A Potent (R)-alpha-bis-lipoyl Derivative Containing 8-Hydroxyquinoline Scaffold: Synthesis and Biological Evaluation of Its Neuroprotective Capabilities in SH-SY5Y Human Neuroblastoma Cells

Abstract

A novel bis-lipoyl derivative containing 8-hydroxyquinoline scaffold (LA-HQ-LA, 5) was synthesized as a new multifunctional drug candidate with antioxidant, chelant, and neuroprotective properties for the treatment of neurodegenerative diseases. We have investigated the potential effectiveness of LA-HQ-LA against the cytotoxicity induced by 6-OHDA and H2O2 on human neuroblastoma SH-SY5Y cell line. Our outcomes showed that LA-HQ-LA resulted in significant neuroprotective and antioxidant effects against H2O2- and 6-OHDA-induced neurotoxicity in human neuroblastoma SH-SY5Y cells, as assessed by MTT assay. In particular, it showed potent neuroprotective effects against 6-OHDA in RA/PMA differentiated cells at all the tested concentrations.

Ibuprofen-Glutathione Conjugate as Anti-inflammatory and Anti-apoptotic Agent in Rat Brain Infused with β Amyloid (1-40)

“…Although the etiology of AD has not been exhaustively elucidated yet, mitochondrial dysfunction, metal-ion dysregulation, and oxidative stress have been linked to the progressive neurological decline associated with this neurodegenerative disorder [3,[31][32][33]. In oxidative stress conditions, GSH is able to detoxify various oxidants by directly scavenging free radicals and acting as a coenzyme in GSH-peroxidase catalysed reactions and/or chelating agent [6,23,34,35]. Moreover, a recent renewed interest in non-steroidal anti-inflammatory drugs for AD treatment stems from findings suggesting that some NSAIDs (e.g.…”

A Glutathione Derivative with Chelating and in vitro Neuroprotective Activities: Synthesis, Physicochemical Properties, and Biological Evaluation

“…The synthetic strategy employed to obtain compound 6 involved preparation of the suitably protected GSH peptide (5) and then condensation to 5-hydroxymethyl-8-hydroxyquinoline [27] by employing solution phase procedures (Scheme 1). The synthesis of Fmoc-Cys(StBu)-Gly-OMe (2) was achieved in 44 % yield starting from readily available Fmoc-Cys(StBu)-OH (1) and H-Gly-OMe·HCl.…”

“…Deprotection of the cysteine-SH group resulted from treatment of the corresponding protected precursor 4 for 1.5 h at room temperature with a small excess (1.2 equiv) of tri-n-butylphosphine in a water/n-propanol solution, made slightly alkaline (pH 8.5) by aqueous ammonia. [29] Finally, desired compound 6 was obtained in 96 % yield, using mild conditions, via condensation of 5-hydroxymethyl-8-hydroxyquinoline [27] and the suitable protected tripeptide 5. Conjugation of the free cysteine of GSH to the hydroxyquinoline moiety increases the lipophilicity of the molecule, acting as a GSH carrier to facilitate the diffusion of the compound into cells.…”

“…In addition, esterification of the two carboxylic groups and acetylation of the amino group of the GSH backbone potentially decreases the overall polarity of the moleScheme 1. Reagents and conditions: a) H-Gly-OMe·HCl, HOBt, NMM, DCC, THF, 3 h, 0 8C, then 16 h, 5 8C; b) 95 % DBU, CH 2 Cl 2 , 20 min, RT; c) Ac-Glu-OMe, [28] EDC·HCl, DIPEA, HOBt, DMF, 24 h, RT; d) nPrOH/H 2 O, NH 4 OH, P(nBu) 3 , 1.5 h, RT; e) 5-hydroxymethyl-8-hydroxyquinoline, [27] TFA, CH 2 Cl 2 , DMF, 10 min, À10 8C.…”

Synthesis, spectroscopic characterization, X-Ray analysis, and DFT-HF calculations of 5-ethoxymethyl-8-hydroxyquinoline

“…8-hydroxyquinoline derivatives are very attractive bioactive molecules especially in the field of drugs and pharmaceuticals (Di Varia et al 2004;Salkovic-Petrisic et al 2015;Cacciatore et al 2013) and as chelating agents for a large number of metal ions (Pollak et al 2013;La Deda et al 2004). Derivatives such as zinc(II) bis (8-hydroxyquinoline) complex have been investigated as electroluminescent (EL) materials over the past decades (Yang et al 2013;Yuan et al 2012;Sokołowski et al 2012;Yuan et al 2013;Zawadzka et al 2013;Yuan et al 2015;Wang et al 2013;D'Souza et al 2008) including electrotransporting and emitting materials, which are applied in molecular-based OLEDs for their thermal stability, high fluorescence and excellent electron-transporting mobility (Shan et al 2014;Huo et al 2010;Zawadzka et al 2002;Zawadzka et al 2016;Zawadzka et al 2013;Zhang et al 2015;Yuan et al 2012).…”