Modulation of the chemical and biological properties of trans platinum complexes: monofunctional platinum complexes containing one nucleobase as potential antiviral chemotypes

Abstract

Replacement of one of the chloride leaving groups in trans-[PtCl2(NH3)(L)] by the nucleobase 9-ethylguanine gives the nucleobase cations [SP-4-2]-[PtCl(9-ethylguanine)(NH3)(L)]+ (L = NH3, 1; L = quinoline, 3), which are models for the monofunctional adduct on DNA. Displacement of Cl- in 1 and 3 by either 5'-guanosine monophosphate (5'-GMP) or N-acetyl-L-methionine (N-AcMet) showed clear kinetic preference for the sulfur (estimated half-lives of 1.5 and 4 h with N-AcMet against 7 and 17 h for 5'-GMP for 1 and 3, respectively). To further examine the kinetic preference, 1-methylcytosine (1-MeCyt) analogs were prepared, [SP-4-2]-[PtCl(1-Me-Cyt)(NH3)(L)]+ (L=NH3, 2; L=quinoline, 4). The -MeCyt compounds, 2 and 4, resulted in slower rates of substitution by both 5'-GMP and N-AcMet in comparison to 1 and 3 (estimated half-lives for N-AcMet of 5 and 13.5 h and for 5'-GMP of 6 and 14 h for 2 and 4, respectively). Interestingly in this case, however, no selectivity for the sulfur site was observed, a possible explanation being that molecular recognition across the square plane enhances the rate of reaction with 5'-GMP. The affinity of 3 towards S-donor ligands was exploited to remove zinc from the zinc-finger site of the C-terminal finger of the HIV-nucleocapsid protein, NCp7. The ability to eject zinc further suggested the biological antiviral application of [SP-4-2]-[PtCl(nucleobase)(NH3)(L)]+. A preliminary survey against HIV and herpes viruses indeed showed encouraging results with some antiviral specificity, dependent on the exact nature of the compound. The initial results suggest consideration of [SP-4-2]-[PtCl(nucleobase)(NH3)(L)]+ as a novel antiviral chemotype.

Zinc finger proteins as templates for metal ion exchange: Substitution effects on the C-finger of HIV nucleocapsid NCp7 using M(chelate) species (M = Pt, Pd, Au)

“…Clearly the issues of both protein selectivity and consequently cellular selectivity (cytotoxicity versus inhibition of viral infectivity) are critical parameters in development of agents with useful antiviral activity. In this respect, it is axiomatic that the zinc finger modifications observed here are likely to lead to loss of protein function, as suggested previously [5,6]. The fact that [AuCl(dien)] + is cytotoxic whereas [PtCl(dien)] + is not suggests that systematic studies of metal complexes with new targets (e.g.…”

“…Such chemistry may be implicated in the antiviral activity of this class of compounds [6]. Finally, novel mechanisms of action of medicinal inorganic compounds have been proposed based on the interaction with diverse zinc finger proteins of aurothiomalate [7] and most recently antimonates [8].…”

Enhancement of the physicochemical properties of [Pt(dien)(nucleobase)]2+ for HIVNCp7 targeting

“…Nevertheless, it is of interest to briefly compare in vitro inhibition of infectivity of the prototype [Pt(dien)(9-EtGua)] 2+ with the compound SP -4-2-[PtCl(NH 3 )(9-EtGua)(quinoline)] + which displayed modest anti-HIV activity. 55 For comparison, exploratory activity of [Pt(dien)(9-EtGua)] 2+ against HIV-1 strains BaL, NL4-3 and 91-US001 strains in peripheral mononuclear blood (PBMC) cells showed only modest HIV inhibitory activity for the latter with an IC 50 = 28.61 μM (Roger Ptak, personal communication). A number of extra factors come into play when considering cellular properties – amongst them the overall stability of the complex in blood and other non-selective interactions.…”

Interaction of cisplatin with a CCHC zinc finger motif

“…We used PAR to qualitatively demonstrate zinc ejection from this CCHC nucleocapsid zinc finger as previously reported . PAR is a tridentate ligand forming ML 2 ‐type complexes with Zn(II) and other transition metals and is used to measure micromolar concentrations of these metals .…”

“…These authors demonstrated that, upon binding to cisplatin, CCCC and CCHC zinc finger domains release zinc ions, undergoing dramatic structural modifications. Other studies have shown that trans ‐platinum derivatives are capable of ejecting zinc ion from a CCHC‐type zinc finger domain of the HIV‐1 nucleocapsid protein (NCp7) and exerting antiretroviral activity . It is worth noting that CCHC zinc binding domains with very high amino acid sequence and functional homology to corresponding domains of retroviral nucleocapsid proteins are present in CNBPs, also known as CCHC‐type zinc finger CNBPs .…”