- Synthesis and antiproliferative activity of hybrid thiosemicarbazone derivatives bearing coumarin and d-galactose moieties with EGFR inhibitory activity and molecular docking study
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A series of substituted N-(2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl)thiosemicarbazones 5a–5j of substituted 3-acetylcoumarins were synthesized with yields of 45–68%. All synthesized thiosemicarbazones were evaluated for cytotoxic activity against several cancer cell lines, such as human breast adenocarcinoma cells MCF7, human liver cancer cells HepG2, human cervical cancer cells HeLa, human melanoma cancer cells SK-Mel-2, and human lung cancer cells LU-1 by using the standard MTT assay. The IC50 values for these cancer cell lines were 1.28–11.81 μM (for MCF-7), 1.53–22.12 μM (for HepG2), 1.43–48.16 μM (for HeLa), 1.82–14.62 μM (for SK-Mel-2), and 1.74–14.62 μM (for LU-1). Most of the compounds were noncytotoxic against human WI-38 normal cell line (IC50 > 16.9 μM). The antiproliferative mechanisms were studied via EGFR inhibition and molecular docking. Docking studies revealed that there are strong interactions between a typical compound with the receptor of the EGFR tyrosine kinase domain with Erlotinib. [Figure not available: see fulltext.]
- Toan, Vu Ngoc,Thanh, Nguyen Dinh
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p. 1868 - 1885
(2021/08/23)
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- Rational Design and Synthesis of Methyl-β- d -galactomalonyl Phenyl Esters as Potent Galectin-8 N Antagonists
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Galectin-8 is a β-galactoside-recognizing protein having an important role in the regulation of bone remodeling and cancer progression and metastasis. Methyl β-d-galactopyranoside malonyl aromatic esters have been designed to target and engage with particular amino acid residues of the galectin-8N extended carbohydrate-binding site. The chemically synthesized compounds had in vitro binding affinity toward galectin-8N in the range of 5-33 μM, as evaluated by isothermal titration calorimetry. This affinity directly correlated with the compounds' ability to inhibit galectin-8-induced expression of chemokines and proinflammatory cytokines in the SUM159 breast cancer cell line. X-ray crystallographic structure determination revealed that these monosaccharide-based compounds bind galectin-8N by engaging its unique arginine (Arg59) and simultaneously cross-linking to another arginine (Arg45) located across the carbohydrate-binding site. This structure-based drug design approach has led to the discovery of novel monosaccharide galactose-based antagonists, with the strongest-binding compound (Kd 5.72 μM) holding 7-fold tighter than the disaccharide lactose.
- Patel, Brijesh,Kishor, Chandan,Houston, Todd. A.,Shatz-Azoulay, Hadas,Zick, Yehiel,Vinik, Yaron,Blanchard, Helen
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supporting information
p. 11573 - 11584
(2020/12/02)
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- Synthesis and characterization of CAPE derivatives as xanthine oxidase inhibitors with radical scavenging properties
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Inhibitors of the enzyme xanthine oxidase (XO) with radical scavenging properties hold promise as novel agents against reperfusion injuries after ischemic events. By suppressing the formation of damaging reactive oxygen species (ROS) by XO or scavenging ROS from other sources, these compounds may prevent a buildup of ROS in the aftermath of a heart attack or stroke. To combine these two properties in a single molecule, we synthesized and characterized the non-purine XO inhibitor caffeic acid phenethylester (CAPE) and 19 derivatives using a convenient microwave-assisted Knoevenagel condensation protocol. Varying systematically the number and positions of the hydroxyl groups at the two phenyl rings, we derived structure-activity relationships based on experimentally determined XO inhibition data. Molecular docking suggested that critical enzyme/inhibitor interactions involved π-π interactions between the phenolic inhibitor ring and Tyr914, hydrogen bonds between inhibitor hydroxyl groups and Glu802, and hydrophobic interactions between the CAPE phenyl ring and non-polar residues located at the entrance of the binding site. To effectively scavenge the stable radical DPPH, two hydroxyl groups in 1,2- or 1,4-position at the phenyl ring were required. Among all compounds tested, E-phenyl 3-(3,4-dihydroxyphenyl)acrylate, a CAPE analog without the ethyl tether, showed the most promising properties.
