Identification of Platinum(II) Sulfide Complexes Suitable as Intramuscular Cyanide Countermeasures

Abstract

The development of rapidly acting cyanide countermeasures using intramuscular injection (IM) represents an unmet medical need to mitigate toxicant exposures in mass casualty settings. Previous work established that cisplatin and other platinum(II) or platinum(IV)-based agents effectively mitigate cyanide toxicity in zebrafish. Cyanide's in vivo reaction with platinum-containing materials was proposed to reduce the risk of acute toxicities. However, cyanide antidote activity depended on a formulation of platinum-chloride salts with dimethyl sulfoxide (DMSO) followed by dilution in phosphate-buffered saline (PBS). A working hypothesis to explain the DMSO requirement is that the formation of platinum− sulfoxide complexes activates the cyanide scavenging properties of platinum. Preparations of isolated NaPtCl 5 −DMSO and Na (NH 3 ) 2 PtCl−DMSO complexes in the absence of excess DMSO provided agents with enhanced reactivity toward cyanide in vitro and fully recapitulated in vivo cyanide rescue in zebrafish and mouse models. The enhancement of the cyanide scavenging effects of the DMSO ligand could be attributed to the activation of platinum(IV) and (II) with a sulfur ligand. Unfortunately, the efficacy of DMSO complexes was not robust when administered IM. Alternative Pt(II) materials containing sulfide and amine ligands in bidentate complexes show enhanced reactivity toward cyanide addition. The cyanide addition products yielded tetracyanoplatinate(II), translating to a stoichiometry of 1:4 Pt to each cyanide scavenger. These new agents demonstrate a robust and enhanced potency over the DMSO-containing complexes using IM administration in mouse and rabbit models of cyanide toxicity. Using the zebrafish model with these Pt(II) complexes, no acute cardiotoxicity was detected, and dose levels required to reach lethality exceeded 100 times the effective dose. Data are presented to support a general chemical design approach that can expand a new lead candidate series for developing next-generation cyanide countermeasures.

Investigating the replacement of carboxylates with carboxamides to modulate the safety and efficacy of platinum(II) thioether cyanide scavengers

“…Complexes 1–3 ( Figure 1 ) were selected for comparative evaluation of formulation stability with suitable efficacy and safety for advanced large animal testing. The complexes 1 and 2 were previously shown to be reactive with cyanide but differences in efficacies were observed in the lethal cyanide exposure models for zebrafish and mouse ( Behymer et al , 2022 ). In fact, the bis -( l - methionine amide) (S,N)platinum(II) dichloride 2 demonstrated a reduction in the cyanide reactivity at a pH near 7 ( Behymer et al , 2022 ).…”

“…Sodium tetracyanoplatinate anhydrous (Na 2 Pt(CN) 4 ) was purchased from Alfa Aesar. Complexes 1–3 with +2NaCl were prepared from K 2 PtCl 4 as described in Behymer et al (2022) .…”

“…Preformulated compounds were added to the wells containing zebrafish at an 8-point dose response curve (1–125 µM), immediately followed by the addition of a lethal dose of cyanide (50 µM). The plates were sealed with adhesive microplate sealing films and incubated at 28°C for 3 h. Heart rate and response to touch was used to assess viability ( Behymer et al , 2022 ). The dose that rescued 100% of the larvae in the well (EC 100 ) was reported.…”

“…C57BL/6 mice were exposed to 587 ppm HCN gas for a total of 40 min as described previously ( Behymer et al , 2022 ; Chan et al , 2015 , 2011 ). After 15 min of HCN exposure, the mice were removed briefly from the exposure chamber and injected intramuscularly with either saline (control animals) or the indicated platinum complex.…”

“…As reported previously, platinum(II) might be an alternative to cobalt which can bind 4 mole equivalents of cyanide ( Nath et al , 2017 ). When administered by IM injection, platinum(II) complexes were efficacious in a mouse cyanide inhalation model at doses as low as 270 µmol/m 2 of platinum ( Behymer et al , 2022 ). These previous studies have demonstrated that platinum(II)-based complexes could offer an IM available agent with high efficacy by increasing binding ratios between metal and cyanide ( Behymer et al , 2022 ).…”