- Template-Hopping Approach Leads to Potent, Selective, and Highly Soluble Bromo and Extraterminal Domain (BET) Second Bromodomain (BD2) Inhibitors
-
A number of reports have recently been published describing the discovery and optimization of bromo and extraterminal inhibitors which are selective for the second bromodomain (BD2); these include our own work toward GSK046 (3) and GSK620 (5). This paper describes our approach to mitigating the genotoxicity risk of GSK046 by replacement of the acetamide functionality with a heterocyclic ring. This was followed by a template-hopping and hybridization approach, guided by structure-based drug design, to incorporate learnings from other BD2-selective series, optimize the vector for the amide region, and explore the ZA cleft, leading to the identification of potent, selective, and bioavailable compounds 28 (GSK452), 39 (GSK737), and 36 (GSK217).
- Aylott, Helen E.,Atkinson, Stephen J.,Bamborough, Paul,Bassil, Anna,Chung, Chun-Wa,Gordon, Laurie,Grandi, Paola,Gray, James R. J.,Harrison, Lee A.,Hayhow, Thomas G.,Messenger, Cassie,Mitchell, Darren,Phillipou, Alexander,Preston, Alex,Prinjha, Rab K.,Rianjongdee, Francesco,Rioja, Inmaculada,Seal, Jonathan T.,Wall, Ian D.,Watson, Robert J.,Woolven, James M.,Demont, Emmanuel H.
-
p. 3249 - 3281
(2021/04/06)
-
- Polyhydrazide-Based Organic Nanotubes as Efficient and Selective Artificial Iodide Channels
-
Reported herein is a series of pore-containing polymeric nanotubes based on a hydrogen-bonded hydrazide backbone. Nanotubes of suitable lengths, possessing a hollow cavity of about a 6.5 ? diameter, mediate highly efficient transport of diverse types of anions, rather than cations, across lipid membranes. The reported polymer channel, having an average molecular weight of 18.2 kDa and 3.6 nm in helical height, exhibits the highest anion-transport activities for iodide (EC50=0.042 μm or 0.028 mol % relative to lipid), whcih is transported 10 times more efficiently than chlorides (EC50=0.47 μm). Notably, even in cholesterol-rich environment, iodide transport activity remains high with an EC50 of 0.37 μm. Molecular dynamics simulation studies confirm that the channel is highly selective for anions and that such anion selectivity arises from a positive electrostatic potential of the central lumen rendered by the interior-pointing methyl groups.
- Aksimentiev, Aleksei,Chen, Feng,Joshi, Himanshu,Roy, Arundhati,Shen, Jie,Ye, Ruijuan,Zeng, Huaqiang
-
supporting information
p. 4806 - 4813
(2020/02/11)
-
- Discovery, synthesis and anti-atherosclerotic activities of a novel selective sphingomyelin synthase 2 inhibitor
-
The sphingomyelin synthase 2 (SMS2) is a potential target for pharmacological intervention in atherosclerosis. However, so far, few selective SMS2 inhibitors and their pharmacological activities were reported. In this study, a class of 2-benzyloxybenzamides were discovered as novel SMS2 inhibitors through scaffold hopping and structural optimization. Among them, Ly93 as one of the most potent inhibitors exhibited IC50 values of 91 nM and 133.9 μM against purified SMS2 and SMS1 respectively. The selectivity ratio of Ly93 was more than 1400-fold for purified SMS2 over SMS1. The in vitro studies indicated that Ly93 not only dose-dependently diminished apoB secretion from Huh7 cells, but also significantly reduced the SMS activity and increased cholesterol efflux from macrophages. Meanwhile, Ly93 inhibited the secretion of LPS-mediated pro-inflammatory cytokine and chemokine in macrophages. The pharmacokinetic profiles of Ly93 performed on C57BL/6J mice demonstrated that Ly93 was orally efficacious. As a potent selective SMS2 inhibitor, Ly93 significantly decreased the plasma SM levels of C57BL/6J mice. Furthermore, Ly93 was capable of dose-dependently attenuating the atherosclerotic lesions in the root and the entire aorta as well as macrophage content in lesions, in apolipoprotein E gene knockout mice treated with Ly93. In conclusion, we discovered a novel selective SMS2 inhibitor Ly93 and demonstrated its anti-atherosclerotic activities in vivo. The preliminary molecular mechanism-of-action studies revealed its function in lipid homeostasis and inflammation process, which indicated that the selective inhibition of SMS2 would be a promising treatment for atherosclerosis.