- Choi, Wonbeen,Villegas, Valente,Istre, Hannah,Heppler, Ben,Gonzalez, Niki,Brusman, Nicole,Snider, Lindsey,Hogle, Emily,Tucker, Janelle,O?ate, Alma,O?ate, Sandra,Ma, Lili,Paula, Stefan
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p. 686 - 695
(2019/03/05)
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- Gaining Insight Into Reactivity Differences Between Malonic Acid Half Thioesters (MAHT) and Malonic Acid Half Oxyesters (MAHO)
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An efficient two-step synthesis of structurally and functionally diverse thiophenol- and (cyclo)alkyl-derived malonic acid half thioesters (MAHTs) and phenol-derived malonic acid half oxyesters (MAHOs) has been achieved using cheap, readily available and easily handled starting materials. The synthesis of the MAHTs and MAHOs (the majority of which have not been previously reported) is readily scalable to afford gram quantities of product. In a hydrogen→deuterium exchange, an interesting stereoelectronic effect was observed when different aryl groups were incorporated. Significant changes in the rates of hydrogen→deuterium exchange and levels of isotope incorporation were observed. By way of example, using [2H]methanol and 4-bromophenol-derived MAHO afforded only 14 % [2H]-incorporation (9 min, k=31) whereas the corresponding 4-bromothiophenol-derived MAHT afforded 97 % [2H]-incorporation (9 min, k=208). In a benchmark procedure and comprehensive DFT study, 54 ester and thioester configurations and conformations were characterized. In the MAHT series, a sulfur-containing molecular orbital provides a path for increased delocalisation of electron density into the enol that is unavailable in MAHOs. This facilitates keto–enol tautomerisation and consequently enhances the rate and percentage of hydrogen→deuterium exchange.
- Bew, Sean P.,Stephenson, G. Richard,Rouden, Jacques,Godemert, Jeremey,Seylani, Haseena,Martinez-Lozano, Luis A.
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supporting information
p. 4557 - 4569
(2017/04/13)
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- Coumarin derivatives as potential inhibitors of acetylcholinesterase: Synthesis, molecular docking and biological studies
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A series of novel hybrids has been synthesized by linking coumarin moiety through an appropriate spacer to various substituted heterocyclic amines and evaluated as dual binding site acetylcholinesterase inhibitors for the treatment of cognitive dysfunction caused by increased hydrolysis of acetylcholine and scopolamine induced oxidative stress. Anti-amnesic activity of the compounds was evaluated using Morris water maze model at a dose of 1?mg/kg with reference to the standard, donepezil. Biochemical estimation of oxidative stress markers (lipid peroxidation, superoxide dismutase, and plasma nitrite) was carried out to assess the antioxidant potential of the synthesized molecules. Among all the synthesized compounds (15a–i, 16a–d, 17a–b), compound 15a [4-[3-(4-phenylpiperazin-1-yl)propoxy]-2H-chromen-2-one] displayed significant antiamnesic activity, AChE inhibitory activity (IC50?=?2.42?μM) and antioxidant activity in comparison to donepezil (IC50?=?1.82?μM). Molecular docking study of 15a indicated that it interacts with all the crucial amino acids present at the CAS, mid-gorge and PAS of TcAChE resulting in increased inhibition of AChE enzyme.
- Singla, Shaffali,Piplani, Poonam
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p. 4587 - 4599
(2016/09/13)
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- Design, synthesis and antifungal activity of coumarin ring-opening derivatives
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Based on our initial design, we synthesized two series of coumarin ring-opening derivatives by the reactions of hydrolysis and methylation. Results of antifungal screening in vitro showed that the target compounds exhibited potent activity against the six
- Zhang, Ming-Zhi,Zhang, Yu,Wang, Jia-Qun,Zhang, Wei-Hua
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- Novel 2H-chromen derivatives: Design, synthesis and anticancer activity
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A series of novel dihydropyrazole derivatives linked with 2H-chromen were designed and synthesized. All of the compounds have been screened for their antiproliferative activity against MGC-803, Bcap-37, SGC-7901 and HepG 2 cell lines in vitro. The results revealed that compounds 4a and 10a exhibited strong inhibitory activity against HepG2 cell and manifested obvious un-toxic effect on GES-1 and L-02 cell lines. Some title compounds were tested against telomerase, compound 10a showed the most potent inhibitory activity with IC50 value at 0.98 ± 0.11 μM, it could fit well into the active site of TERT. The further molecular mechanism of antiproliferation was explored, the data suggested that compound 10a could inhibit hTERT expression and Wnt/β-catenin signaling.
