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Using Theory To Reinterpret the Kinetics of Monofunctional Platinum Anticancer Drugs: Stacking Matters
journal contribution
posted on 2018-09-06, 00:00 authored by Daniele Veclani, Andrea Melchior, Marilena Tolazzi, José P. Cerón-CarrascoThe
monofunctional platinum drug phenanthriplatin (phenPt) blocks the replication of cancer cells even if it reacts with only
one guanine base. However, there is still insufficient experimental
data to improve its cytotoxicity and all previously proposed chemical
modifications of the parent structure have resulted in a loss of activity.
We use theoretical tools to illustrate the key steps in the biological
mechanisms of phenPt; that is, its activation in water
and the subsequent attack on DNA. Our simulations suggest that the
measured kinetic parameters, which are based on free nucleobases in
solution, need to be reinterpreted because the self-assembled stacked
reactive adduct formed in the reaction is inaccessible in real DNA.
The constants reported here will help guide future work in the synthesis
of anticancer platinum drugs.
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cancer cellsconstantchemical modificationssolutionmechanismnucleobaseanticancer platinum drugsStacking MattersReinterpretself-assembledguide future workparameteractivationsynthesiscytotoxicityDNAtoolreplicationphenPtreactive adductdatamonofunctional platinum drug phenanthriplatinparent structuresimulationMonofunctional Platinum Anticancer Drugsguanine baseKinetic
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