New
organometallic gold(III) and platinum(II) complexes containing
iminophosphorane ligands are described. Most of them are more cytotoxic
to a number of human cancer cell lines than cisplatin. Cationic Pt(II)
derivatives <b>4</b> and <b>5</b>, which differ only in
the anion, Hg<sub>2</sub>Cl<sub>6</sub><sup>2–</sup> or PF<sub>6</sub><sup>–</sup> respectively, display almost identical
IC<sub>50</sub> values in the sub-micromolar range (25–335-fold
more active than cisplatin on these cell lines). The gold compounds
induced mainly caspase-independent cell death, as previously reported
for related cycloaurated compounds containing IM ligands. Cycloplatinated
compounds <b>3</b>, <b>4</b>, and <b>5</b> can also
activate alternative caspase-independent mechanisms of death. However,
at short incubation times cell death seems to be mainly caspase dependent,
suggesting that the main mechanism of cell death for these compounds
is apoptosis. Mercury-free compound <b>5</b> does not interact
with plasmid (pBR322) DNA or with calf thymus DNA. Permeability studies
of <b>5</b> by two different assays, <i>in vitro</i> Caco-2 monolayers and a rat perfusion model, have revealed a high
permeability profile for this compound (comparable to that of metoprolol
or caffeine) and an estimated oral fraction absorbed of 100%, which
potentially makes it a good candidate for oral administration