1135-23-5Relevant articles and documents
Synthesis, biological evaluation and mechanism study of a class of benzylideneindanone derivatives as novel anticancer agents
Hu, Jinhui,Yan, Jun,Chen, Jie,Pang, Yanqing,Huang, Ling,Li, Xingshu
, p. 1318 - 1327 (2015)
A series of new benzylideneindanone derivatives were designed, synthesized and evaluated as antitumor agents. Structure-activity relationship (SAR) studies showed that derivatives with 4,5,6-trimethoxyl on an indanone moiety displayed good anti-proliferative activities. Especially, compound 5a demonstrated the most potent inhibitory activity, with GI50 values from 0.172 to 0.57 μM for five kinds of cancer cell lines. Further investigation showed that 5a could inhibit microtubule polymerization and thus induce G2/M phase arrest and apoptosis in A549 cells. Our findings revealed the benzylideneindanone moiety as a new attractive scaffold for mitosis-targeting drug discovery.
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Brand,Westerburg
, p. 326,334 (1931)
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Sjoequist,Aenggard
, p. 2297,2298 (1972)
Multifunctional donepezil analogues as cholinesterase and BACE1 inhibitors
Green, Keith D.,Fosso, Marina Y.,Garneau-Tsodikova, Sylvie
, (2018)
A series of 22 donepezil analogues were synthesized through alkylation/benzylation and compared to donepezil and its 6-O-desmethyl adduct. All the compounds were found to be potent inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), two enzymes responsible for the hydrolysis of the neurotransmitter acetylcholine in Alzheimer’s disease patient brains. Many of them displayed lower inhibitory concentrations of EeAChE (IC50 = 0.016 ± 0.001 μM to 0.23 ± 0.03 μM) and EfBChE (IC50 = 0.11 ± 0.01 μM to 1.3 ± 0.2 μM) than donepezil. One of the better compounds was tested against HsAChE and was found to be even more active than donepezil and inhibited HsAChE better than EeAChE. The analogues with the aromatic substituents were generally more potent than the ones with aliphatic substituents. Five of the analogues also inhibited the action of β-secretase (BACE1) enzyme.
Combining chalcones with donepezil to inhibit both cholinesterases and aβ fibril assembly
Chandrika, Nishad Thamban,Fosso, Marina Y.,Tsodikov, Oleg V.,LeVine, Harry,Garneau-Tsodikova, Sylvie
, (2020)
The fact that the number of people with Alzheimer's disease is increasing, combined with the limited availability of drugs for its treatment, emphasize the need for the development of novel effective therapeutics for treating this brain disorder. Herein, we focus on generating 12 chalcone-donepezil hybrids, with the goal of simultaneously targeting amyloid-β (Aβ) peptides as well as cholinesterases (i.e., acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)). We present the design, synthesis, and biochemical evaluation of these two series of novel 1,3-chalcone-donepezil (15a-15f) or 1,4-chalcone-donepezil (16a-16f) hybrids. We evaluate the relationship between their structures and their ability to inhibit AChE/BChE activity as well as their ability to bind Aβ peptides. We show that several of these novel chalcone-donepezil hybrids can successfully inhibit AChE/BChE as well as the assembly of N-biotinylated Aβ(1-42) oligomers. We also demonstrate that the Aβ binding site of these hybrids differs from that of Pittsburgh Compound B (PIB).
Identification and cloning of an NADPH-dependent hydroxycinnamoyl-CoA double bond reductase involved in dihydrochalcone formation in Malus × domestica Borkh.
Ibdah, Mwafaq,Berim, Anna,Martens, Stefan,Valderrama, Andrea Lorena Herrera,Palmieri, Luisa,Lewinsohn, Efraim,Gang, David R.
