- Bisthioureas of pimelic acid and 4-methylsalicylic acid derivatives as selective inhibitors of tissue-nonspecific alkaline phosphatase (TNAP) and intestinal alkaline phosphatase (IAP): Synthesis and molecular docking studies
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Alkaline phosphatases (ALPs) are membrane bound metalloenzymes, distributed all over the body. Recent studies have revealed that by targeting ALPs can lead towards the treatment of many deadliest diseases including cardiac, cancerous and brain diseases. Thioureas and their derivatives are of considerable significance and are privileged scaffolds in medicinal chemistry. They show a wide range of pharmacological activities such as antibacterial, antiparasitic, anti-inflammatory and antioxidants etc. On the other hand, salicylic acid and its derivatives are known for its broad spectrum of activities. The work presented comprises of synthesis of N-acyl-N'-aryl substituted bisthioureas of pimelic acid (1–7) and 3,5-dimethyl pyrazole (11), 1-aroyl-3-aryl thiourea (12) and 1,3,4-oxadiazole (13) derivatives of 4-methyl salicylic acid. Structures of all the synthesized compounds were characterized by FT-IR and 1H NMR spectroscopic analysis. Synthesized compounds were evaluated for their alkaline phosphatases inhibition potential and exhibited high potency as well as selectivity towards h-TNAP and h-IAP. Compound 7 and 12 which were the bisthiourea derivative of pimmelic acid and thiourea derivative of 4-methyl salicylic acid, respectively, showed excellent selectivity against h-TNAP and h-IAP, respectively.
- Iqbal, Jamshed,Mahmood, Abid,Mumtaz, Amara,Pelletier, Julie,Sévigny, Jean,Saeed, Aamer,Saeed, Kiran,Zaib, Sumera
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Read Online
- Decarboxylative Borylation of mCPBA-Activated Aliphatic Acids
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A decarboxylative borylation of aliphatic acids for the synthesis of a variety of alkylboronates has been developed by mixing m-chloroperoxybenzoic acid (mCPBA)-activated fatty acids with bis(catecholato)diboron in N,N-dimethylformamide (DMF) at room temperature. A radical chain process is involved in the reaction which initiates from the B-B bond homolysis followed by the radical transfer from the boron atom to the carbon atom with subsequent decarboxylation and borylation.
- Wei, Dian,Liu, Tu-Ming,Zhou, Bo,Han, Bing
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supporting information
p. 234 - 238
(2020/01/02)
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- Small-Molecule Activators of Glucose-6-phosphate Dehydrogenase (G6PD) Bridging the Dimer Interface
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We recently identified AG1, a small-molecule activator that functions by promoting oligomerization of glucose-6-phosphate dehydrogenase (G6PD) to the catalytically competent forms. Biochemical experiments indicate that the activation of G6PD by the original hit molecule (AG1) is noncovalent and that one C2-symmetric region of the G6PD homodimer is important for ligand function. Consequently, the disulfide in AG1 is not required for activation of G6PD, and a number of analogues were prepared without this reactive moiety. Our study supports a mechanism of action whereby AG1 bridges the dimer interface at the structural nicotinamide adenine dinucleotide phosphate (NADP+) binding sites of two interacting G6PD monomers. Small molecules that promote G6PD oligomerization have the potential to provide a first-in-class treatment for G6PD deficiency. This general strategy could be applied to other enzyme deficiencies in which control of oligomerization can enhance enzymatic activity and/or stability.
- Raub, Andrew G.,Hwang, Sunhee,Horikoshi, Naoki,Cunningham, Anna D.,Rahighi, Simin,Wakatsuki, Soichi,Mochly-Rosen, Daria
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supporting information
p. 1321 - 1324
(2019/07/04)
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- Thermotropic liquid crystalline polyesters derived from 2-chloro hydroquinone
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Abstract: Synthesis of thermotropic liquid crystalline polyesters derived from bis[4-hydroxy benzoyloxy]-2-chloro-1,4-benzene (BHBOCB) and aliphatic dicarboxylic acid chlorides by interfacial polycondensation methodology is presented. Synthesised polyesters consist of bis[4-hydroxy benzoyloxy]-2-chloro-1,4-benzene as a mesogen and aliphatic diacid chloride as flexible spacer. The length of oligomethylene units in the polymer was varied from the trimethylene to the dodecamethylene groups. Synthesized polyesters were characterized by differential scanning calorimetry and optical microscopy. The transition temperatures and thermodynamic properties were studied for all these polymers. These polyesters exhibited thermotropic liquid crystalline behavior and showed nematic texture except decamethylene spacer. Decamethylene spacer based polyester showed marble texture of smectic C. Mesophase stability of these polyesters was higher than 123 °C (except first heating cycle of PE-1). Graphical Abstract:: SYNOPSIS The present study deals with the synthesis of thermotropic liquid crystalline polyesters derived from bis[4-hydroxy benzoyloxy]-2-chloro-1,4-benzene (BHBOCB) and aliphatic dicarboxylic acid chlorides by interfacial polycondensation methodology. [Figure not available: see fulltext.].
