741280-49-9Relevant academic research and scientific papers
Design, synthesis, and enzymatic evaluation of N1-acyloxyalkyl- and N1-oxazolidin-2,4-dion-5-yl-substituted β-lactams as novel inhibitors of human leukocyte elastase
Moreira, Rui,Santana, Ana Bela,Iley, Jim,Neres, Jo?o,Douglas, Kenneth T.,Horton, Peter N.,Hursthouse, Michael B.
, p. 4861 - 4870 (2007/10/03)
Human leukocyte elastase (HLE) is a serine protease that very efficiently degrades various tissue matrix proteins such as elastin. The imbalance between HLE and its endogenous inhibitors leads to excessive elastin proteolysis and is considered to be respo
Kinetics and Mechanism of Hydrolysis of N-Acyloxymethyl Derivatives of Azetidin-2-one
Valente, Emilia,Gomes, Jose R. B.,Moreira, Rui,Iley, Jim
, p. 3359 - 3367 (2007/10/03)
The pH-independent, acid-catalyzed and base-catalyzed hydrolyses of N-acyloxymethylazetidin-2-ones all occur at the ester function. The pH-independent hydrolysis involves rate-limiting alkyl C-O fission and formation of an exocyclic β-lactam iminum ion. This iminium ion is then trapped by water at the exocyclic iminium carbon atom, rather than at the β-lactam carbonyl carbon atom, to form the corresponding N-hydroxymethylazetidin-2-ones. Calculations carried out at the B3LYP/6-31+G(d) level of theory also support that nucleophilic attack by water takes place at the exocyclic carbon rather than at the β-lactam carbonyl carbon of the iminium ion. The mechanism for the acid-catalyzed pathway involves a preequilibrium protonation, probably at the β-lactam nitrogen, followed by rate-limiting alkyl C-O fission with formation of an exocyclic iminum ion. The base-catalyzed hydrolysis involves rate-limiting hydroxide attack at the ester carbonyl carbon. These results imply formation of a β-lactam system containing a positively charged amide nitrogen atom that hydrolyzes via a pathway that preserves the β-lactam structure in the product and provide further evidence that cleavage of the β-lactam C-N bond is not as facile as is commonly imagined.
Design, synthesis and stability of N-acyloxymethyl- and N-aminocarbonyloxymethyl-2-azetidinones as human leukocyte elastase inhibitors
Clemente,Domingos,Grancho,Iley,Moreira,Neres,Palma,Santana,Valente
, p. 1065 - 1068 (2007/10/03)
A series of N-acyloxymethyl- and N-aminocarbonyloxymethyl derivatives of 2-azetidinones, 3, with different substituent patterns at the β-lactam C-3 and C-4 positions, were designed as potential mechanism-based inhibitors for human leukocyte elastase and f
