Identification of Platinum(II) Sulfide Complexes Suitable as Intramuscular Cyanide Countermeasures
Matthew M Behymer1, Huaping Mo2, Naoaki Fujii2
1Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana47907, United States.
Chemical Research in Toxicology
|October 6, 2022
Summary
New platinum-based compounds show promise as rapidly acting cyanide antidotes for mass casualty events. These agents are effective via intramuscular injection, offering a potential breakthrough in emergency medicine.
Area of Science:
- Chemical biology
- Toxicology
- Medicinal chemistry
Background:
- Intramuscular injection (IM) cyanide antidotes are needed for mass casualty events.
- Platinum(II) and platinum(IV) agents show efficacy against cyanide toxicity.
- Dimethyl sulfoxide (DMSO) formulations were previously required for platinum-based cyanide antidotes.
Purpose of the Study:
- To develop novel, rapidly acting cyanide countermeasures for IM administration.
- To investigate platinum complexes with enhanced cyanide scavenging properties.
- To establish a chemical design strategy for next-generation cyanide antidotes.
Main Methods:
- Synthesized and tested isolated platinum-sulfoxide complexes.
- Evaluated alternative platinum(II) complexes with sulfide and amine ligands.
- Assessed antidote efficacy in zebrafish, mouse, and rabbit models via IM injection.
- Determined cyanide addition product stoichiometry and cardiotoxicity.
Main Results:
- Isolated platinum-sulfoxide complexes showed enhanced reactivity and recapitulated in vivo rescue.
- New platinum(II) complexes with sulfide/amine ligands demonstrated superior IM efficacy over DMSO formulations.
- No acute cardiotoxicity was observed in zebrafish with Pt(II) complexes at high doses.
- These novel agents offer significantly improved potency and safety profiles.
Conclusions:
- A general chemical design approach using platinum complexes with sulfur-containing ligands is effective for cyanide countermeasures.
- Novel platinum(II) bidentate complexes represent promising candidates for next-generation IM cyanide antidotes.
- This research provides a pathway for developing robust and rapidly acting cyanide mitigation strategies.
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