Gold(III) Complexes of Pyridyl- and Isoquinolylamido Ligands: Structural, Spectroscopic, and Biological Studies of a New Class of Dual Topoisomerase I and II Inhibitors

The
structures, spectroscopy, and cytotoxicity of four novel nominally
square-planar gold­(III) chelates 1–4 with the general formula cis-AuCl2(X),
where the ligand X is an anionic bidentate pyridyl- or isoquinolylamido
chelating agent, are described. The Au–Namido, Au–Npyridyl, and Au–Nisoquinolyl distances are
2.002(9)–2.016(3), 2.01(1)–2.037(3), and 2.037(3) Å,
respectively. Density functional theory simulations afforded accurate
gold­(III) coordination geometries for 1–4 (bond distances and angles to within 5% of the X-ray values),
while accurate transition energies were limited to those calculated
in the UV spectral region. The complexes had variable stability in
dimethyl sulfoxide: compound 3 (relatively rigid) was
indefinitely stable, compounds 1 and 2 (conformationally
flexible) slowly demetalated over 30 days, and 4 (extensively
aromatic) formed an insoluble precipitate after 10 days (72 h in an
aqueous buffer). The isoquinolylamido derivative 4 was
sufficiently cytotoxic in the NCI-60 screen to undergo full five-dose
testing. Notably low GI50 (1.8, 2.3, and 3.2 μM)
and IC50 (4.0, 9.8, and 15 μM) values were recorded
for the OVCAR-3, IGROV1, and SW-620 cell lines, respectively. Hierarchical
cluster analysis employing the National Cancer Institute (NCI) data
for known anticancer drugs and 4 revealed that compound 4 is mechanistically identical with the topoisomerase IIα
(Top2) poison zorubicin and statistically similar to the topoisomerase
IB (Top1) poisons camptothecin and 9-methoxycamptothecin. The Top2-catalyzed
decatenation reaction of kinetoplast DNA was studied as a function
of the concentration of 4: the compound acts as an interfacial
poison of Top2 at low concentrations (<1 μM) and a catalytic
inhibitor of the enzyme above 5 μM. Gel mobility shift assays
(plasmid DNA substrate) showed that the catalytic inhibition of Top2
likely correlates with DNA binding by 4 at concentrations
>5 μM. Compound 4 is also a catalytic inhibitor
of Top1 at higher concentrations, consistent with DNA binding by the
complex.