Anticancer Activity, Reduction Mechanism and G-Quadruplex DNA Binding of a Redox-Activated Platinum(IV)–Salphen Complex

Abstract

Aiming at reducing the unselective cytotoxicity of Pt(II) chemotherapeutics, a great deal of effort has been concentrated into the design of metal-containing drugs with different anticancer mechanisms of action. Inert Pt(IV) prodrugs have been proposed to be a valid alternative as they are activated by reduction directly into the cell releasing active Pt(II) species. On the other hand, a promising strategy for designing metallodrugs is to explore new potential biological targets rather than canonical B-DNA. G-quadruplex nucleic acid, obtained by self-assembly of guanine-rich nucleic acid sequences, has recently been considered an attractive target for anticancer drug design. Therefore, compounds capable of binding and stabilizing this type of DNA structure would be greatly beneficial in anticancer therapy. Here, computational analysis reports the mechanism of action of a recently synthesized Pt(IV)–salphen complex conjugating the inertness of Pt(IV) prodrugs with the ability to bind G-quadruplexes of the corresponding Pt(II) complex. The reduction mechanism of the Pt(IV) complex with a biological reducing agent was investigated in depth by means of DFT, whereas classical MD simulations were carried out to shed light into the binding mechanism of the released Pt(II) complex. The results show that the Pt(IV) prodrug may be reduced by both inner- and outer-sphere mechanisms, and the active Pt(II) complex, as a function of its protonation state, stabilizes the G-quadruplex DNA prevalently, either establishing π-stacking interactions with the terminal G-tetrad or through electrostatic interactions along with H-bonds formation.

The current status in computational exploration of Pt(iv) prodrug activation by reduction

“…68 In the theoretical exploration, to reduce the computational effort, the complex structure has been simplified by replacing piperidine groups with hydrogen atoms and named Pt IV –Sal (Scheme 6). 67 The mechanisms of action of these two types of complexes will be separately addressed and discussed on the basis of the employed RA.…”

“…Despite several studies reported in the literature for the synthesis of Pt IV prodrugs bearing chlorido ligands in axial positions, only for a few of them has a detailed computational investigation been carried out to clarify the mode of release of the square-planar Pt II active species. 47,48,52,66,67 Among these, three examples have been selected that can be useful for elucidating the real mechanism of Pt IV complex reduction. Two of them are classical Pt IV -based complexes of the type [Pt(N^N)Cl 4 ], with N^N = ethylenediamine, diaminocyclohexane (tetraplatin in Scheme 1), whose activity, once reduced, remains that of classical Pt II complexes: hydrolysis and DNA platination.…”

G-quadruplex DNA selective targeting for anticancer therapy: a computational study of a novel PtII monofunctional complex activated by adaptive binding

“…In the MD1 simu-lation, the complex nearly aligns with the potassium ion channel as observed previously for other metal complexes. [51][52][53] Modeling depicts a different scenario for MD2, as in this case,…”

Promising Anticancer Prodrugs Based on Pt(IV) Complexes with Bis-organosilane Ligands in Axial Positions

“…The canonical mechanism of reduction of Pt­(IV) complexes involves the loss of the ligands in axial positions, rendering the divalent form capable of interacting with DNA and eventually eliciting the activation of apoptotic pathways. ,− The rate of reduction is strongly dependent on the nature of the ligands bound to the Pt center, with the axial ligands exerting the stronger influence. , Thus, based on the reduction potentials, Pt­(IV) complexes with chloride axial ligands suffer faster reduction than carboxylate or hydroxo species . However, some Pt­(IV) complexes with carbamate axial ligands show faster reduction than their carboxylate derivatives .…”