- Manurkar, Nagesh,More, Sayaji,Mulani, Khudbudin,Ganjave, Nitin,Chavan, Nayaku
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p. 1461 - 1468
(2017/09/27)
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- Preparation method of 1,7-pimeloyl dichloride
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The invention discloses a preparation method of 1,7-pimeloyl dichloride. The compound, 1,7-pimeloyl dichloride, which has a complex structure, is synthesized with 1,7-pimelic acid, thionyl chloride and the like raw materials. The product is high in yield, is good in crystallization effect, is high in purity and can be used as high-purity reference products and standard samples for follow-up chemical and biological experiments.
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Paragraph 0012; 0013; 0014
(2016/11/28)
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- Tailoring flavins for visible light photocatalysis: organocatalytic [2+2] cycloadditions mediated by a flavin derivative and visible light
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A new application of flavin derivatives in visible light photocatalysis was found. 1-Butyl-7,8-dimethoxy-3-methylalloxazine, when irradiated by visible light, was shown to allow an efficient cyclobutane ring formation via an intramolecular [2+2] cycloaddition of both styrene dienes, considered as electron-rich substrates, and electron-poor bis(arylenones), presumably proceeding via an energy transfer mechanism.
- Mojr, Viktor,Svobodová, Eva,Straková, Karolína,Nevesely, Tomá?,Chudoba, Josef,Dvo?áková, Hana,Cibulka, Radek
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supporting information
p. 12036 - 12039
(2015/07/28)
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- NOVEL TRANSCRIPTION FACTOR MODULATORS
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The present disclosure provides novel compounds capable of functioning as transcription factor modulators, as well as compositions, pharmaceutical formulations, and kits. Also provided are methods of treating a condition regulatable by a transcription factor and/or cofactor using the compounds, compositions, pharmaceutical formulations, and kits provided herein.
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Paragraph 0178; 0179; 0180
(2014/09/29)
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- Synthesis and binding profile of haloperidol-based bivalent ligands targeting dopamine D2-like receptors
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Homodimers of dopamine D2-like receptors are suggested to be of particular importance in the pathophysiology of schizophrenia and, thus, serve as promising targets for the discovery of atypical antipsychotics. This study describes the development of a series of novel bivalent molecules with a pharmacophore derived from the dopamine receptor antagonist haloperidol. These dimers were investigated in comparison to their monomeric analogues for their D2long, D2short, D3, and D4 receptor binding and the ability to bridge two neighboring receptor protomers. Radioligand binding studies provided diagnostic insights when Hill slopes close to two for the bivalent ligand 13 incorporating 22 spacer atoms and a comparative analysis with monovalent control ligands indicated a bivalent binding mode with a simultaneous occupancy of two neighboring binding sites.
- Salama, Ismail,L?ber, Stefan,Hübner, Harald,Gmeiner, Peter
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supporting information
p. 3753 - 3756
(2014/09/16)
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- Synthesis and biological evaluation of novel sinomenine derivatives as anti-inflammatory agents
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Sinomenine (1) is clinically available for the treatment of rheumatoid arthritis (RA), however, its efficacy is quite weak. In the present study, a library of novel sinomenine-based homodimers and monomers through variable-length linkers were designed and synthesized, and their bioactivities were evaluated using RAW264.7 cells and mice. Among the compounds, 2f and 3b possessed much more potent inhibitory effects on the production of nitric oxide (NO), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) than 1. Preliminary mechanism investigation revealed that 3b inhibited nuclear factor-κB (NF-κB) signaling pathway specifically, 2f suppressed both NF-κB and mitogen-activated protein kinase (MAPK) cascades. Moreover, 3b and 2f significantly alleviated the lipopolysaccharide (LPS)-induced mortality. These two compounds might serve as valuable candidates for anti-inflammatory drug discovery.
- Teng, Peng,Liu, Hai-Liang,Zhang, Lei,Feng, Li-Li,Huai, Yue,Deng, Zhang-Shuang,Sun, Yang,Xu, Qiang,Li, Jian-Xin
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experimental part
p. 63 - 74
(2012/07/14)
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- Anion recognition by N,N′-diarylalkanediamides
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The preparation of N,N′-diarylalkanediamides from the respective aliphatic dicarboxylic acids and 4-nitroaniline via microwave-prompted reactions is presented. The most positive effect of microwave irradiation was observed for N,N′-bis(4-nitrophenyl)butanediamide. Anion binding studies on the obtained diamides were carried out in DMSO and acetonitrile using UV-vis and 1H NMR spectroscopy. A mechanism for selective fluoride recognition by N,N′-bis(4-nitrophenyl)butanediamide in DMSO is proposed.
