Selected molybdenum sulfur compounds with the formulas (M)[Mo2O2S4L] where (Et4N)2(1), L=S4(2-), (Et4N)(2), L=Cp, (3), L=DMF, K(5), L=serine, M=Et4N(+), K(+), Na(+) and [Mo2O2S2L2] where Na2(4), L=cysteine, and (6), L=threonine, were prepared and subjected to cytotoxicity studies in vitro. The results were analyzed to rank the compounds according to their relative cytotoxicity and to correlate the observed toxicity to specific composition. The results guide future efforts to synthesize highly water soluble, non-toxic, compounds. Strong correlation was observed between toxicity and cation selection, as well as selection of biocompatible ligands combined with alkali metal salts. The most toxic compound analyzed showed about 50 times less cytotoxicity than the cisplatin reference compound in HT-29 cells. Preliminary results from in vivo data agree with the ranking obtained in vitro.

Removal of cyanide as nontoxic thiocyanate under physiological conditions may serve as a catalytic detoxification route in vivo. Aqueous catalytic reaction conditions were explored where at the conditions employed the reaction proceeded to exhaustion in 1 h. The complex, syn-[Mo 2 O 2 (μ-S) 2 (S 2 )(DMF) 3 ] 1, participates in a ligand exchange reaction of the dimethylformamide ligands and cyanide. Simultaneous sulfur abstraction reaction from the terminal disulfide group forms thiocyanate and terminal sulfido ligand. Respective reaction rates for the two reactions appear competitive where different products were isolated solely based on change of reaction temperature. The approach to determine the number of cyanide ligands participating in the ligand exchange reaction by varying the stoichiometry and reaction temperature led to identification and isolation of tetranuclear complexes 2 and 5 and dinuclear complexes 3, 4, and 6. A synthesized and fully characterized thiocyanate analog of 6 (7) supports spectroscopic characterization of 6. The tetranuclear anion, [Mo 4 O 4 (μ-S) 6 (CN) 4 ] 4− , 2, was crystallized from a reaction at ambient temperature. The dinuclear anion, [Mo 2 O 2 (μ-S) 2 (S)(CN) 3 ] 3− , 3, was crystallized from similar reaction conditions at lower temperature. The reaction yield of thiocyanate obtained at pH of 7.4 and at 9.2 as a function of time, for several ratios of cyanide, favors the sulfur abstraction reaction at elevated pH. The sulfur abstraction reaction is the first step in a proposed mechanism of the reaction of cyanide and thiosulfate to form thiocyanate and sulfite by 1.

Water-soluble complexes are desirable for the aqueous detoxification of cyanide. Molybdenum complexes with α-amino acid and disulfide ligands with the formula K­[(L)­Mo2O2(μ-S)2(S2)] (L = leu (1), met (2), thr (3), and ser (4)) were synthesized in a reaction of [(DMF)3MoO­(μ-S)2(S2)] with deprotonated α-amino acids; leu, met, thr, and ser are the carboxylate anions of l-leucine, l-methionine, l-threonine, and l-serine, respectively. Potassium salts of α-amino acids (leu (1a), met (2a), thr (3a), and ser (4a)) were prepared as precursors for complexes 1–4, respectively, by employing a nonaqueous synthesis route. The ligand exchange reaction of [Mo2O2(μ-S)2(DMF)6]­(I)2 with deprotonated α-amino acids afforded bis-α-amino acid complexes, [(L)2Mo2O2(μ-S)2] (6–8). A tris-α-amino acid complex, [(leu)2Mo2O2(μ-S)2(μ-leu + H)] (5; leu + H is the carboxylate anion of l-leucine with the amine protonated), formed in the reaction with leucine. 5 crystallized from methanol with a third weakly bonded leucine as a bridging bidentate carboxylate. An adduct of 8 with SCN coordinated, 9, crystallized and was structurally characterized. Complexes 1–4 are air stable and highly water-soluble chiral molecules. Cytotoxicity studies in the A549 cell line gave IC50 values that range from 80 to 400 μM. Cyclic voltammetry traces of 1–8 show solvent-dependent irreversible electrochemical behavior. Complexes 1–4 demonstrated the ability to catalyze the reaction of thiosulfate and cyanide in vitro to exhaustively transform cyanide to thiocyanate in less than 1 h.

Binuclear molybdenum sulfur complexes are effective for the catalytic conversion of cyanide into thiocyanate. The complexes themselves exhibit low toxicity and high aqueous solubility, which render them suitable as antidotes for cyanide poisoning. The binuclear molybdenum sulfur complex [(thr)­Mo2O2(μ-S)2(S2)]− (thr - threonine) was subjected to biological studies to evaluate its cellular accumulation and mechanism of action. The cellular uptake and intracellular distribution in human alveolar (A549) cells, quantified by inductively coupled plasma mass spectrometry (ICP-MS) and cell fractionation methods, revealed the presence of the compound in cytosol, nucleus, and mitochondria. The complex exhibited limited binding to DNA, and using the expression of specific protein markers for cell fate indicated no effect on the expression of stress-sensitive channel components involved in cell volume regulation, weak inhibition of cell proliferation, no increase in apoptosis, and even a reduction in autophagy. The complex is anionic, and the sodium complex had higher solubility compared to the potassium. As the molybdenum complex possibly enters the mitochondria, it is considered as a promising remedy to limit mitochondrial cyanide poisoning following, e.g., smoke inhalation injuries.

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