- Li, Yali,Huang, Taomin,Lou, Bin,Ye, Deyong,Qi, Xiangyu,Li, Xiaoxia,Hu, Shuang,Ding, Tingbo,Chen, Yan,Cao, Yang,Mo, Mingguang,Dong, Jibin,Wei, Min,Chu, Yong,Li, Huiti,Jiang, Xian-Cheng,Cheng, Nengneng,Zhou, Lu
-
supporting information
p. 864 - 882
(2019/01/04)
-
- Metal-free Synthesis of Spiro-2,2′-benzo[b]furan-3,3′-ones via PhI(OAc)2-Mediated Cascade Spirocyclization
-
Treating the benzyl protected 3-hydroxy-1,3-bis(2-hydroxyphenyl)prop-2-en-1-ones solely with PhI(OAc)2 (PIDA) in DCE at room temperature readily furnished the seldom studied spiro-2,2′-benzo[b]furan-3,3′-ones in satisfactory to excellent yields. The hypervalent iodine reagent enables the metal-free cascade spirocyclization resulting in the dual oxidative C?O bond formation. (Figure presented.).
- Xing, Qingyu,Liang, Huiyuan,Bao, Mingmai,Li, Xuemin,Zhang, Jingran,Bi, Tianhao,Zhang, Yilin,Xu, Jun,Du, Yunfei,Zhao, Kang
-
supporting information
p. 4669 - 4673
(2019/09/17)
-
- Design, synthesis and biological activity of selective hCAs inhibitors based on 2-(benzylsulfinyl)benzoic acid scaffold
-
A large library of derivatives based on the scaffold of 2-(benzylsulfinyl)benzoic acid were synthesised and tested as atypical inhibitors against four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). The exploration of the chemical space around the main functional groups led to the discovery of selective hCA IX inhibitors in the micromolar/nanomolar range, thus establishing robust structure-activity relationships within this versatile scaffold. HPLC separation of some selected chiral compounds and biological evaluation of the corresponding enantiomers was performed along with molecular modelling studies on the most active derivatives.
- Rotondi, Giulia,Guglielmi, Paolo,Carradori, Simone,Secci, Daniela,De Monte, Celeste,De Filippis, Barbara,Maccallini, Cristina,Amoroso, Rosa,Cirilli, Roberto,Akdemir, Atilla,Angeli, Andrea,Supuran, Claudiu T.
-
p. 1400 - 1413
(2019/08/26)
-
- Total Synthesis of Mycobacterium tuberculosis Dideoxymycobactin-838 and Stereoisomers: Diverse CD1a-Restricted T Cells Display a Common Hierarchy of Lipopeptide Recognition
-
Mycobacterium tuberculosis produces dideoxymycobactin-838 (DDM-838), a lipopeptide that potently activates T cells upon binding to the MHC-like antigen-presenting molecule CD1a. M. tuberculosis produces DDM-838 in only trace amounts and a previous solid-phase synthesis provided sub-milligram quantities. We describe a high-yielding solution-phase synthesis of DDM-838 that features a Mitsunobu substitution that avoids yield-limiting epimerization at lysine during esterification, and amidation conditions that prevent double-bond isomerization of the Z-C20:1 acyl chain, and provides material with equivalent antigenicity to natural DDM-838. Isomers of DDM-838 that varied in stereochemistry at the central lysine and the C20:1 acyl chain were compared for their ability to be recognised by CD1a-restricted T cell receptors (TCRs). These TCRs, derived from unrelated human donors, exhibited a similar spectrum of reactivity towards the panel of DDM-838 isomers, highlighting the exquisite sensitivity of lipopeptide-reactive T cells for the natural DDM stereochemistry.
