35677-89-5Relevant articles and documents
β-Lactones as a new class of cysteine proteinase inhibitors: inhibition of hepatitis A virus 3C proteinase by N-Cbz-serine β-Lactone
Lall, Manjinder S.,Karvellas, Constantine,Vederas, John C.
, p. 803 - 806 (1999)
Formula presented N-Benzyloxycarbonyl-L-serine β-lactone (1) is shown to irreversibly inactivate the 3C cysteine proteinase of hepatitis A virus (HAV) with kinact = 0.70 min-1, KI = 1.84 x 10-4 M and kinact/KI = 3800 M-1 min-1 at an enzyme concentration of 0.1 μM. Mass spectrometric and HMQC NMR studies using 13C-labeled 1 show that the active site cysteine (Cys-172) thiol of the HAV 3C proteinase attacks the β-position (i.e. C-4) of the oxetanone ring, thereby leading to ring opening and alkylation of the sulfur. In contrast, the enantiomer of this β-lactone, 2, is a reversible competitive inhibitor (Ki = 1.50 x 10-6 M) at similar enzyme concentrations. The β-lactone motif represents a new class of inhibitors of cysteine proteinases.
Biological evaluation and docking studies of new carbamate, thiocarbamate, and hydrazide analogues of ACYL homoserine lactones as vibrio fischeri-quorum sensing modulators
Zhang, Qiang,Queneau, Yves,Soulère, Laurent
, p. 1 - 12 (2020/05/25)
A series of carbamate, thiocarbamate, and hydrazide analogues of acylhomoserine lactones (AHLs) were synthesized and their ability to modulate Vibrio fischeri-quorum sensing was evaluated. The compounds in the series exhibit variable side chain length and the possible presence of a diversely substituted phenyl substituent. Biological evaluation on the Vibrio fischeri quorum sensing system revealed that the ethyl substituted carbamate (1) display a weak agonistic activity whereas compounds with longer chain length or benzyl substituents display significant antagonistic activity. The most active compounds in the series were the 4-nitrobenzyl carbamate and thiocarbamate 7 and 11 which exhibited an IC50 value of about 20 μM. These activities are in the range of other reported of AHL-structurally related quorum sensing (QS) inhibitors. Docking experiments conducted on the LuxR model showed that, compared to the natural ligand OHHL, the additional heteroatom of the carbamate group induces a new hydrogen bond with Tyr70 leading to a different global hydrogen-bond network. Tyr70 is an important residue in the binding site and is strictly conserved in the LuxR family. For the 4-nitrobenzyl carbamate and thiocarbamate analogues, the docking results highlight an additional hydrogen bond between the nitro group and Lys178. For hydrazide analogues, which are deprived of any activity, docking shows that the orientation of the carbonyl group is opposite as compared with the natural ligand, leading to the absence of a H-bond between the C=O with Tyr62. This suggests that, either this later interaction, or the influence of the C=O orientation on the overall ligand conformation, are essential for the biological activity.
Concise Synthesis of Enantiomerically Pure (1′S,2′R)-and (1′R,2′S)-2S-Amino-3-(2′-aminomethyl-cyclopropyl)propionic Acid: Two E-Diastereoisomers of 4,5-Methano-l-lysine
Altamore, Timothy M.,Nguyen, Oanh T. K.,Churches, Quentin I.,Cavanagh, Kate,Nguyen, Xuan T. T.,Duggan, Sandhya A. M.,Krippner, Guy Y.,Duggan, Peter J.
, p. 1105 - 1111 (2013/09/24)
A concise synthesis of both E-isomers of 2S-amino-3-(2′-aminomethyl- cyclopropyl)propionic acid, new methano-l-lysines, is described. The synthetic route includes nine steps from l-methionine, with a key step involving the cyclopropanation of an intermediate E-allylic alcohol. The resultant hydroxymethylcyclopropanes were readily separated and converted into the title α-amino acids. The stereochemistry around the cyclopropane rings was deduced by conducting the cyclopropanation in the presence of N,N,N′,N′-tetramethyl-d-tartaric acid diamide butylboronate, a chiral controller which is known to favour the production of S-hydroxymethyl cyclopropanes from allylic alcohols.
