delivery, University of Minnesota, MN, 55455, US.
authors.forename: Swayam
authors.initials: S
authors.lastname: Prabha
authors.affiliation: Departamento de Química Inorgánica, Universidad de Valencia, Burjassot, Valencia, 46100, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Sanaú
authors.affiliation: Biology PhD Program, The Graduate Center, The City University of New York, 365 Fifth Avenue, New York, NY, 10016, US.|Department of Chemistry and Biochemistry, Queens College, The City University of New York, Flushing, NY, 11367, US.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Rotenberg
authors.affiliation: Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, 96813, US.
authors.forename: Joe W
authors.initials: JW
authors.lastname: Ramos
authors.affiliation: Department of Chemistry, Brooklyn College and The Graduate Center, The City University of New York, Brooklyn, NY, 11210, US.|Biology PhD Program, The Graduate Center, The City University of New York, 365 Fifth Avenue, New York, NY, 10016, US.|Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, 96813, US.
authors.forename: María
authors.initials: M
authors.lastname: Contel