The Chiral Potential of Phenanthriplatin and Its Influence on Guanine Binding

The monofunctional platinum complex cis-[Pt­(NH3)2Cl­(Am)]+,
also known as phenanthriplatin,
where Am is the N-heterocyclic base phenanthridine,
has promising anticancer activity. Unlike bifunctional compounds such
as cisplatin, phenanthriplatin can form only one covalent bond to
DNA. Another distinguishing feature is that phenanthriplatin is chiral.
Rotation about the Pt–N bond of the phenanthridine ligand racemizes
the complex, and the question arises as to whether this process is
sufficiently slow under physiological conditions to impact its DNA-binding
properties. Here we present the results of NMR spectroscopic, X-ray
crystallographic, molecular dynamics, and density functional theoretical
investigations of diastereomeric phenanthriplatin analogs in order
to probe the internal dynamics of phenanthriplatin. These results
reveal that phenanthriplatin rapidly racemizes under physiological
conditions. The information also facilitated the interpretation of
the NMR spectra of small molecule models of phenanthriplatin-platinated
DNA. These studies indicate, inter alia, that one diastereomeric form
of the complexes cis-[Pt­(NH3)2(Am)­(R-Gua)]2+, where R-Gua is 9-methyl- or 9-ethylguanine,
is preferred over the other, the origin of which stems from an intramolecular
interaction between the carbonyl oxygen of the platinated guanine
base and a cis-coordinated ammine. The relevance
of this finding to the DNA-damaging properties of phenanthriplatin
and its biological activity is discussed.