- Wagner-Wysiecka, Ewa,Lukasik, Natalia
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supporting information
p. 6029 - 6034,6
(2020/08/20)
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- Catalytic, asymmetric transannular aldolizations: Total synthesis of (+)-hirsutene
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We report an asymmetric, catalytic transannular aldolization that provides polycyclic products useful for natural product synthesis. We found that a proline-derivative catalyzes the transannular aldol reaction of 1,4-cyclooctanediones to the corresponding cyclic β-hydroxy ketones in good yields and with high enantioselectivities. The utility of our reaction has been demonstrated in a total synthesis of (+)-hirustene. Copyright
- Chandler, Carley L.,List, Benjamin
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p. 6737 - 6739
(2008/12/22)
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- Low-energy collision-induced fragmentation of negative ions derived from diesters of aliphatic dicarboxylic acids made with hydroxybenzoic acids
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Diesters of ortho-hydroxybenzoic acid (salicylic acid) made with glutaric, adipic, and pimelic acids are the monomers of some potential drug candidates for aspirin patches. Collision-induced dissociation (CID) spectra of negative ion derived from these compounds show a 120-Da 'neutral loss' specific to the ortho isomers. In contrast, the anions derived from diesters of meta- and para-hydroxybenzoic acids show a 138-Da loss for an elimination of elements of hydroxybenzoic acid by a charge-remote mechanism. Deuterium labeling studies confirmed that the hydrogen atom transferred for hydroxybenzoic acid loss originates specifically from the α position of the dicarboxylic acid moiety. Although all spectra showed a peak at m/z 137, a charge-mediated process specific for the ortho compounds renders it the most prominent peak in the spectra of ortho compounds. Appropriate deuterium labeling experiments demonstrated that the hydrogen atom transferred for the formation of the m/z 137 ion in ortho compounds is specifically derived from the α position of the dicarboxylic acid moiety. Copyright
- Nishshanka, Upul,Attygalle, Athula B.
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experimental part
p. 1502 - 1511
(2009/10/10)
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- Synthesis, modelling, and μ-opioid receptor affinity of N-3(9)-arylpropenyl-N-9(3)-propionyl-3,9-diazabicyclo[3.3.1]nonanes
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A series of N-3-arylpropenyl-N-9-propionyl-3,9-diazabicyclo[3.3.1]nonanes (1a-g) and of reverted N-3-propionyl-N-9-arylpropenyl isomers (2a-g), as homologues of the previously reported analgesic 3,8-diazabicyclo[3.2.1]octanes (I-II), were synthesized and evaluated for the binding affinity towards opioid receptor subtypes μ, δ and κ. Compounds 1a-g and 2a-g exhibited a strong selective μ-affinity with Ki values in the nanomolar range, which favourably compared with those of I and II. In addition, contrary to the trend observed for DBO-I, II, the μ-affinity of series 2 is markedly higher than that of the isomeric series 1. This aspect was discussed on the basis of the conformational studies performed on DBN which allowed hypotheses on the mode of interaction of these compounds with the μ receptor.
- Pinna,Murineddu,Curzu,Villa,Vianello,Borea,Gessi,Toma,Colombo,Cignarella
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p. 553 - 562
(2007/10/03)
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- Preparation and Structural Analysis of Several New α,α,α',α'-Tetraaryl-1,3-dioxolane-4,5-dimethanols (TADDOL's) and TADDOL Analogs, Their Evaluation as Titanium Ligands in the Enantioselective Addition of Methyltitanium and Diethylzinc Reagents to Benzaldehyde, and Refinement of ...
