Robust Structure and Reactivity of Aqueous Arsenous Acid–Platinum(II) Anticancer Complexes

Abstract

Anticancer drugs based on molecular adducts of platinum and arsenic (arsenoplatins) show an unanticipated structure, substitution chemistry, and cellular cytotoxicity. The PtII–AsIII bonds in these complexes are stable in aqueous solution and strongly influence the lability of the trans ligand.

Arsenoplatin-1 Is a Dual Pharmacophore Anticancer Agent

“…[20][21][22] The identification of a novel Pt-As bond in a nanoparticulate delivery system loaded with arsenic trioxide and cisplatin in our lab 13 spurred the development of arsenoplatins (Chart 1). 23 These complexes can be synthesized directly from reaction of arsenic trioxide with cisplatin in a suitable solvent mixture. Arsenoplatins in their structure possess an arsenous acid moiety covalently linked to platinum(II) center with an unusual five coordinate As(III)geometry.…”

“…AP-1 is stable in phosphate buffer saline, saline, DMSO, and methanol solutions for over 48 hours (Figures S1 and S2). 195 Pt NMR studies of AP-1 dissolved in DMSO 23 or methanol reveal that the Pt-Cl bond remains intact in both solvents ( Figure S3 and Table S1). Unlike cisplatin, which is prone to solvolysis in DMSO solution at longer times 24 AP-1, oxaliplatin, and carboplatin are stable in neat DMSO 25 .…”

“…Analytical studies of AP-1/DNA adducts in the triple negative breast MDA-MB-231 cancer cell line are consistent with a model in which the gradual release of As(OH) 2 moiety in the cellular milieu contributes to the increased toxicity of arsenoplatin-1 compared to cisplatin. Intriguingly, arsenoplatin compounds, AP-1 and AP-2 23 , also satisfy the Lipinski rule of five used to predict not only the permeability through the cell membrane, but also the overall drug-likeness (Table S5). 42 Taken together, these data suggest that arsenoplatin-1 acts as a unique and dual pharmacophore anti-cancer agent which has the potential to simultaneously deliver platinum and arsenic species to a variety of hematological and solid cancers.…”

Arsenoplatin-Ferritin Nanocage: Structure and Cytotoxicity

“…Given these promising results, a new class of metal compounds containing a PtAs core has been designed [ 15 ]. Arsenoplatin-1 ([Pt(µ-NHC(CH 3 )O) 2 ClAs(OH) 2 ]), also called AP-1 ( Figure 1 ), is the most representative member of this class.…”

Speciation, Metabolism, Toxicity, and Protein-binding of Different Arsenic Species in Human Cells

“…1.8) in the hopes of developing a therapeutic agent that is more suitable to treat refractory malignancies. 95 Arsenoplatin-1was found to be more cytotoxic in certain cancer lines than cisplatin. Moreover, in cisplatin resistant cells it was two times more cytotoxic than cisplatin itself and the development of cross resistance between the two drugs has not been observed.…”