46119-06-6Relevant academic research and scientific papers
4-Hydroxy-7-oxo-5-heptenoic acid lactone can induce mitochondrial dysfunction in retinal pigmented epithelial cells
Ayyash, Naji,Cheng, Yu-Shiuan,Gardella, Anthony,Li, Haoting,Linetsky, Mikhail,Salomon, Robert G.
, p. 719 - 733 (2020/10/02)
Oxidation of docosahexaenoate (DHA)-containing phospholipids in the cell plasma membrane leads to release of the α,β-unsaturated aldehyde 4-hydroxy-7-oxo-5-heptenoic acid (HOHA) lactone which is capable of inducing retinal pigmented epithelial (RPE) cell dysfunction. Previously, HOHA lactone was shown to induce apoptosis and angiogenesis, and to activate the alternative complement pathway. RPE cells metabolize HOHA lactone through enzymatic conjugation with glutathione (GSH). Competing with this process is the adduction of HOHA lactone to protein lysyl residues generating 2-(ω-carboxyethyl)pyrrole (CEP) derivatives that have pathological relevance to age-related macular degeneration (AMD). We now find that HOHA lactone induces mitochondrial dysfunction. It decreases ATP levels, mitochondrial membrane potentials, enzymatic activities of mitochondrial complexes, depletes GSH and induces oxidative stress in RPE cells. The present study confirmed that pyridoxamine and other primary amines, which have been shown to scavenge γ-ketoaldehydes formed by carbohydrate or lipid peroxidation, are ineffective for scavenging the α,β-unsaturated aldehydes. Histidyl hydrazide (HH), that has both hydrazide and imidazole nucleophile functionalities, is an effective scavenger of HOHA lactone and it protects ARPE-19 cells against HOHA lactone-induced cytotoxicity. The HH α-amino group is not essential for this electrophile trapping activity. The Nα-acyl L-histidyl hydrazide derivatives with 2- to 7-carbon acyl groups with increasing lipophilicities are capable of maintaining the effectiveness of HH in protecting ARPE-19 cells against HOHA lactone toxicity, which potentially has therapeutic utility for treatment of age related eye diseases.
Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin: Fragment-Based Drug Design Facilitated by Dynamic Combinatorial Chemistry
Mondal, Milon,Radeva, Nedyalka,Fanlo-Virgós, Hugo,Otto, Sijbren,Klebe, Gerhard,Hirsch, Anna K. H.
supporting information, p. 9422 - 9426 (2016/08/05)
Fragment-based drug design (FBDD) affords active compounds for biological targets. While there are numerous reports on FBDD by fragment growing/optimization, fragment linking has rarely been reported. Dynamic combinatorial chemistry (DCC) has become a powerful hit-identification strategy for biological targets. We report the synergistic combination of fragment linking and DCC to identify inhibitors of the aspartic protease endothiapepsin. Based on X-ray crystal structures of endothiapepsin in complex with fragments, we designed a library of bis-acylhydrazones and used DCC to identify potent inhibitors. The most potent inhibitor exhibits an IC50value of 54 nm, which represents a 240-fold improvement in potency compared to the parent hits. Subsequent X-ray crystallography validated the predicted binding mode, thus demonstrating the efficiency of the combination of fragment linking and DCC as a hit-identification strategy. This approach could be applied to a range of biological targets, and holds the potential to facilitate hit-to-lead optimization.
The reaction of optically active α-aminocarboxylic acid hydrazides with triethyl orthoesters
Kudelko, Agnieszka,Zieliński, Wojciech,Ejsmont, Krzysztof
, p. 7838 - 7845 (2011/10/12)
New derivatives of 2-(1-amino-1-phenylmethyl)-1,3,4-oxadiazole and 1,2,4-triazin-6-one were synthesised in the reactions of optically active α-aminocarboxylic acid hydrazides and triethyl orthoesters in xylene. The electronic and steric effects of substituents at the α position influencing the formation of five- or six-membered products are discussed.
