Using Theory To Reinterpret the Kinetics of Monofunctional Platinum Anticancer Drugs: Stacking Matters

Abstract

The 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.

Rationalization of the Superior Anticancer Activity of Phenanthriplatin: An In‐Depth Computational Exploration

“…Indeed, when the phenanthridine ring is oriented parallel to guanineafavorable p-p interaction stabilizes the adduct formed between the complexa nd the base, whereas the energy of the corresponding transition state does not change, with ac onsequent increase of the barrierh eight. Our calculations, as shown in Figure 2b,c onfirm that the height of the barriert hat is necessary to overcome increases and becomes 19.1 kcal mol À1 .T he authors, however,c laim that such arrangement is inaccessible in the real environment as, on the basis of computational outcomes, [17] during DNA platination the phenanthridine ring is oriented outward from the double helix and is not intercalated between two base pairs.…”

“…However, the value of 14.0 kcal mol −1 , or eventually 16.3 kcal mol −1 , calculated for Phen is lower than the barrier experimentally estimated by Lippard and co‐workers that is 23.5 kcal mol −1 . Such discrepancy has been rationalized by Cerón‐Carrasco and co‐workers as a consequence of the particular more stable arrangement adopted by the isolated base in the experiments. Indeed, when the phenanthridine ring is oriented parallel to guanine a favorable π–π interaction stabilizes the adduct formed between the complex and the base, whereas the energy of the corresponding transition state does not change, with a consequent increase of the barrier height.…”

Which Stereoinductor Is Better for Asymmetric Functionalization of α‐Amino Acids in a Nickel(II) Coordination Environment? Experimental and DFT Considerations

“…The 3D structure of a molecule is determined not only by its basic structural network, which is defined by covalent bonding, but also by noncovalent interactions. Intricate noncovalent interactions govern many areas of biology and chemistry, including the design of new materials and drugs . Weak noncovalent interactions encompass hydrogen bonding, dipole–dipole interactions, steric repulsion, and London dispersion forces.…”

Theoretical Prediction of Dual-Potency Anti-Tumor Agents: Combination of Oxoplatin with Other FDA-Approved Oncology Drugs

“…The resulting structures were fully optimized at the B3LYP-D3 theory level, which consisted of Becke’s three-parameter hybrid exchange functional (B3); the correlation functional of Lee, Yang and Parr (LYP); and Grimme’s dispersion contribution term [ 29 , 30 , 31 ]. That approach has been shown to provide reliable results for the thermochemistry and kinetics of Pt-based compounds [ 32 , 33 ]. The def2-SVP basis set was used to describe all the atoms, except the Pt centers, where the core electrons were replaced with the effective core potentials def2-ECP to account for scalar relativistic effects without increasing the computational cost [ 34 , 35 ].…”