- Qiang, Dong Zhi,Shi, Jing Bo,Song, Bao An,Liu, Xin Hua
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p. 5607 - 5617
(2014/01/23)
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- Synthesis and antitumor activity of feruloyl and caffeoyl derivatives This paper is dedicated to Prof. Wei-xiao Hu for his lifelong commitment to mentoring graduate students
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We developed two efficient protocols for the synthesis of feruloyl and caffeoyl derivatives from commercial vanillin and veratraldehyde. Pharmacological activities were assessed against a panel of human cancer cell lines in vitro. Most synthesized compounds demonstrated attractive cytotoxicity. Several new compounds demonstrated significant antiproliferative and cytotoxic activities against HeLa and Bewo tumor cell lines. In particular, 5-nitro caffeic adamantyl ester showed broad spectrum of tumor inhibition in 10 cell lines, and reduced tumor weight by 36.7% in vivo when administered at a dose of 40 mg kg-1.
- Chen, Hui-Zhen,Chen, You-Bao,Lv, Ya-Ping,Zeng, Fang,Zhang, Juan,Zhou, Yong-Lie,Li, Han-Bing,Chen, Li-Fei,Zhou, Bin-Jie,Gao, Jian-Rong,Xia, Chun-Nian
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supporting information
p. 4367 - 4371
(2015/02/06)
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- Malonic acid half oxyesters and thioesters: Solvent-free synthesis and DFT analysis of their enols
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A much improved synthetic route to malonic acid half thioesters (MAHTs) and oxyesters (MAHOs), the easy incorporation of deuterium labeling expecially in MAHTs, and an unexpectedly large difference in enolization chemistry between MAHTs and MAHOs are repo
- Bew, Sean P.,Stephenson, G. Richard,Rouden, Jacques,Martinez-Lozano, Luis A.,Seylani, Haseena
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supporting information
p. 3805 - 3807
(2013/09/02)
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- Synthesis of the reported structure of crassiflorone, a naturally occurring quinone isolated from the African ebony Diospyros crassiflora, and regioisomeric pentacyclic furocoumarin naphthoquinones
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A synthesis of the structure reported for the natural product crassiflorone, a furocoumarin naphthoquinone, is described. The key steps are a Diels-Alder reaction to form 2-bromo-8-hydroxy-6-methylnaphthoquinone, followed by O-protection and copper(ii) mediated coupling to 4-hydroxy-5-methylcoumarin to establish the pentacyclic framework whose structure was unambiguously confirmed by X-ray crystallography. Since the spectroscopic data of the synthetic material did not match those reported for the natural product, three further regioisomeric furocoumarin naphthoquinones were prepared by copper(ii) mediated coupling of 4-hydroxy-5- or 8-methyl coumarins with 5-benzyloxy-2-bromo-7-methyl- or 8-benzyloxy-2-bromo-6-methyl-1,4- naphthoquinone. Again the spectroscopic data did not match those of the natural material and therefore the true structure of crassiflorone remains unknown.
- Padwal, Jalindar,Lewis, William,Moody, Christopher J.
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experimental part
p. 3484 - 3493
(2011/06/20)
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- Clean and convenient one-pot synthesis of 4-hydroxycoumarin and 4-hydroxy-2-quinolinone derivatives
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A simple, efficient, and environmentally friendly procedure has been developed for the reaction of Meldrum's acid with phenol, substituted phenols, aniline, or substituted anilines with Eaton's reagent (phosphoric anhydride+methylsulfonic acid) as cyclization reagent. 4-Hydroxycoumarins and 4-hydroxy-2-quinolinones were synthesized in moderate yields by carrying out the reaction in solvent-free, convenient, and clean one-pot preparation.
- Gao, Wen-Tao,Hou, Wen-Duan,Zheng, Mei-Ru,Tang, Li-Jun
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experimental part
p. 732 - 738
(2011/03/17)
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- Decarboxylative ketone aldol reactions: Development and mechanistic evaluation under metal-free conditions
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(Chemical Equation Presented) Malonic acid half thioesters (MAHTs) and malonic acid half oxyesters (MAHOs) are shown to undergo decarboxylative nucleophilic addition reactions with ketone and aldehyde electrophiles in the presence of stoichiometric or catalytic quantities of triethylamine at room temperature. The ability to perform these reactions under metal-free conditions has enabled a detailed mechanistic analysis of the reaction pathway leading to the 1H NMR spectroscopic characterization of a postnucleophilic addition/predecarboxylation intermediate and experimental evidence for a reversible formation of this intermediate followed by an irreversible decarboxylation. Rate constants for each of the bond forming/bond breaking steps in the reaction pathway were also determined, casting light on the differing reactivity betweenMAHOandMAHT nucleophiles in these processes. Finally, the mechanistic insights gained through these studies have been employed in the development of a new decarboxylative coumarin synthesis.