- Cheng, Janice M. H.,Liu, Ligong,Pellicci, Daniel G.,Reddiex, Scott J. J.,Cotton, Rachel N.,Cheng, Tan-Yun,Young, David C.,Van Rhijn, Ildiko,Moody, D. Branch,Rossjohn, Jamie,Fairlie, David P.,Godfrey, Dale I.,Williams, Spencer J.
-
supporting information
p. 1694 - 1701
(2017/02/10)
-
- 2-ALKYLOXY BENZENE FORMYL ARYLAMINE COMPOUND AND PHARMACEUTICAL USE THEREOF
-
The present invention relates to 2-alkoxy benzene formyl arylamine compounds as scheme I , in which the R, G, X, Y, Z are consistent with the detailed description in the patent claim. The compounds can act as sphingomyelin synthase (SMS) inhibitors to treat diseases caused by abnormal increasing of sphingomyelin(SM). This invention also includes compounds as scheme I , their pharmaceutically acceptable salts, pharmaceutical compositions as the active ingredients, and their application in drugs which can prevent and cure diseases caused by SM level abnormal increase. These diseases include atherosclerosis, fatty liver, obesity, type II diabetes, and other metabolic syndromes.
- -
-
Paragraph 0024; 0025
(2017/08/29)
-
- LANTHANIDE CLUSTERS AND METHODS OF USE THEREOF
-
The present invention is directed to multinuclear lanthanides chiral clusters, based on phenyl-oxazoline-amide (POxA) ligands, and to methods of use thereof. The chiral clusters of this invention are highly fluorescent with high stability.
- -
-
Paragraph 0187; 0188
(2016/01/30)
-
- The discovery of allyltyrosine based tripeptides as selective inhibitors of the HIV-1 integrase strand-transfer reaction
-
From library screening of synthetic antimicrobial peptides, an O-allyltyrosine-based tripeptide was identified to possess inhibitory activity against HIV-1 integrase (IN) exhibiting an IC50 value of 17.5 μM in a combination 3′-processing and strand transfer microtitre plate assay. The tripeptide was subjected to structure-activity relationship (SAR) studies with 28 peptides, incorporating an array of natural and non-natural amino acids. Resulting SAR analysis revealed the allyltyrosine residue was a key feature for IN inhibitory activity whilst incorporation of a lysine residue and extended hydrophilic chains bearing a terminal methyl ester was advantageous. Addition of hydrophobic aromatic moieties to the N-terminal of the scaffold afforded compounds with improved inhibitory activity. Consolidation of these functionalities lead to the development of the tripeptide 96 which specifically inhibited the IN strand-transfer reaction with an IC50 value of 2.5 μM.
- Dalton, Neal,Gordon, Christopher P.,Boyle, Timothy P.,Vandegraaf, Nicholas,Deadman, John,Rhodes, David I.,Coates, Jonathan A.,Pyne, Stephen G.,Keller, Paul A.,Bremner, John B.
-
supporting information
p. 6010 - 6023
(2016/07/06)
-
- Benzoic hydroxamate-based iron complexes as model compounds for humic substances: Synthesis, characterization and algal growth experiments
-
A series of monomeric and dimeric FeIII complexes bearing benzoic hydroxamates as O,O-chelates has been prepared and characterized by elemental analysis, IR spectroscopy, UV-Vis spectroscopy, electrospray ionization mass spectrometry (ESI-MS), cyclic voltammetry, EPR spectroscopy and for some examples by X-ray diffraction analysis. The stability of the synthesized complexes in pure water and seawater was monitored over 24 h by means of UV-Vis spectrometry. The ability to release iron from the synthesized model complexes has been investigated with algae growth experiments.
- Orlowska, Ewelina,Roller, Alexander,Wiesinger, Hubert,Pignitter, Marc,Jirsa, Franz,Krachler, Regina,Kandioller, Wolfgang,Keppler, Bernhard K.
