17604-74-9Relevant articles and documents
Tacrine-xanomeline and tacrine-iperoxo hybrid ligands: Synthesis and biological evaluation at acetylcholinesterase and M1 muscarinic acetylcholine receptors
Cirillo, Davide,Dallanoce, Clelia,De Amici, Marco,Holzgrabe, Ulrike,Maspero, Marco,Messerer, Regina,Sotriffer, Christoph,Volpato, Daniela,Yuan Chen, Natalia
, (2020/02/11)
We synthesized a set of new hybrid derivatives (7-C8, 7-C10, 7-C12 and 8-C8, 8-C10, 8-C12), in which a polymethylene spacer chain of variable length connected the pharmacophoric moiety of xanomeline, an M1/M4-preferring orthosteric muscarinic agonist, with that of tacrine, a well-known acetylcholinesterase (AChE) inhibitor able to allosterically modulate muscarinic acetylcholine receptors (mAChRs). When tested in vitro in a colorimetric assay for their ability to inhibit AChE, the new compounds showed higher or similar potency compared to that of tacrine. Docking analyses were performed on the most potent inhibitors in the series (8-C8, 8-C10, 8-C12) to rationalize their experimental inhibitory power against AChE. Next, we evaluated the signaling cascade at M1 mAChRs by exploring the interaction of Gαq-PLC-β3 proteins through split luciferase assays and the myo-Inositol 1 phosphate (IP1) accumulation in cells. The results were compared with those obtained on the known derivatives 6-C7 and 6-C10, two quite potent AChE inhibitors in which tacrine is linked to iperoxo, an exceptionally potent muscarinic orthosteric activator. Interestingly, we found that 6-C7 and 6-C10 behaved as partial agonists of the M1 mAChR, at variance with hybrids 7-Cn and 8-Cn containing xanomeline as the orthosteric molecular fragment, which were all unable to activate the receptor subtype response.
Hydroxynitrile Lyase Isozymes from Prunus communis: Identification, Characterization and Synthetic Applications
Zheng, Yu-Cong,Xu, Jian-He,Wang, Hui,Lin, Guo-Qiang,Hong, Ran,Yu, Hui-Lei
, p. 1185 - 1193 (2017/04/13)
Biocatalysts originating from Badamu (Prunus communis) have been applied to catalyze the asymmetric synthesis of (R)-4-methylsulfanylmandelonitrile, a key building block of thiamphenicol and florfenicol. Here, four hydroxynitrile lyase (HNL) isozymes from Badamu were cloned and heterologously expressed in Pichia pastoris. The biochemical properties and catalytic performances of these isozymes were comprehensively explored to evaluate their efficiency and selectivity in asymmetric synthesis. Among then, PcHNL5 was identified with outstanding activity and enantioselectivity in asymmetric hydrocyanation. Under the optimized mild biphasic reaction conditions, seventeen prochiral aromatic aldehydes were converted to valuable chiral cyanohydrins with good yields (up to 94%) and excellent optical purities (up to >99.9% ee), which provide a facile access to numerous chiral amino alcohols, hypoglycemic agents, angiotension converting enzyme (ACE) inhibitors and β-blockers. This work therefore underlines the importance of discovering the most potent biocatalyst among a group of isozymes for converting unnatural substrates into value-added products. (Figure presented.).
Silylcyanation of aldehydes, ketones, and imines catalyzed by a 6,6'-bis-sulfonamide derivative of 7,7'-dihydroxy-8,8'-biquinolyl (azaBINOL)
Sephton, Selena Milicevic,Wang, Chao,Zakharov, Lev N.,Blakemore, Paul R.
experimental part, p. 3249 - 3260 (2012/08/08)
6,6'-Bis(methylaminosulfonyl)-7,7'-dihydroxy-8,8'-biquinolyl (3) catalyzes (5-10 mol-%) the addition of trimethylsilyl cyanide to aldehydes (aryl, alkyl, and α,β-unsaturated; 42-92 % yields), ketones (aryl alkyl, dialkyl; 22-82 % yields), and N-benzylaldimines (14-78 % yields) in toluene (0 °C or room temp.) to give the expected cyanohydrin and Strecker adducts following desilylation. Among a series of closely related compounds lacking any one of their defining structural features, bis-sulfonamide 3 and its N,N'-dimethyl derivative are exceptional in catalyzing the silylcyanation of benzaldehyde in the absence of all other additives. Hammett analysis of the competitive silylcyanation of para-substituted benzaldehydes catalyzed by 3 showed a linear free-energy relationship (R2 = 0.928) with a modest positive reaction constant (ρ = +1.52). X-ray diffraction analysis of (±)-3 indicated a cisoid biaryl conformation and the existence of an intramolecular hydrogen bond between C7'-OH and C7-O. Resolution of (±)-3 was achieved by HPLC separation of its tetravalerate derivative on a chiral stationary phase. The absolute configurations of the optical isomers of 3 were assigned by correlation of the ECD spectra with those of related biquinolyls of known configuration. The silylcyanation of aldehydes catalyzed by (-)-(aR)-3 leads to cyanohydrins with a preference for the (S)-configured product with an ee of 10 %. The organocatalytic action of 3 is ascribed to hydrogen bonding and Bronsted acid catalysis effects that are dependent on its acidifying sulfonamide groups, general base capability, and interannular proximity effects made possible by the biaryl structure. Copyright
