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Organometallic Titanocene–Gold Compounds as Potential Chemotherapeutics in Renal Cancer. Study of their Protein Kinase Inhibitory Properties
journal contribution
posted on 2015-12-17, 05:59 authored by Jacob Fernández-Gallardo, Benelita T. Elie, Florian J. Sulzmaier, Mercedes Sanaú, Joe W. Ramos, María ContelEarly–late
transition metal TiAu2 compounds [(η-C5H5)2Ti{OC(O)CH2PPh2AuCl}2] (3) and new [(η-C5H5)2Ti{OC(O)-4-C6H4PPh2AuCl}2] (5) were evaluated
as potential anticancer agents in vitro against 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 (for 5 in the nanomolar range) was considerably
higher than that of cisplatin and highly active titanocene Y. Initial
mechanistic studies in Caki-1 cells in vitro coupled
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 (IC50 3 = 91 nM, IC50 5 = 117 nM). The selectivity of the compounds in vitro against 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 (especially 5) are excellent candidates
for further development as potential renal cancer chemotherapeutics.
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5Hkidney cell linePotential Chemotherapeutics35 kinasescompoundcancer chemotherapeuticstitanocene YRenal Cancer117 nMprotein kinases91 nMnanomolar rangeAKTIC 50 3IC 50 5monometallic titanocene dichlorideCHanticancer agentsHEK6Hheterometallic speciesMAPKAPK 3cancer cell linesMAPKAPK familiestoxicity profileoncological interestC 57black miceHOCprostate cancer cell lines
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