-
p. 40238 - 40249
(2016/05/24)
-
- Solubility and thermodynamic analysis of N′-(1-(N-(methyl) benzylaminomethyl)-2-oxoindolin-3-ylidene)-2-(benzyloxy) benzohydrazide in different neat solvents at different temperatures
-
The present study was undertaken to determine the solubilities of newly synthesized anticancer compound N′-(1-(N-(methyl) benzylaminomethyl)-2-oxoindolin-3-ylidene)-2-(benzyloxy) benzohydrazide (NMBOBB) in nine different neat solvents including water, isopropanol (IPA), ethanol, ethylene glycol (EG), 1.2-propanediol (PG), 1-butanol, 2-butanol, polyethylene glycol-400 (PEG-400) and Transcutol (diethylene glycol monoethyl ether) at T = 298.15 K to 318.15 K and p = 0.1 MPa. Experimental solubility data of NMBOBB was fitted with Apelblat and ideal models. The mole fraction solubility of NMBOBB was recorded highest in PEG-400 (1.14 × 10- 2 at T = 318.15 K) followed by Transcutol (7.14 × 10- 3 at T = 318.15 K), 2-butanol (1.45 × 10- 3 at T = 318.15 K), 1-butanol (1.38 × 10- 3 at T = 318.15 K), ethanol (9.69 × 10- 4 at T = 318.15 K), PG (9.52 × 10- 4 at T = 318.15 K), IPA (9.41 × 10- 4 at T = 318.15 K), EG (8.09 × 10- 4 at T = 318.15 K) and water (3.00 × 10- 6 at T = 318.15 K). The highest solubility of NMBOBB in PEG-400 was possible due to lower polarity and higher molar mass of PEG-400. The dissolution behavior of NMBOBB was observed as an endothermic, spontaneous and an entropy-driven due to positive values of standard enthalpies, Gibbs free energies and entropies in all nine neat solvents investigated. The results of this work would be helpful in purification, recrystallization and dosage form design of NMBOBB.
- Shakeel, Faiyaz,Haq, Nazrul,Radwan, Awwad A.,Alanazi, Fars K.,Alsarra, Ibrahim A.
-
p. 108 - 112
(2016/05/09)
-
- Target β-catenin/CD44/Nanog axis in colon cancer cells by certain N′-(2-oxoindolin-3-ylidene)-2-(benzyloxy)benzohydrazides
-
Cell surface molecule CD44 plays a major role in regulation of cancer stem cells CSCs on both phenotypic and functional level, however chemical inhibition approach of CD44 to targets CSCs is poorly studied. Herein, we report the discovery of certain N′-(2-oxoindolin-3-ylidene)-2-(benzyloxy)benzohydrazides as a novel inhibitor of CD44. Molecular docking study showed interference of the scaffold of these compounds with β-catenin/TCF-4 complex, building a direct relationship between CD44 inhibition and observed well-fitted binding domain. Compound 11a, most potent member elicits inhibition effect on TCF/LEF reporter activity conformed the involvement of Wnt pathway inhibition as a mechanism of action. Furthermore, the treatment by the mentioned compound leads to inhibition of embryonic transcriptional factor Nanog but not Sox2 or Oct-4 suggested specific targeted effect. Moreover, the cytotoxicity and cell cycle effect of this series seems to be dependent on CD44 expression.
- Radwan, Awwad A.,Al-Mohanna,Alanazi, Fares K.,Manogaran,Al-Dhfyan, Abdullah
-
p. 1664 - 1670
(2016/12/22)
-
- Oxidative cyclization of alkenoic acids promoted by AgOAc
-
Alkenoic acids derived from salicylic acid and analogues undergo an unexpected oxidative cyclization process triggered by AgOAc leading to 4H-benzo[d][1,3]dioxin-4-ones. The process is affected by the substitution on the aryl and the allyl units.
