title: Organometallic Titanocene-Gold Compounds as Potential Chemotherapeutics in Renal Cancer. Study of their Protein Kinase Inhibitory Properties.
abstract: Early-late transition metal TiAu2compounds [(η-C5H5)2Ti{OC(O)CH2PPh2AuCl}2] (3) and new [(η-C5H5)2Ti{OC(O)-4-C6H4PPh2AuCl}2] (5) were evaluated as potential anticancer agentsin vitroagainst renal and prostate cancer cell lines. The compounds were significantly more effective than monometallic titanocene dichloride and gold(I) [{HOC(O)RPPh2}AuCl] (R = -CH2-6, -4-C6H4-7) derivatives in renal cancer cell lines, indicating a synergistic effect of the resulting heterometallic species. The activity on renal cancer cell lines (for5in the nanomolar range) was considerably higher than that of cisplatin and highly active titanocene Y. Initial mechanistic studies in Caki-1 cellsin vitrocoupled with studies of their inhibitory properties on a panel of 35 kinases of oncological interest indicate that these compounds inhibit protein kinases of the AKT and MAPKAPK families with a higher selectivity toward MAPKAPK3 (IC503= 91 nM, IC505= 117 nM). The selectivity of the compoundsin vitroagainst renal cancer cell lines when compared to a nontumorigenic human embryonic kidney cell line (HEK-293T) and the favorable preliminary toxicity profile on C57black6 mice indicate that these compounds (especially5) are excellent candidates for further development as potential renal cancer chemotherapeutics.
authors.affiliation: Department of Chemistry, Brooklyn College and The Graduate Center, The City University of New York , Brooklyn, New York 11210, United States.
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, New York 11210, United States.
authors.forename: Benelita T
authors.initials: BT
authors.lastname: Elie
authors.affiliation: Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa , Honolulu, Hawaii 96813, United States.
authors.forename: Florian J
authors.initials: FJ
authors.lastname: Sulzmaier
authors.affiliation: Departamento de Química Inorgánica, Universidad de Valencia , Burjassot, Valencia, 46100, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Sanaú
authors.affiliation: Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa , Honolulu, Hawaii 96813, United States.
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, New York 11210, United States ; Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa , Honolulu, Hawaii 96813, United States.
authors.forename: María
authors.initials: M
authors.lastname: Contel