, p. 24 - 31 (2014)
The apple tree (Malus sp.) is an agriculturally and economically important source of food and beverages. Many of the health beneficial properties of apples are due to (poly)phenolic metabolites that they contain, including various dihydrochalcones. Although many of the genes and enzymes involved in polyphenol biosynthesis are known in many plant species, the specific reactions that lead to the biosynthesis of the dihydrochalcone precursor, p-dihydrocoumaroyl-CoA (3), are unknown. To identify genes involved in the synthesis of these metabolites, existing genome databases of the Rosaceae were screened for apple genes with significant sequence similarity to Arabidopsis alkenal double bond reductases. Herein described are the isolation and characterization of a Malus hydroxycinnamoyl-CoA double bond reductase, which catalyzed the NADPH-dependent reduction of p-coumaroyl-CoA and feruloyl-CoA to p-dihydrocoumaroyl-CoA and dihydroferuloyl-CoA, respectively. Its apparent Km values for p-coumaroyl-CoA, feruloyl-CoA and NADPH were 96.6, 92.9 and 101.3 μM, respectively. The Malus double bond reductase preferred feruloyl-CoA to p-coumaroyl-CoA as a substrate by a factor of 2.1 when comparing catalytic efficiencies in vitro. Expression analysis of the hydroxycinnamoyl-CoA double bond reductase gene revealed that its transcript levels showed significant variation in tissues of different developmental stages, but was expressed when expected for involvement in dihydrochalcone formation. Thus, the hydroxycinnamoyl-CoA double bond reductase appears to be responsible for the reduction of the α,β-unsaturated double bond of p-coumaroyl-CoA, the first step of dihydrochalcone biosynthesis in apple tissues, and may be involved in the production of these compounds.
Semi-aromatic biobased polyesters derived from lignin and cyclic carbonates
Horn, Jessica,Locklin, Jason,Ring, John,White, Evan M.,Winfield, Demichael
supporting information, p. 9658 - 9668 (2021/12/09)
The synthesis of biobased aromatic polyesters from lignin-derived monomers has become well described in the literature, but robust extrusion, thermomechanical, tensile and degradation studies of these materials is lacking. In this work, we have systematically investigated the mechanical and biodegradation properties of semi-aromatic polyesters that can potentially be derived from lignin. AB monomers were synthesized from reduced analogues of coumaric, ferulic, and sinapic acids along with cyclic carbonates, where the synthetic methodology was assessed using E-Factor and EcoScale. Polymerization yielded both semi-crystalline and amorphous polyesters with mechanical properties varying over three orders of magnitude. Detailed characterization revealed a wide array of properties including a highly ductile thermoplastic, a strong and rigid thermoplastic, and an elastomer. Composting biodegradation tests showed both degradable and nondegradable polymers can be achieved in this class. This work demonstrates the versatility of this class of polymers and illustrates their potential to replace non-sustainably derived plastics. This journal is
Design, synthesis, and in silico multitarget pharmacological simulations of acid bioisosteres with a validated in vivo antihyperglycemic effect
Colín-Lozano, Blanca,Domínguez-Mendoza, Elix Alberto,Galván-Ciprés, Yelzyn,Hernández-Bolio, Gloria I.,Hernández-Nú?ez, Emanuel,Martínez-Miranda, Josué,Miranda-González, Cristian,Navarrete-Vazquez, Gabriel,Palomino-Hernández, Oscar
, (2021/06/12)
Substituted phenylacetic (1–3), phenylpropanoic (4–6), and benzylidenethiazolidine-2,4-dione (7–9) derivatives were designed according to a multitarget unified pharmacophore pattern that has shown robust antidiabetic activity. This bioactivity is due to the simultaneous polypharmacological stimulation of receptors PPARα, PPARγ, and GPR40 and the enzyme inhibition of aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP-1B). The nine compounds share the same four pharmacophore elements: An acid moiety, an aromatic ring, a bulky hydrophobic group, and a flexible linker between the latter two elements. Addition and substitution reactions were performed to obtain molecules at moderated yields. In silico pharmacological consensus analysis (PHACA) was conducted to determine their possible modes of action, protein affinities, toxicological activities, and drug-like properties. The results were combined with in vivo assays to evaluate the ability of these compounds to decrease glucose levels in diabetic mice at a 100 mg/kg single dose. Compounds 6 (a phenylpropanoic acid derivative) and 9 (a benzylidenethiazolidine-2,4-dione derivative) ameliorated the hyperglycemic peak in a statically significant manner in a mouse model of type 2 diabetes. Finally, molecular dynamics simulations were executed on the top performing compounds to shed light on their mechanism of action. The simulations showed the flexible nature of the binding pocket of AR, and showed that both compounds remained bound during the simulation time, although not sharing the same binding mode. In conclusion, we designed nine acid bioisosteres with robust in vivo antihyperglycemic activity that were predicted to have favorable pharmacokinetic and toxicological profiles. Together, these findings provide evidence that supports the molecular design we employed, where the unified pharmacophores possess a strong antidiabetic action due to their multitarget activation.
