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.

Keywords: antimetabolites; antitumor drugs; antiviral drugs; coordination compounds; nucleoside analogues; platinum compounds.

Figure 1

Schematic representation indicating the most common chemical modifications of nucleobases, nucleosides, and nucleotides suitable to give pharmacologically active antitumor and/or antiviral analogues. Adapted from [2], published by Nature Publishing Group, 2013.

Figure 2

Mechanism of action of NAs. The NAs generally enter cells crossing the cell membrane by an active transport mechanism operated by plasma membrane transporters. Once inside cells, the NAs are progressively phosphorylated and so produce the final triphosphate derivatives.

Figure 3

Schematic representation of cisplatin mechanism of action.

Figure 4

Chemical structure of cationic triamine complexes. A = ammonia; Am = heterocyclic amine based on pyridine, pyrimidine, purine, piperidine, or saturated amine.

Figure 5

Schematic representation of the cis-dichloridoplatinum(II)-N-aminated nucleoside complexes. (a) Pt-cytosine analogues; (b) Pt-guanosine-like derivatives. R = deoxyribosyl, ribofuranosyl, arabinofuranosyl.

Figure 6

Chemical structure of 3-amino-2′-deoxycytidine-dichloridoplatinum(II) and 3-aminocytidine-dichloridoplatinum(II).

Figure 7

Structural formula of adenine, with the preferred coordination sites of platinum to nitrogen evidenced. The atom numbering scheme, for nucleotides, is also reported.

Figure 8

Chemical structure of the cis-K₄[PtCl₂ATP] complex, adapted from [10], published by Nature Publishing Group, 2020.

Figure 9

Schematic representation of the platinum complexes synthesized by Maeda et al.

Figure 10

Chemical structures of model platinum(II) and (IV) nucleoside monoadducts of the type (a) [Pt(DACH)LCl]NO₃ and (b) [Pt(DACH){trans-(Y)₂}LCl]NO₃, respectively. DACH = trans-1R,2R-diaminocyclohexane; L = adenine, guanine, hypoxanthine, cytosine, adenosine, guanosine, inosine, cytidine, 9-ethylguanine, or 1-methylcytosine; Y = OH, acetate.

Figure 11

Schematic representation of the [Pt(dien)(N7-5′-GTP)] and [Pt(dien)(N7-5′-dGTP)], with R = OH and H, respectively.

Figure 12

Schematic representation of the insertion mechanism of platinated nucleotides operated by DNA polymerases, during the synthesis of the complementary DNA chain, in the presence of platinated guanines in the nucleotides cellular pool.

Figure 13

Proposed mechanism of action of platinated nucleos(t)ides.