- Carrillo-Arcos, Ulises A.,Rojas-Ocampo, Jonathan,Porcel, Susana
-
p. 479 - 483
(2016/01/09)
-
- Design, synthesis and molecular docking of salicylic acid derivatives containing metronidazole as a new class of antimicrobial agents
-
A series of novel salicylic acid derivatives containing metronidazole as Staphylococcus aureus Tyrosyl-tRNA synthetase (TyrRS) inhibitors have been synthesized and evaluated their biology activities as potential antibacterial agents. Among these compounds
- Guo, Zhi-Hua,Yin, Yong,Wang, Cong,Wang, Peng-Fei,Zhang, Xing-Tao,Wang, Zhong-Chang,Zhu, Hai-Liang
-
p. 6148 - 6156
(2015/09/15)
-
- Structure-activity relationships for vitamin D3-based aromatic a-ring analogues as hedgehog pathway inhibitors
-
A structure-activity relationship study for a series of vitamin D3-based (VD3) analogues that incorporate aromatic A-ring mimics with varying functionality has provided key insight into scaffold features that result in potent, selective Hedgehog (Hh) pathway inhibition. Three analogue subclasses containing (1) a single substitution at the ortho or para position of the aromatic A-ring, (2) a heteroaryl or biaryl moiety, or (3) multiple substituents on the aromatic A-ring were prepared and evaluated. Aromatic A-ring mimics incorporating either single or multiple hydrophilic moieties on a six-membered ring inhibited the Hh pathway in both Hh-dependent mouse embryonic fibroblasts and cultured cancer cells (IC50 values 0.74-10 μM). Preliminary studies were conducted to probe the cellular mechanisms through which VD3 and 5, the most active analogue, inhibit Hh signaling. These studies suggested that the anti-Hh activity of VD3 is primarily attributed to the vitamin D receptor, whereas 5 affects Hh inhibition through a separate mechanism.
- Deberardinis, Albert M.,Madden, Daniel J.,Banerjee, Upasana,Sail, Vibhavari,Raccuia, Daniel S.,De Carlo, Daniel,Lemieux, Steven M.,Meares, Adam,Hadden, M. Kyle
-
p. 3724 - 3736
(2014/05/20)
-
- Recyclable CuO nanoparticles-catalyzed synthesis of novel-2,5-disubstituted 1,3,4-oxadiazoles as antiproliferative, antibacterial, and antifungal agents
-
A series of new 2,5-disubstituted 1,3,4-oxadiazoles have been conveniently synthesized through an oxidative C-O coupling by direct C-H bond activation of N-aroyl-N-arylidinehydrazines using a catalytic quantity of CuO nanoparticles. Twenty compounds have been synthesized in good to excellent yields (75-90 %). All the synthesized compounds were evaluated for their in vitro antiproliferative, antibacterial, and antifungal activity. Compounds 8d and 10d are more promising antiproliferative agents with IC50 value of 3.66 and 3.89 μM in MCF-7 cell line, and compounds 8a and 10a were showed more potent antifungal activity than standard drug.
- Murty,Penthala, Raju,Buddana, Sudheer Kumar,Prakasham,Das, Pompi,Polepalli, Sowjanya,Jain,Bojja, Sreedhar
-
p. 4579 - 4594
(2016/02/20)
-
- A Novel Series of 2,5-Disubstituted 1,3,4-oxadiazoles: Synthesis and SAR Study for their Anticonvulsant Activity
-
In search for a better anticonvulsant drug and the importance of semicarbazones and 2,5-disubstituted 1,3,4-oxadiazoles as anticonvulsant pharmacophore, a series of novel substituted semicarbazones were designed, synthesized, and evaluated for their anticonvulsant activity. The chemical structures of the synthesized molecules were confirmed by elemental and spectral (IR, 1H NMR, 13C NMR and MS) analysis. The anticonvulsant activities of the compounds were investigated using maximal electroshock seizure and subcutaneous pentylenetetrazole (scPTZ) models. Efforts were also made to establish structure-activity relationships among synthesized compounds. The results of the present study validated that the pharmacophore model with four binding sites is essential for anticonvulsant activity.
