Platinum-Nucleos(t)ide Compounds as Possible Antimetabolites for Antitumor/Antiviral Therapy: Properties and Perspectives

Abstract

Nucleoside analogues (NAs) are a family of compounds which include a variety of purine and pyrimidine derivatives, widely used as anticancer and antiviral agents. For their ability to compete with physiological nucleosides, NAs act as antimetabolites exerting their activity by interfering with the synthesis of nucleic acids. Much progress in the comprehension of their molecular mechanisms has been made, including providing new strategies for potentiating anticancer/antiviral activity. Among these strategies, new platinum-NAs showing a good potential to improve the therapeutic indices of NAs have been synthesized and studied. This short review aims to describe the properties and future perspectives of platinum-NAs, proposing these complexes as a new class of antimetabolites.

Incorporation of N7-Platinated Guanines into Thermus Aquaticus (Taq) DNA Polymerase: Atomistic Insights from Molecular Dynamics Simulations

“…In other words, these molecules hold the promise to be a new class of antitumor/antiviral antimetabolites, products of the merging of the two classes of platinum-based drugs and modified NAs. The suitability of this approach was confirmed by some previously reported studies evaluating the antitumor/antiviral properties of platinum-nucleos(t)ide compounds [ 11 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ].…”

“…In our previous studies, we discovered that Thermus Aquaticus (Taq) and Mitochondrial γ DNA polymerases (see Figure 1 ) can recognize and incorporate the model [Pt(dien)( N7 -dGTP)], complex 1 {dien = diethylenetriamine; dGTP = 5′-(2′-deoxy)guanosine triphosphate, see Scheme 1 }, into synthesized DNA [ 59 , 60 , 61 ], as is generally the case for nucleos(t)ide analogue-based drugs [ 48 ]. This enables site-specific metalation, interference with the metabolism of nucleic acids, and the potential for pharmacological effects [ 59 , 61 , 63 ].…”

Compatibility of Nucleobases Containing Pt(II) Complexes with Red Blood Cells for Possible Drug Delivery Applications

“…Metal-based drugs are a class of compounds that have been extensively studied for their wide range of applications, from anticancer [39][40][41] to antiviral applications [42,43] and for several other disorders [38,44]. The development of metallo-drugs for clinical purposes began with the discovery of the antitumor properties of cisplatin, a platinum(II) derivative, and its FDA approval in 1978 [45].…”

“…Despite the great success of platinum drugs in the clinic for the treatment of several solid tumors, their therapeutic outcomes are still limited by severe side effects, drug resistance, and poor pharmacokinetic properties, which limit the efficacy of these antitumor agents [37]. Thousands of new platinum drug candidates have been synthesized and studied with the aim of reducing drug resistance and drug-induced side effects, improving oral bioavailability, and overcoming inter-individual variability of responses [42,[46][47][48]. Among these, new platinum-based nucleoside analogues derivatives were synthesized [42,43,[49][50][51][52].…”

“…Thousands of new platinum drug candidates have been synthesized and studied with the aim of reducing drug resistance and drug-induced side effects, improving oral bioavailability, and overcoming inter-individual variability of responses [42,[46][47][48]. Among these, new platinum-based nucleoside analogues derivatives were synthesized [42,43,[49][50][51][52]. This new class of compounds has recently been demonstrated to have very interesting properties derived from the combination of those of platinum compounds and nucleoside analogs, with their potential application ranging from antitumor to antiviral use [42].…”