- Blaquiere, Nicole,Shore, Daniel G.,Rousseaux, Sophie,Fagnou, Keith
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supporting information; experimental part
p. 6190 - 6198
(2009/12/24)
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- Synthesis of trans-caffeate analogues and their bioactivities against HIV-1 integrase and cancer cell lines
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Forty caffeate analogues were synthesized via a convenient method starting from vanillin with moderate to good yields. The testing of biological activity of these compounds against HIV-1 integrase indicates that four compounds: bornyl caffeate, bornyl 2-nitrocaffeate, 5-nitrocaffeic acid and 5-nitrocaffeic acid phenethyl ester (5-nitroCAPE) possess a good HIV integrase inhibitory activity, IC50 19.9, 26.8, 25.0 and 13.5 μM, respectively. Twelve caffeate analogues were tested by MTT assay on growth of human hepatocellular carcinoma BEL-7404, human breast MCF-7 adenocarcinoma, human lung A549 adenocarcinoma and human gastric cancer BCG823 cell lines, respectively. And the best result is IC50 5.5 μM for CAPE against BEL-7404.
- Xia, Chun-nian,Li, Hai-bo,liu, Feng,Hu, Wei-xiao
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supporting information; experimental part
p. 6553 - 6557
(2009/09/06)
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- Scope and mechanism of enantioselective michael additions of 1,3-dicarbonyl compounds to nitroalkenes catalyzed by nickel(II)-diamine complexes
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Readily prepared Ni(II)-bis[(R,R)-N,N′-dibenzylcyclohexane-1,2- diamine]Br2 was shown to catalyze the Michael addition of 1,3-dicarbonyl compounds to nitroalkenes at room temperature in good yields with high enantioselectivities. The two diamine ligands in this system each play a distinct role: one serves as a chiral ligand to provide stereoinduction in the addition step while the other functions as a base for substrate enolization. Ligand modification within the catalyst was also investigated to facilitate the reaction of aliphatic nitroalkenes, 1,3-diketones, and β-ketoacids. Ni(II)-bis[(R,R)-N,N′-di-p-bromo-benzylcyclohexane-1,2-diamine]Br 2 was found to be an effective catalyst in these instances. Furthermore, monodiamine complex, Ni(II)-[(R,R)-N,N′-dibenzylcyclohexane- 1,2-diamine]Br2, catalyzed the addition reaction in the presence of water. The proposed model for stereochemical induction is shown to be consistent with X-ray structure analysis.
- Evans, David A.,Mito, Shizue,Seidel, Daniel
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p. 11583 - 11592
(2008/03/15)
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- Inhibitors of VEGF receptor and HGF receptor signaling
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The invention relates to the inhibition of VEGF receptor signaling and HGF receptor signaling. The invention provides compounds and methods for inhibiting VEGF receptor signaling and HGF receptor signaling. The invention also provides compositions and methods for treating cell proliferative diseases and conditions
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Page/Page column 76
(2010/11/25)
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- One-pot preparation of caffeic acid esters from 3,4-dihydroxybenzaldehyde
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A convenient one-pot process for preparing various esters of caffeic acid from 3,4-dihydroxybenzaldehyde has been developed. The alcohols or phenols react with Meldrum's acid to form malonic acid mono-esters, which, without separating, immediately react with 3,4-dihydroxybenzaldehyde to afford the desired esters in good yield. The 1H NMR data and X-ray diffraction analyses indicate that these α,β-unsaturated esters are in trans (E) form in accord with natural esters.
- Hu, Wei-Xiao,Xia, Chun-Nian,Wang, Guo-Hong,Zhou, Wei
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p. 586 - 588
(2007/10/03)
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- Self-condensation of activated malonic acid half esters: A model for the decarboxylative Claisen condensation in polyketide biosynthesis
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The reaction of a malonic acid half oxyester with a N-hydroxysuccinimidyl ester-forming reagent resulted in self-condensation to provide the corresponding 1,3-acetonedicarboxylic acid diester. This new method does not require a divalent metal chelator or a coordinating solvent for successful condensation.
- Ryu, Youngha,Scott, A. Ian
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p. 7499 - 7502
(2007/10/03)
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- Synthesis of bone-targeted oestrogenic compounds for the inhibition of bone resorption
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Syntheses have been realised for several members of a new class of potential bone resorption inhibitors consisting of steroidal oestrogenic compounds linked at the 17 position to a geminal bis(phosphonic acid) moiety through an ester linkage. The approach used has the potential to allow other biologically active compounds to be coupled to the geminal bisphosphonate unit.
- Bulman Page, Philip C,Moore, Jonathan P.G,Mansfield, Ian,McKenzie, Michael J,Bowler, Wayne B,Gallagher, James A
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p. 1837 - 1847
(2007/10/03)
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