- Rajak, Harish,Singour, Pradeep,Kharya, Murli Dhar,Mishra, Pradeep
-
experimental part
p. 152 - 158
(2012/01/06)
-
- Novel 4- and 7-sulfonylated 2-substituted benzoxazoles
-
The efficient synthesis of sulfonylated benzoxazoles at positions C 4 or C7 is reported. The condensation reactions involve original anilide acetal reagents which, upon acid catalysis, allow an easy cyclization reaction with the sulfonylated o-aminophenol partners. This method circumvents the classical use of orthoesters which drawback is the limited access to aromatic reagents. Georg Thieme Verlag Stuttgart.
- Bruyneel, Frédéric,Marchand-Brynaert, Jacqueline
-
supporting information; experimental part
p. 1974 - 1978
(2010/10/03)
-
- CYCLIC TRIAZO AND DIAZO SODIUM CHANNEL BLOCKERS
-
Compounds of general structure in which X and Y are each N or C with at least one of X and Y being N; Z is a single bond or an optionally substituted linking group R1 is hydrogen or a substituent group; R2 is amino or a substituent group; N* is amino when RI is hydrogen or =NH when R1 is a substituent group; or N* is a group NRaRb where Ra and Rb are independently H or an alkyl group; or N* is an optionally substituted piperazinyl ring; and A is an optionally substituted heterocyclic or carbocyclic ring system which may be linked to the triazo/diazo ring through R2 to form a fused multicyclic ring; are indicated as suitable for treatment of disorders in mammals that are susceptible to sodium channel blockers and antifolates, and particularly disorders such epilepsy, multiple sclerosis, glaucoma and uevitis, cerebral traumas and cerebral ischaemias, stroke, head injury, spinal cord injury, surgical trauma, neurodegenerative disorders, motorneurone disease, Alzheimer's disease, Parkinson's disease, chronic inflammatory pain, neuropathic pain, migraine, bipolar disorder, mood, anxiety and cognitive disorders, schizophrenia and trigeminal autonomic cephalalgias; for treatment of mammalian cancers; and for treatment of malaria.
- -
-
Page/Page column 33
(2009/08/16)
-
- Antibacterial Agents
-
The invention provides compounds of formula (I) and salts thereof: R1-L-R2—B wherein R1, L, R2, and B have any of the values defined herein, as well as compositions comprising such compounds, and therapeutic methods comprising the administration of such compounds or salts. The compounds block siderophore production in bacteria and are useful as antibacterial agents.
- -
-
Page/Page column 37
(2009/01/20)
-
- Ginger and its bioactive component inhibit enterotoxigenic Escherichia coli heat-labile enterotoxin-induced diarrhea in mice
-
Ginger is one of the most commonly used fresh herbs and spices. Enterotoxigenic Escherichia coli heat-labile enterotoxin (LT)-induced diarrhea is the leading cause of infant death in developing countries. In this study, we demonstrated that ginger significantly blocked the binding of LT to cell-surface receptor GM1, resulting in the inhibition of fluid accumulation in the closed ileal loops of mice. Biological-activity-guided searching for active components showed that zingerone (vanillylacetone) was the likely active constituent responsible for the antidiarrheal efficacy of ginger. Further analysis of chemically synthesized zingerone derivatives revealed that compound 31 (2-[(4-methoxybenzyl)oxy]benzoic acid) significantly suppressed LT-induced diarrhea in mice via an excellent surface complementarity with the B subunits of LT. In conclusion, our findings provide evidence that ginger and its derivatives may be effective herbal supplements for the clinical treatment of enterotoxigenic Escherichia coli diarrhea.
- Chen, Jaw-Chyun,Huang, Li-Jiau,Wu, Shih-Lu,Kuo, Sheng-Chu,Ho, Tin-Yun,Hsiang, Chien-Yun
-
experimental part
p. 8390 - 8397
(2009/09/29)
-
- Synthesis and anticancer evaluation of bis(benzimidazoles), bis(benzoxazoles), and benzothiazoles
-
Four classes of UK-1 analogues were synthesized and their cytotoxicity testing against human A-549, BFTC-905, RD, MES-SA, and HeLa carcinoma cell lines was determined. The results revealed that UK-1 and four of these analogues (15-18) are potent against the cancer cell lines. In particular, compound 16 is more potent than UK-1 against A-549 and HeLa cell lines, and compounds 15, 17, and 18 selectively exhibit potent cytotoxic activity against the BFTV-905 cells (IC50 9.6 μM), A-549 cells (IC50 6.6 μM), and MES-SA cells (IC50 9.2 μM), respectively.
