Z-L-leucine chloromethylketone
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Z-L-leucine chloromethylketone

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Category
CBZ-Amino Acids
Catalog number
BAT-003359
CAS number
52467-54-6
Molecular Formula
C15H20NO3Cl
Molecular Weight
297.78
Z-L-leucine chloromethylketone
IUPAC Name
benzyl N-[(3S)-1-chloro-5-methyl-2-oxohexan-3-yl]carbamate
Synonyms
Z-L-Leu-CMK; (S)-Benzyl (1-Chloro-5-Methyl-2-Oxohexan-3-Yl)Carbamate
Appearance
White powder
Purity
≥ 99% (TLC)
Melting Point
34-37 °C
Storage
Store at 2-8 °C
InChI
InChI=1S/C15H20ClNO3/c1-11(2)8-13(14(18)9-16)17-15(19)20-10-12-6-4-3-5-7-12/h3-7,11,13H,8-10H2,1-2H3,(H,17,19)/t13-/m0/s1
InChI Key
FZWQHSCPNKTIRU-ZDUSSCGKSA-N
Canonical SMILES
CC(C)CC(C(=O)CCl)NC(=O)OCC1=CC=CC=C1
1. The aminopeptidase inhibitor, z-L-CMK, is toxic and induces cell death in Jurkat T cells through oxidative stress
E H Yeo, W L Goh, S C Chow Toxicol Mech Methods. 2018 Mar;28(3):157-166. doi: 10.1080/15376516.2017.1373882. Epub 2017 Sep 11.
The leucine aminopeptidase inhibitor, benzyloxycarbonyl-leucine-chloromethylketone (z-L-CMK), was found to be toxic and readily induce cell death in Jurkat T cells. Dose-response studies show that lower concentration of z-L-CMK induced apoptosis in Jurkat T cells whereas higher concentration causes necrosis. In z-L-CMK-induced apoptosis, both the initiator caspases (-8 and -9) and effector caspases (-3 and -6) were processed to their respective subunits. However, the caspases remained intact in z-L-CMK-induced necrosis. The caspase inhibitor, z-VAD-FMK inhibited z-L-CMK-mediated apoptosis and caspase processing but has no effect on z-L-CMK-induced necrosis in Jurkat T cells. The high mobility group protein B1 (HMGB1) protein was found to be released into the culture medium by the necrotic cells and not the apoptotic cells. These results indicate that the necrotic cell death mediated by z-L-CMK at high concentrations is via classical necrosis rather than secondary necrosis. We also demonstrated that cell death mediated by z-L-CMK was associated with oxidative stress via the depletion of intracellular glutathione (GSH) and increase in reactive oxygen species (ROS), which was blocked by N-acetyl cysteine. Taken together, the results demonstrated that z-L-CMK is toxic to Jurkat T cells and induces apoptosis at low concentrations, while at higher concentrations the cells die of necrosis. The toxic side effects in Jurkat T cells mediated by z-L-CMK are associated with oxidative stress via the depletion of GSH and accumulation of ROS.
2. Serine protease inhibitors N-alpha-tosyl-L-lysinyl-chloromethylketone (TLCK) and N-tosyl-L-phenylalaninyl-chloromethylketone (TPCK) are potent inhibitors of activated caspase proteases
Ivo Frydrych, Petr Mlejnek J Cell Biochem. 2008 Apr 1;103(5):1646-56. doi: 10.1002/jcb.21550.
Serine protease inhibitors N-alpha-tosyl-L-lysinyl-chloromethylketone (TLCK) and N-tosyl-L-phenylalaninyl-chloromethylketone (TPCK) exhibit multiple effects on cell death pathways in mammalian cells. Thus, they are able to induce apoptosis by itself or promote cell death induced by other cytotoxic stimuli [King et al., 2004; Murn et al., 2004]. On the other hand, TLCK and TPCK were reported to prevent apoptosis by inhibiting the processing of caspases in response to some cell death inducing stimuli [Stefanis et al., 1997; Jones et al., 1998]. We observed that the pretreatment of HL-60 cells with TLCK or TPCK diminished caspases 3 and -7 (DEVDase) and caspase-6 (VEIDase) activity in response to various cell death inducing stimuli such as staurosporine (STS), etoposide (ETP), or N6-(2-isopentenyl)adenosine. In addition, TLCK but not TPCK inhibited collapse of mitochondrial transmembrane potential Delta Psi m (delta psi) in dying HL-60 cells. Such effects used to be considered as protective, however, the protection was only presumable since neither TLCK nor TPCK actually prevented cells from death. Our results further indicated that serine protease inhibitors TLCK and particularly TPCK acted as efficient direct inhibitors of mature caspases. Indeed, experiments with human recombinant caspases provided unequivocal evidence that TLCK and TPCK are very potent but non-specific inhibitors of activated caspases, namely caspases 3, -6, and -7. Interestingly, TPCK exhibited similar efficiency towards human recombinant caspases to that found for panspecific caspase inhibitor Boc-D-CMK. Such properties of TLCK and TPCK, previously considered as specific inhibitors of serine proteases, might offer novel consistent explanation for several protective or protective-like effects on apoptotic cells.
3. Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs
Kanchan Anand, John Ziebuhr, Parvesh Wadhwani, Jeroen R Mesters, Rolf Hilgenfeld Science. 2003 Jun 13;300(5626):1763-7. doi: 10.1126/science.1085658. Epub 2003 May 13.
A novel coronavirus has been identified as the causative agent of severe acute respiratory syndrome (SARS). The viral main proteinase (Mpro, also called 3CLpro), which controls the activities of the coronavirus replication complex, is an attractive target for therapy. We determined crystal structures for human coronavirus (strain 229E) Mpro and for an inhibitor complex of porcine coronavirus [transmissible gastroenteritis virus (TGEV)] Mpro, and we constructed a homology model for SARS coronavirus (SARS-CoV) Mpro. The structures reveal a remarkable degree of conservation of the substrate-binding sites, which is further supported by recombinant SARS-CoV Mpro-mediated cleavage of a TGEV Mpro substrate. Molecular modeling suggests that available rhinovirus 3Cpro inhibitors may be modified to make them useful for treating SARS.
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