Arsenoplatin-1 Is a Dual Pharmacophore Anticancer Agent

Abstract

Arsenoplatins are adducts of two chemically important anticancer drugs, cisplatin and arsenic trioxide, that have a Pt(II) bond to an As(III) hydroxide center. Screens of the NCI-60 human tumor cell lines reveal that arsenoplatin-1 (AP1), [Pt(μ-NHC(CH 3)O) 2 ClAs(OH) 2 ], the first representative of this novel class of anti-cancer agents, displays a superior activity profile relative to the parent drugs As 2 O 3 or cisplatin in majority of cancer cell lines tested. These activity profiles are important because the success of arsenic trioxide in blood cancers (such as APL) has not been seen in solid tumors due to the rapid clearance of arsenous acid from the body. To understand the biological chemistry of these compounds, we evaluated interactions of AP-1 with the two important classes of biomolecules-proteins and DNA. The first structural studies of AP-1 bound to model proteins reveal that platinum(II) binds the Nε of His in a manner that preserves the Pt-As bond. We find that AP-1 readily enters cells and binds to DNA with an intact Pt-As bond (Pt:As ratio of 1). At longer incubation times, however, the Pt:As ratio in DNA samples increases, suggesting that the Pt-As bond breaks and releases the As(OH) 2 moiety. We conclude that

Reactivity of arsenoplatin complex versus water and thiocyanate: a DFT benchmark study

“…Indeed, arsenoplatin, an adduct bearing a square-planar Pt(II) center resembling the coordinative structure of cisplatin coordinated by an arsenic trioxide moiety [13], shows a synergistic effect of its two components, displaying an antitumor activity superior to both parent drugs As 2 O 3 and cisplatin in the majority of cell lines [13,14].…”

“…The mechanism of action of AP is still unclear, and different hypotheses have been proposed on the basis of its reactivity with cell DNA and model proteins [13]. The presence of an easily removable chloride on Pt(II), as in most Pt-based anticancer compounds, suggests that AP could easily undergo hydrolysis followed by the facile binding of the resulting aquo complex to a DNA nucleobase to give monofunctional adducts.…”

An anticancer gold(III)-activated porphyrin scaffold that covalently modifies protein cysteine thiols

“…gold | porphyrin | ligand reactivity | cysteine thiol conjugation | antitumor agents T ransition metal complexes can be developed to display effective anticancer therapeutic properties by the judicious choice/combination of metal ions and coordination ligands (1)(2)(3)(4)(5)(6)(7)(8). The mechanisms of cytotoxic action of many anticancer metal complexes are usually attributable to 3 modes: 1) the coordination of metal ions to biomolecules via ligand exchange reactions, with notable examples being the formation of the platinum-DNA adducts of cisplatin (1) and gold-thiol/selenol adducts of gold(I) phosphine compounds such as auranofin (9).…”

Arsenoplatin-Ferritin Nanocage: Structure and Cytotoxicity

“…Indeed, AP-1 shows a higher cytotoxicity with respect to As2O3 and cisplatin on many cancer cell lines. It is able to bind proteins and DNA [17]; upon binding to DNA AP-1 releases the As(OH)2 moiety over time [17]. Thanks to the promising properties of AP-1, it is useful to evaluate if it is possible to improve its performances by encapsulation within a nanocarrier.…”