Redox activation of metal-based prodrugs as a strategy for drug delivery

Abstract

This review provides an overview of metal-based anticancer drugs and drug candidates. In particular, we focus on metal complexes that can be activated in the reducing environment of cancer cells, thus serving as prodrugs. There are many reports of Pt and Ru complexes as redox-activatable drug candidates, but other d-block elements with variable oxidation states have a similar potential to serve as prodrugs in this manner. In this context are compounds based on Fe, Co, or Cu chemistry, which are also covered. A trend in the field of medicinal inorganic chemistry has been toward molecularly targeted, metal-based drugs obtained by functionalizing complexes with biologically active ligands. Another recent activity is the use of nanomaterials for drug delivery, exploiting passive targeting of tumors with nanosized constructs made from Au, Fe, carbon, or organic polymers. Although complexes of all of the above mentioned metals will be described, this review focuses primarily on Pt compounds, including constructs containing nanomaterials.

Interactions of arene ruthenium metallaprisms with human proteins

“…The proteins human serum albumin, transferrin, myoglobin, ubiquitin and cytochrome c were obtained from Sigma Aldrich. The arene ruthenium metallaprisms [1] 6 in 0.05 mL D 2 O with 0.1 equivalent of the proteins. All reactions were monitored by 1D 1 H NMR spectroscopy over a time period of up to 96 h. All experiments were undertaken at pD = 7, i.e.…”

“…NMR data were acquired at a temperature of 37°C using a Bruker AvanceII 500 MHz NMR spectrometer, equipped with an inverse 1.7 mm triple channel ( 1 H, 31 P, 13 C) z-gradient 6 ) in 1 mL H 2 O, were incubated with the selected protein at a 10 : 1 molar ratio for 48 h at 37°C. Then, all samples were analysed using various matrices depending on the protein.…”

“…All experiments were measured using a Hellma Suprasil R 100-QS 0.1 cm cuvette. The metallaprisms [1](CF 3 SO 3 ) 6 - [3](CF 3 SO 3 ) 6 and the proteins were dissolved in H 2 O and incubated for 48 h before data collection. For each sample, the mixture was scanned three times using a rate of 50 nm min −1 at 20°C.…”

“…3,4 The increased selectivity represents the most important feature of the newly developed drugs in order to minimize side effects and to prevent the development of resistance mechanisms. 5,6 As emphasized in the literature, in order to successfully design and develop new and selective metal-based drugs, it is of the highest importance to understand the mode of action of established and also of newly developed anticancer drugs. 7,8 Among the new generation of metal-based drugs, ruthenium derivatives appear to be quite promising.…”

“…Our previous work describing the reactivity of the metallaprisms [( p-cymene) 6 [3] 6+ , with in some cases the formation of degradation products, especially in the presence of basic amino acids (Arg, His and Lys). [33][34][35] For this reason, interactions can be expected with proteins, especially with ubiquitin.…”