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Preparation and screening of twenty new ligands, all analogs of α,α,α',α'-tetraaryl-1,3-dioxolane-4,5-dimethanol (TADDOL), for the Ti-catalyzed asymmetric addition of methyltri(isopropoxy)titanium and diethylzinc to benzaldehyde are described.These ligands have the dioxolane ring of the TADDOL's replaced by cyclobutane, cyclopentane, cyclohexene, cyclohexane, bicycloheptene and -heptane and bicyclooctene and -octane moieties; several have H-atoms or alkyl groups in place of the aryl groups, and nine of them have C2 symmetry.X-Ray crystallography and molecular mechanics are used to analyze the structure of the ligands, and two structural features appear to correlate with selectivity: i) the torsion angle for the chelating O-atom and the ortho-C-atom of the axial Ph group (a small, ca. 19 deg, angle is optimum, Fig. 8) and ii) the "degree of perpendicularity" of the axial Ph group (Fig. 9).Competition experiments indicate that TADDOL 1a catalyzes both the methyltitanium and diethylzinc additions >/= 50 times faster than the related dioxolane analogs 12a, 12c, and 12e (Scheme 7), indicating that both axial and equatorial aryl groups (see Footnote 6) are necessary for ligand-accelerated catalysis of these reactions.A refined mechanistic hypotesis is presented (Fig. 10) to explain the selectivities observed for these new ligands.Our analysis suggests that a combination of structural features appear necessary for good catalytic efficiency and high selectivity.These features, especially the rather subtle conformational effects, appear to be optimized (among the ligands tested) in the TADDOL's.
- Ito, Yoshio N.,Ariza, Xavier,Beck, Albert K.,Bohac, Andrej,Ganter, Camille,et al.
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p. 2071 - 2110
(2007/10/02)
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- Structural Aspects of the Protonation of Small Cages. Preparation of the New Aza-cage 12,17-Dimethyl-1,9,12,17-tetra-azabicyclononadecane (L). Thermodynamic Studies on Solution Equilibria. Crystal Structures of and Salts
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The synthesis and characterisation of the new aza-cage 12,17-dimethyl-1,9,12,17-tetra-azabicyclononadecane (L) are described.The basicity behaviour in both aqueous and water-DMSO (50:50), mol:mol) solutions has been investigated by potentiometric and microcalorimetric (25 deg C, 0.15 mol dm-3 NaCl) techniques.L behaves in aqueous solution as a fairly strong base (log K1 = 12.00; ΔH01 = -54.0 kJ mol-1; TΔS = 14.5 kJ mol-1) in the first protonation step and as a moderate base in the second step (log K2 = 7.86; ΔH02 = -44.8 kJ mol-1; TΔS02 ca. 0).The enthalpic and entropic contributions are discussed in terms of molecular topology and translational entropy.The Cu(II) ion is encapsulated by L, the electronic spectra being diagnostic of a square-planar structure.The molecular structures of the diprotonated salts and (L1 = 5,12,17-trimethyl-1,5,9,12,17-penta-azabicyclononadecane have been determined by single crystal X-ray analysis.Crystals of are orthorombic, space group Pbn21, with a = 9.311(3) Angstroem, b = 15.480(2) Angstroem, c = 16.636(6) Angstroem, and Z = 4.Final R values of 0.043 (RW = 0.037) for 1358 observed reflections.X-Ray analysis shows that the protonation occurs on the N-CH3 groups.Each hydrogen atom of the NH+-CH3 interacts with the two bridgehead nitrogen atoms.The compound crystallizes in a monoclinic unit cell (space group P21) with lattice constants a = 8.877(3) Angstroem, b = 14.088(8) Angstroem, c = 10.122(5) Angstroem, β = 105.51(4) deg, and Z = 2.Final R values of 0.064 (RW = 0.049) for 2374 observed reflections.In this case the conformation of the diprotonated cage is different and the protonation probably occurs at one of the two methylated nitrogens and at the apical nitrogen atom.
- Bencini, Andrea,Bianchi, Antonio,Borselli, Angela,Ciampolini, Mario,Micheloni, Mauro,et al.
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p. 209 - 214
(2007/10/02)
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- Conception et synthese de chelatants du fer III pour le traitement de la chlorose ferrique
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New iron chelates containing pyrocatechol subunits bounded in α-position of a linear dicarboxylic acid are reported.The design of the structure and the choice of the synthetic scheme (with the help of Assisted Organic Synthesis) are presented.The six steps synthesis scheduled, needs the protection-deprotection of the carboxylic acids and the use of gaiacol preferably to pyrochatecol.The synthetic route is discussed.The individual steps and the characteristics of 20 reaction intermediates and products are described.The scope of the study is presented.
- Mhenni, F.,Bouraoui, A.,Mighri, Z.,Gallo, R.
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p. 824 - 829
(2007/10/02)
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- SYNTHESIS AND DIRECT PHOTOLYSIS OF CIS-1,2-DI-TERT.-BUTYL-CYCLOHEPTENE
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1,2-Di-tert.-butyl-cycloheptene 6 was obtained from pimelic acid 1 in a three step sequence via intramolecular reductive coupling of the diketone 5.Direct photolysis of 6 gave endo-1,7-di-tert.-butyl-norcarane 7.
- Jendralla, Heiner
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p. 3657 - 3660
(2007/10/02)
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