3612-20-2Relevant articles and documents
Evaluation of γ-carboline-phenothiazine conjugates as simultaneous NMDA receptor blockers and cholinesterase inhibitors
Arndt, Hans-Dieter,Gaube, Friedemann,Raztsou, Ihar,Robaa, Dina,Rohrbach, Marius M.,Sager, Henrike,Schwarthoff, Sigrid,Tischer, Nicolas,Winckler, Thomas,Sch?tz, Bianca
, (2021)
Alzheimer's disease (AD) is the most common form of dementia. It is associated with the impairment of memory and other cognitive functions that are mainly caused by progressive defects in cholinergic and glutamatergic signaling in the central nervous system. Inhibitors of acetylcholinesterase (AChE) and ionotropic glutamate receptors of the N-methyl-D-aspartate (NMDA) receptor family are currently approved as AD therapeutics. We previously showed using a cell-based assay of NMDA receptor-mediated glutamate-induced excitotoxicity that bis-γ-carbolinium conjugates are useful NMDA receptor blockers. However, these compounds also act as subnanomolar AChE inhibitors, which may cause serious anticholinergic side effects when applied in vivo. Here, we evaluated new structures containing γ-carbolines linked to phenothiazine via a propionyl spacer. These compounds were superior to the previously characterized bis-γ-carbolinium conjugates because they blocked NMDA receptors without requiring a quaternary pyridine N-atom and inhibited AChE with moderate IC50 values of 0.54–5.3 μM. In addition, these new compounds displayed considerable selectivity for the inhibition of butyrylcholinesterase (BChE; IC50 = 0.008–0.041 μM), which may be favorable for AD treatment. Inhibitory activities towards the NMDA receptors and AChE were in the same micromolar range, which may be beneficial for equal dosing against multiple targets in AD patients.
Novel quinolone-based potent and selective HDAC6 inhibitors: Synthesis, molecular modeling studies and biological investigation
Relitti, Nicola,Saraswati, A. Prasanth,Chemi, Giulia,Brindisi, Margherita,Brogi, Simone,Herp, Daniel,Schmidtkunz, Karin,Saccoccia, Fulvio,Ruberti, Giovina,Ulivieri, Cristina,Vanni, Francesca,Sarno, Federica,Altucci, Lucia,Lamponi, Stefania,Jung, Manfred,Gemma, Sandra,Butini, Stefania,Campiani, Giuseppe
, (2020/11/24)
In this work we describe the synthesis of potent and selective quinolone-based histone deacetylase 6 (HDAC6) inhibitors. The quinolone moiety has been exploited as an innovative bioactive cap-group for HDAC6 inhibition; its synthesis was achieved by applying a multicomponent reaction. The optimization of potency and selectivity of these products was performed by employing computational studies which led to the discovery of the diethylaminomethyl derivatives 7g and 7k as the most promising hit molecules. These compounds were investigated in cellular studies to evaluate their anticancer effect against colon (HCT-116) and histiocytic lymphoma (U9347) cancer cells, showing good to excellent potency, leading to tumor cell death by apoptosis induction. The small molecules 7a, 7g and 7k were able to strongly inhibit the cytoplasmic and slightly the nuclear HDAC enzymes, increasing the acetylation of tubulin and of the lysine 9 and 14 of histone 3, respectively. Compound 7g was also able to increase Hsp90 acetylation levels in HCT-116 cells, thus further supporting its HDAC6 inhibitory profile. Cytotoxicity and mutagenicity assays of these molecules showed a safe profile; moreover, the HPLC analysis of compound 7k revealed good solubility and stability profile.
Cobalt-Catalyzed Aerobic Oxidative Cleavage of Alkyl Aldehydes: Synthesis of Ketones, Esters, Amides, and α-Ketoamides
Li, Tingting,Hammond, Gerald B.,Xu, Bo
supporting information, p. 9737 - 9741 (2021/05/31)
A widely applicable approach was developed to synthesize ketones, esters, amides via the oxidative C?C bond cleavage of readily available alkyl aldehydes. Green and abundant molecular oxygen (O2) was used as the oxidant, and base metals (cobalt and copper) were used as the catalysts. This strategy can be extended to the one-pot synthesis of ketones from primary alcohols and α-ketoamides from aldehydes.