Photoactivation of trans diamine platinum complexes in aqueous solution and effect on reactivity towards nucleotides

Abstract

We show that UVA irradiation (365 nm) of the Pt IV complex trans,trans,trans-[Pt IV Cl 2 (OH) 2 (dimethylamine)(isopropylamine)], 1, induces reduction to Pt II photoproducts. For the mixed amine Pt II complex, trans-[Pt II Cl 2 (isopropylamine)(methylamine)] (2), irradiation at 365 nm increases the rate and extent of hydrolysis, triggering the formation of diaqua species. Additionally, irradiation increases the extent of reaction of complex 2 with guanosine-5′-monophosphate (GMP) and affords mainly the bis-adduct, while reactions with adenosine-5′-monophosphate (AMP) and cytidine-5′-monophosphate (CMP) give rise only to mono-nucleotide adducts. Density Functional Theory calculations have been used to obtain insights into the electronic structure of complexes 1 and 2, and their photophysical and photochemical properties. UVA-irradiation can contribute to enhanced cytotoxic effects of diamine platinum drugs with trans geometry.

The photochemistry of transition metal complexes using density functional theory

“…Non-toxic precursors can be activated by light excitation to form cytotoxic species that act with novel mechanisms of action. Compared with classical photodynamic therapy sensitizers whose antiproliferative activity relies on the 3 DFT and TD-DFT calculations were used to investigate the singlet and triplet excited states of several Pt(IV) azido derivatives, with both cis and trans geometry, and obtain information on their photochemistry [86][87][88][89][90]. Computational methods have proved insightful and are able to confirm experimental findings (NMR) on the nature of photoproducts [91], obviating to the absence of time-resolved optical data owing to the high reactivity of such systems.…”

Understanding trans platinum complexes as potential antitumor drugs beyond targeting DNA

“…Early adduct formation was clearly promoted, in particular the bisadduct. We think that this behavior is of particular interest, as we can modulate and favor selectively the reactivity of these trans-complexes with model bases and it might be an indication of the high value of these complexes as antitumor drugs [26] (Fig. 4).…”

Laser Photo Chemotherapy: An Alternative Treatment for Cancer

“…An initial report by Nahabedian et al (1988) on photochemotherapy using cisplatin and laser (wavelength 688nm) showed that laser treatment was enhancement by systemic chemotherapy in murine tumors, and was the first in vivo evidence of cisplatin-photo activation by visible light. More recently, the development of photoactivatable prodrugs of platinum-based antitumor agents is aimed at increasing the selectivity and thereby lowering toxicity of this important class of antitumor drugs (Bednarski, 2007;Crescenzi et al, 2004;Mackay et al, 2007;Cubo et al, 2010). Cisplatin forms mainly intrastrand cis-diguanine cross-links on DNA between neighboring nucleotides, whereas photoactivated complex-1 rapidly forms unusual trans azido/guanine, and then trans diguanine Pt(II) adducts, which are probably mainly intrastrand cross-links between two guanines separated by a third base.…”

“…Cell death is not solely dependent on activation of the caspase 3 pathway and, in contrast to cisplatin, p53 protein did not accumulate in cells after photosensitization of photoactivated complex-1. The trans diazido Pt(IV) complex-1 therefore has remarkable properties and is a candidate for use in photoactivated cancer chemotherapy (Cubo et al, 2010). Even though there was a lack of basic science evidence supporting photochemotherapy with cisplatin in the beguining of the eighties, a wealth of clinical investigations followed testing this experimental treatment for cancer.…”