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Identification of Platinum(II) Sulfide Complexes Suitable as Intramuscular Cyanide Countermeasures
Behymer, Matthew M. ; Mo, Huaping ; Fujii, Naoaki , et al. Chem. Res. Toxicol.,2022,35(11):1983-1996. DOI: 10.1021/acs.chemrestox.2c00157 PubMed ID: 36201358
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Abstract: The development of rapidly acting cyanide countermeasures using i.m. 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 DMSO (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 NaPtCl5-DMSO and Na (NH3)2PtCl-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 ED. Data are presented to support a general chem. design approach that can expand a new lead candidate series for developing next-generation cyanide countermeasures.
Purchased from AmBeed: 65-82-7 ; 15663-27-1 ; 18542-42-2 ; 1187-84-4 ; 63-68-3 ; 16120-92-6 ; 4104-45-4
CAS No. : | 63-68-3 | MDL No. : | |
Formula : | C5H11NO2S | Boiling Point : | - |
Linear Structure Formula : | CH3SC2H4CH(NH2)CO2H | InChI Key : | FFEARJCKVFRZRR-BYPYZUCNSA-N |
M.W : | 149.21 | Pubchem ID : | 6137 |
Synonyms : |
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Chemical Name : | (S)-2-Amino-4-(methylthio)butanoic acid |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P501-P270-P264-P301+P312+P330 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
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* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; sodium hydrogencarbonate; ethyl acetate; | (S)-2-Benzyloxycarbonylamino-4-methylsulfanyl-butyric acid methyl ester (59) L-methionine (3.70 g, 18.5 mmol) was dissolved in a biphasic mixture of EtOAc (75 mL) and water (75 mL). This was cooled in ice and sodium hydrogen bicarbonate (7.78 g, 5 equiv) and benzyl chloroformate (2.98 mL, 1.1 equiv) were added. This was stirred in ice for one h and then at rt for a further eighteen h before the mixture was allowed to partition. The organic phase was washed sequentially with 1M hydrochloric acid, saturated aqueous sodium hydrogen bicarbonate and brine before being dried (MgSO4), filtered and concentrated in vacuo to afford a yellow oil, 5.40 g, 98%. 1H-NMR (500 MHz in CDCl3) 7.29 (5H, m, Ar-H), 5.79 (1H, d J=7.9 Hz, NH), 5.08 (2H, s, CH2Ph), 4.43-4.47 (1H, m, CHCO2CH3), 3.70 (3H, s, CHCO2CH3), 2.49 (2H, dd J=7.4 Hz, J=7.4 Hz, CHCH2CH2S), 2.11 (1H, ddd J=7.2 Hz, J=12.8 Hz, J=14.4 Hz, CHCH2CH2S), 2.04 (3H, s, SCH3), 1.93 (1H, ddd J=7.1 Hz, J=7.1 Hz, J=14.4 Hz, CHCH2CH2S). LRMS (ES) 298.1 (MH+). C14H19NO4S requires 298.1. |
Yield | Reaction Conditions | Operation in experiment |
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In aq. buffer; at 37℃;pH 7.3; | General procedure: <strong>[1236199-60-2]NL-101</strong> (0.03 g) was incubated with amino acids (0.02 g) and peptides (0.03 g) at 37 oC in a buffer solution, which pH was 5.3,7.3 and 9.3 respectively as the experimental surroundings. The pH of the samples was determined by a pH-meter (FE 20, MettlerToledo). All samples were kept at -20 oC until further analysis. The desalting step of the <strong>[1236199-60-2]NL-101</strong> adducts obtained under theexperimental conditions was not carried out before MS analysis. |
A170637[ 348-67-4 ]
(R)-2-Amino-4-(methylthio)butanoic acid
Reason: Optical isomers
A2667840[ 348-67-4 ]
(R)-2-Amino-4-(methylthio)butanoic acid
Reason: Optical isomers