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Title

2-Aminohydroxamic acid derivatives as inhibitors of Bacillus cereus phosphatidylcholine preferred phospholipase C PC-PLCBc

AuthorsGonzález-Bulnes, Patricia; González-Roura, Albert; Canals, Daniel; Delgado, Antonio; Casas, Josefina; Llebaria, Amadeu
KeywordsPhospholipase C
Bacillus cereus
2-Aminohydroxamic acids
Trimethylammonium
Choline lipids
Inhibitors
Issue Date2010
PublisherElsevier
CitationBioorganic and Medicinal Chemistry
AbstractPhosphatidylcholine preferring phospholipase C (PC-PLC) is an important enzyme that plays a key role in a variety of cellular events and lipid homoeostases. Bacillus cereus phospholipase C (PC-PLCBc) has antigenic similarity with the elusive mammalian PC-PLC, which has not thus far been isolated and purified. Therefore the discovery of inhibitors of PC-PLCBc is of current interest. Here, we describe the synthesis and biological evaluation of a new type of compounds inhibiting PC-PLCBc. These compounds have been designed by evolution of previously described 2-aminohydroxamic acid PC-PLCBc inhibitors that block the enzyme by coordination of the zinc active site atoms present in PC-PLCBc [Gonzalez-Roura, A.; Navarro, I.; Delgado, A.; Llebaria, A.; Casas, J. Angew. Chem. Int. Ed.2004, 43, 862]. The new compounds maintain the zinc coordinating groups and possess an extra trimethylammonium function, linked to the hydroxyamide nitrogen by an alkyl chain, which is expected to mimic the trimethylammonium group of the phosphatidylcholine PC-PLCBc substrates. Some of the compounds described inhibit the enzyme with IC50’s in the low micromolar range. Unexpectedly, the most potent inhibitors found are those that possess a trimethylammonium group but have chemically blocked the zinc coordinating functionalities. The results obtained suggest that PC-PLCBc inhibition is not due to the interaction of compounds with the phospholipase catalytic zinc atoms, but rather results from the inhibitor cationic group recognition by the PC-PLCBc amino acids involved in choline lipid binding.
Publisher version (URL)http://dx.doi.org/10.1016/j.bmc.2010.10.031
URIhttp://hdl.handle.net/10261/46904
DOI10.1016/j.bmc.2010.10.031
ISSN0968-0896
E-ISSN1464-3391
Appears in Collections:(IQAC) Artículos
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