- Huang, Shu-Ting,Hsei, I-Jen,Chen, Chinpiao
-
p. 6106 - 6119
(2007/10/03)
-
- Rationally-designed nucleoside antibiotics that inhibit siderophore biosynthesis of Mycobacterium tuberculosis
-
A rationally designed nucleoside inhibitor of Mycobacterium tuberculosis growth (MIC99 = 0.19 μM) that disrupts siderophore biosynthesis was identified. The activity is due to inhibition of the adenylate-forming enzyme MbtA which is involved in
- Somu, Ravindranadh V.,Boshoff, Helena,Qiao, Chunhua,Bennett, Eric M.,Barry III, Clifton E.,Aldrich, Courtney C.
-
-
- PESTICIDAL SUBSTITUTED PHENYLETHERS
-
The invention relates to the use of phenylether derivatives of formula (I), to compositions thereof for the control of pests, including arthropods and helminths.
- -
-
Page/Page column 42; 44
(2008/06/13)
-
- Synthesis and anticancer activity of benzyloxybenzaldehyde derivatives against HL-60 cells
-
A series of benzyloxybenzaldehyde derivatives were prepared and tested against the HL-60 cell line for anticancer activity. Preliminary structure-activity relationships were established. It was discovered that 2-(benzyloxy)benzaldehyde (17), 2-(benzyloxy)-4-methoxybenzaldehyde (26), 2-(benzyloxy)-5-methoxybenzaldehyde (27), 2-(benzyloxy)-5-chlorobenzaldehyde (28), 2-[(3-methoxybenzyl)oxy]benzaldehyde (29), 2-[(2-chlorobenzyl)oxy] benzaldehyde (30), and 2-[(4-chlorobenzyl)oxy]benzaldehyde (31) exhibited significant activity at 1-10 μM. Among them, compound 29 was the most potent one. The morphological assessment and DNA fragmentation analysis indicated that these compounds arrested cell cycle progression at G2/M phase and induced cell apoptosis. They resulted in the loss of mitochondrial membrane potential after 12 h of treatment.
- Lin, Chin-Fen,Yang, Jai-Sing,Chang, Chiung-Yun,Kuo, Sheng-Chu,Lee, Miau-Rong,Huang, Li-Jiau
-
p. 1537 - 1544
(2007/10/03)
-
- Synthesis and anticonvulsant activity of new 2-substituted-5-(2- benzyloxyphenyl)-1,3,4-oxadiazoles
-
A series of new 2-substituted-5-(2-benzyloxyphenyl)-1,3,4-oxadiazoles have been synthesized and evaluated as anticonvulsant agents. Compound 4b shows considerable anticonvulsant activity both in PTZ and MES models. It seems this effect is mediated through benzodiazepine receptors mechanism.
- Zarghi, Afshin,Tabatabai, Sayyed A.,Faizi, Mehrdad,Ahadian, Avideh,Navabi, Parisa,Zanganeh, Vahideh,Shafiee, Abbas
-
p. 1863 - 1865
(2007/10/03)
-
- N-acylation of 5-substituted indoles with carboxylic acids via DCC coupling
-
A method for the N-acylation of 5-substituted indoles with carboxylic acids using DCC and DMAP is presented. High yields were obtained when an electron-withdrawing group was present at C-5, however the method was less effective with a C-5 electron-donating group.
- Bremner, John B.,Samosorn, Siritron,Ambrus, Joseph I.
