13474-68-5Relevant articles and documents
New aziridine-based inhibitors of cathepsin L-like cysteine proteases with selectivity for the Leishmania cysteine protease LmCPB2.8
Fey, Philipp,Chartomatsidou, Roula,Kiefer, Werner,Mottram, Jeremy C.,Kersten, Christian,Schirmeister, Tanja
, p. 587 - 597 (2018)
In the present work a series of aziridine-2,3-dicarboxylate inhibitors of papain-like cysteine proteases was designed, synthesized and tested. The compounds displayed selectivity for the parasitic protozoon Leishmania mexicana cathepsin L-like cysteine protease LmCPB2.8. The computational methods of homology modelling and molecular docking predicted some significant differences in the S2 pocket of LmCPB2.8 and cruzain, a related enzyme from Trypanosoma cruzi. Due to the presence of Tyr209 in LmCPB2.8 rather than Glu208 in cruzain sterically demanding, lipophilic ester groups (inhibitor 7d, 9d, 12d and 14d) are predicted to occupy the S2 pocket of the Leishmania protease, but do not form favorable interactions in cruzain, which is in common with our experimental results. Further, inhibitor 18 bearing a free carboxylic acid attached to the aziridine moiety showed a time-dependent inhibition of LmCPB2.8 (Ki = 0.41 μM; k2nd = 190,569 M?1 min?1). Docking results suggested a strong ionic interaction with the positively charged His163 of the active site. Biological and theoretical data confirm that the novel selective aziridine-based inhibitors are promising candidates for further optimization as LmCPB2.8 inhibitors.
Structure-activity relationships of trans-substituted-propenoic acid derivatives on the nicotinic acid receptor HCA2 (GPR109A)
Van Veldhoven,Blad,Artsen,Klopman,Wolfram,Abdelkadir,Lane,Brussee,Ijzerman
supporting information; experimental part, p. 2736 - 2739 (2011/06/20)
Nicotinic acid (niacin) has been used for decades as an antidyslipidemic drug in man. Its main target is the hydroxy-carboxylic acid receptor HCA2 (GPR109A), a G protein-coupled receptor. Other acids and esters such as methyl fumarate also interact with the receptor, which constituted the basis for the current study. We synthesized a novel series of substituted propenoic acids, such as fumaric acid esters, fumaric acid amides and cinnamic acid derivatives, and determined their affinities for the HCA2 receptor. We observed a rather restricted binding pocket on the receptor with trans-cinnamic acid being the largest planar ligand in our series with appreciable affinity for the receptor. Molecular modeling and analysis of the structure-activity relationships in the series suggest a planar trans-propenoic acid pharmacophore with a maximum length of 8 ? and out-of-plane orientation of the larger substituents.
Ring-opening of cyclic anhydrides using ionic liquids
Jiang, Dong,Wang, Yuan Yuan,Xu, Yan Nan,Dai, Li Yi
experimental part, p. 167 - 169 (2009/10/15)
Four novel Bronsted acidic ionic liquids with two different acid sites on the imidazolium cations were synthesised and employed as catalysts and solvents for the ring-opening of cyclic anhydrides to synthesise half-esters. The results showed that these novel Bronsted acidic ionic liquids were efficient and recyclable. Good yields, short reaction times and mild reaction conditions were achieved.
