2 research outputs found
Organometallic TitanoceneāGold Compounds as Potential Chemotherapeutics in Renal Cancer. Study of their Protein Kinase Inhibitory Properties
Earlyālate
transition metal TiAu<sub>2</sub> compounds [(Ī·-C<sub>5</sub>H<sub>5</sub>)<sub>2</sub>TiĀ{OCĀ(O)ĀCH<sub>2</sub>PPh<sub>2</sub>AuCl}<sub>2</sub>] (<b>3</b>) and new [(Ī·-C<sub>5</sub>H<sub>5</sub>)<sub>2</sub>TiĀ{OCĀ(O)-4-C<sub>6</sub>H<sub>4</sub>ĀPPh<sub>2</sub>AuCl}<sub>2</sub>] (<b>5</b>) were evaluated
as potential anticancer agents <i>in vitro</i> against renal
and prostate cancer cell lines. The compounds were significantly more
effective than monometallic titanocene dichloride and goldĀ(I) [{HOCĀ(O)ĀRPPh<sub>2</sub>}ĀAuCl] (R = āCH<sub>2</sub>ā <b>6</b>,
ā4-C<sub>6</sub>H<sub>4</sub>ā <b>7</b>) derivatives
in renal cancer cell lines, indicating a synergistic effect of the
resulting heterometallic species. The activity on renal cancer cell
lines (for <b>5</b> in the nanomolar range) was considerably
higher than that of cisplatin and highly active titanocene Y. Initial
mechanistic studies in Caki-1 cells <i>in vitro</i> 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 (IC<sub>50</sub> <b>3</b> = 91 nM, IC<sub>50</sub> <b>5</b> = 117 nM). The selectivity of the compounds <i>in vitro</i> 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 <b>5</b>) are excellent candidates
for further development as potential renal cancer chemotherapeutics
In Vitro and in Vivo Evaluation of Water-Soluble Iminophosphorane Ruthenium(II) Compounds. A Potential Chemotherapeutic Agent for Triple Negative Breast Cancer
A series
of organometallic rutheniumĀ(II) complexes containing iminophosphorane
ligands have been synthesized and characterized. Cationic compounds
with chloride as counterion are soluble in water (70ā100 mg/mL).
Most compounds (especially highly water-soluble <b>2</b>) are
more cytotoxic to a number of human cancer cell lines than cisplatin.
Initial mechanistic studies indicate that the cell death type for
these compounds is mainly through canonical or caspase-dependent apoptosis,
nondependent on p53, and that the compounds do not interact with DNA
or inhibit protease cathepsin B. In vivo experiments of <b>2</b> on MDA-MB-231 xenografts in NOD.CB17-Prkdc SCID/J mice showed an
impressive tumor reduction (shrinkage) of 56% after 28 days of treatment
(14 doses of 5 mg/kg every other day) with low systemic toxicity.
Pharmacokinetic studies showed a quick absorption of <b>2</b> in plasma with preferential accumulation in the breast tumor tissues
when compared to kidney and liver, which may explain its high efficacy
in vivo