-
p. 2653 - 2658
(2007/10/03)
-
- Intramolecular condensation reactions via tricarbonyl-chromium complexed benzylic carbanions
-
The synthesis of two heterocyclic systems by KOBut/DMSO promoted cyclization of Cr(CO)3-activated benzylic sites is reported. Thus 2-[(phenyl)Cr(CO)3]-3-hydroxybenzofurane and 2-[(phenyl)Cr(CO)3]-3-hydroxyindole were obtained starting from the methyl ester of O-[(benzyl)Cr(CO)3]salicylic acid and methyl ester of N-[(benzyl)Cr(CO)3]anthranylic acid, respectively. In both cases an enol structure of products is conceivable following the IR and NMR evidence. An attempt to generate a four-membered ring by cyclization of appropriate substrate has remained unsuccessful, the reaction taking the course of an intermolecular condensation.
- Rosca, Sanziana,Stan, Raluca,Parlea, Elena,Rosca, Sorin I.,Grandclaudon, Pierre
-
p. 427 - 432
(2007/10/03)
-
- Structure-based design of cathepsin K inhibitors containing a benzyloxy- substituted benzoyl peptidomimetic
-
Peptidomimetic cathepsin K inhibitors have been designed using binding models which were based on the X-ray crystal structure of an amino acid- based, active site-spanning inhibitor complexed with cathepsin K. These inhibitors, which contain a benzyloxybenzoyl group in place of a Cbz-leucine moiety, maintained good inhibitory potency relative to the amino acid-based inhibitor, and the binding models were found to be very predictive of relative inhibitor potency. The binding mode of one of the inhibitors was confirmed by X-ray crystallography, and the crystallographically determined structure is in close qualitative agreement with the initial binding model. These results strengthen the validity of a strategy involving iterative cycles of structure-based design, inhibitor synthesis and evaluation, and crystallographic structure determination for the discovery of peptidomimetic inhibitors.
- Thompson, Scott K.,Smith, Ward W.,Zhao, Baoguang,Halbert, Stacie M.,Tomaszek, Thaddeus A.,Tew, David G.,Levy, Mark A.,Janson, Cheryl A.,D'Alessio, Karla J.,McQueney, Michael S.,Kurdyla, Jeff,Jones, Christopher S.,Desjarlais, Renee L.,Abdel-Meguid, Sherin S.,Veber, Daniel F.
-
p. 3923 - 3927
(2007/10/03)
-
- Selective endothelin A receptor ligands. 1. Discovery and structure-activity of 2,4-disubstituted benzoic acid derivatives
-
This paper describes the discovery of a new non-peptide endothelin A (ET(A)) selective ligand, 2,4-dibenzyloxybenzoic acid 3, which inhibits the binding of [125I]ET-1 to ET(A) receptors with an IC50 of 9 μM (ET-1 = endothelin-1). Optimisation of 3 resulted in compound 52 which had an IC50 of 1 μM. One of the analogues of 3, compound 15, was examined in a functional assay and shown to antagonise ET-1-induced contraction of rat aorta. The identification of 3 was made through the application of ChemDBS-3D searching of our corporate database. The 3D query, using an aromatic ring to a carboxylic acid group separated by 10.2 ± 1.1 A, was derived from an examination of common pharmacophoric distances found in the low energy conformations of two known ET(A) antagonists, the cyclic pentapeptide BQ 123 1 and myriceron caffeoyl ester 2.
- Astles,Brown,Handscombe,Harper,Harris,Lewis,Lockey,McCarthy,McLay,Porter,Roach,Smith,Walsh
-
p. 409 - 423
(2007/10/03)
-
- Facile alkoxyl exchange of 2-methoxybenzoates via nucleophilic aromatic substitution with sodium alkoxides in dimethylformamide
-
Methyl 2-methoxybenzoate undergoes facile nuclear-methoxyl displacement by treatment with sodium butexide or isopropoxide in dimethylformamide.
- Hattori,Satoh,Miyano
-
p. 3840 - 3842
(2007/10/02)
-
- Total Synthesis of Parabactin, a Spermidine Siderophore
-
The stereoselective total synthesis of parabactin (1) has been efficiently carried out using substituted 1,3-thiazolidine-2-thione as a leaving group.
- Nagao, Yoshimitsu,Miyasaka, Tadayo,Hagiwara, Yuichi,Fujita, Eiichi
-
p. 183 - 187
(2007/10/02)
-