Phenanthriplatin
(PtPPH) is a monovalent platinum(II)-based complex
with a large cytotoxicity against cancer cells. Although the aqua-activated
drug has been assumed to be the precursor for DNA damage, it is still
under debate whether the way in which that metallodrug attacks to
DNA is dominated by a direct binding to a guanine base or rather by
an intercalated intermediate product. Aiming to capture the mechanism
of action of PtPPH, the present contribution used theoretical tools
to systematically assess the sequence of all possible mechanisms on
drug activation and reactivity, for example, hydrolysis, intercalation,
and covalent damage to DNA.
Ab initio
quantum mechanical
(QM) methods, hybrid QM/QM′ schemes, and independent gradient
model approaches are implemented in an unbiased protocol. The performed
simulations show that the cascade of reactions is articulated in three
well-defined stages: (i) an early and fast intercalation of the complex
between the DNA bases, (ii) a subsequent hydrolysis reaction that
leads to the aqua-activated form, and (iii) a final formation of the
covalent bond between PtPPH and DNA at a guanine site. The permanent
damage to DNA is consequently driven by that latter bond to DNA but
with a simultaneous π–π intercalation of the phenanthridine
into nucleobases. The impact of the DNA sequence and the lateral backbone
was also discussed to provide a more complete picture of the forces
that anchor the drug into the double helix.