- Substituent contributions to the transport of substituted p-toluic acids across lipid bilayer membranes
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The fluxes of p-toluic acid and seven α-methylene-substituted analogs have been determined as a function of pH across planar egg lecithin/decane bilayers to construct a set of well-isolated polar functional group contributions to the free energy of transfer from water to the bilayer transport barrier domain. Nonlinear regression analyses of flux-pH profiles using a model which accounts for unstirred layer effects yielded membrane permeability coefficients (P(RX)) that varied from 1.1 cm/s for p-toluic acid to 4.1 x 10-5 cm/s for the α-carbamoyl-p-toluic acid. Bulk organic solvent/water partition coefficients (K(RX)) were obtained for the same set of permeants using four solvent systems to identify a bulk solvent which closely resembles the chemical nature of the bilayer barrier microenvironment for these permeants. The slopes of plots of log P(RX) vs log K(RX) were 0.85, 0.91, 0.99, and 2.4, respectively, for hexadecane/water, hexadecane/water, 1,9-decadiene/water, and octanol/water with the best model solvent being that which yielded a slope closest to unity. A significant deviation in the slope from 1, as observed in the correlation with octanol/water partition coefficients, reveals that this relatively polar, hydrogen-bonding solvent is a poor model solvent for describing the barrier microenvironment for these permeants. Thus, the polar interfacial regions occupied by phospholipid head groups are not the barrier domain for the transport of the series examined in this study. The incremental group contributions to the free energy of transfer to the barrier domain (cal/mol) for the functional groups, Cl, OCH3, CN, OH, COOH, and CONH2, were found to be 325, 687, 2170, 3860, 5170, and 6060, respectively. Except for Cl, these group contributions are generally 500-1200 cal/mol smaller than those for transfer between water and hexadecane, resembling most closely the values obtained for transfer from water to 1,9-decadiene.
- Xiang,Anderson
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Read Online
- Pd(OH)2/C, a Practical and Efficient Catalyst for the Carboxylation of Benzylic Bromides with Carbon Monoxide
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A simple, efficient, cheap, and broadly applicable system for the carboxylation of benzylic bromides with carbon monoxide and water is reported. Upon simple reaction with only 2.5 wt % of Pearlman's catalyst and 10 mol % of tetrabutylammonium bromide in tetrahydrofuran at 110 °C for 4 h, a range of benzylic bromides can be smoothly converted to the corresponding arylacetic acids in good to excellent yields after simple extraction and acid-base wash. The reaction was found to be broadly applicable, scalable, and could be successfully extended to the use of ex situ-generated carbon monoxide and applied to the synthesis of the nonsteroidal anti-inflammatory drug diclofenac.
- Wakuluk-Machado, Anne-Marie,Dewez, Damien F.,Baguia, Hajar,Imbratta, Miguel,Echeverria, Pierre-Georges,Evano, Gwilherm
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p. 713 - 723
(2020/02/04)
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- Spiroindoline-Capped Selective HDAC6 Inhibitors: Design, Synthesis, Structural Analysis, and Biological Evaluation
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Histone deacetylase inhibitors (HDACi) have emerged as promising therapeutics for the treatment of neurodegeneration, cancer, and rare disorders. Herein, we report the development of a series of spiroindoline-based HDAC6 isoform-selective inhibitors based on the X-ray crystal studies of the hit 6a. We identified compound 6j as the most potent and selective hHDAC6 inhibitor of the series. Biological investigation of compounds 6b, 6h, and 6j demonstrated their antiproliferative activity against several cancer cell lines. Western blotting studies indicated that they were able to increase tubulin acetylation, without significant variation in histone acetylation state, and induced PARP cleavage indicating their apoptotic potential at the molecular level. 6j induced HDAC6-dependent pSTAT3 inhibition.
- Saraswati, A. Prasanth,Relitti, Nicola,Brindisi, Margherita,Osko, Jeremy D.,Chemi, Giulia,Federico, Stefano,Grillo, Alessandro,Brogi, Simone,McCabe, Niamh H.,Turkington, Richard C.,Ibrahim, Ola,O'Sullivan, Jeffrey,Lamponi, Stefania,Ghanim, Magda,Kelly, Vincent P.,Zisterer, Daniela,Amet, Rebecca,Hannon Barroeta, Patricia,Vanni, Francesca,Ulivieri, Cristina,Herp, Daniel,Sarno, Federica,Di Costanzo, Antonella,Saccoccia, Fulvio,Ruberti, Giovina,Jung, Manfred,Altucci, Lucia,Gemma, Sandra,Butini, Stefania,Christianson, David W.,Campiani, Giuseppe
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p. 2268 - 2276
(2020/12/17)
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- Synthetic method of fatty acid containing nitrogen heterocycle
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The invention discloses a synthetic method of fatty acid containing nitrogen heterocycle. The synthetic method comprises the following steps: (S1) adding a heterocyclic compound with substitution of chloromethyl groups, a catalyst and a solvent DMF into a reaction kettle; (S2) introducing carbon dioxide to lead the pressure in the kettle to be 2-4MPa, adjusting and reacting for 10-16 hours at thetemperature of 40-50 DEG C; (S3) adding diluted hydrochloric acid into the reaction kettle to carry out acidification, using ethyl acetate for extraction, combining organic phases, carrying out rotaryevaporation to remove liquid, and further carrying out vacuum drying, thus obtaining the fatty acid containing nitrogen heterocycle. The synthetic method disclosed by the invention has the beneficialeffects that a one-pot method is adopted, the raw materials are easy to obtain, price is low, aftertreatment of products is also simpler, the universality for a substrate is also very high, and the promotion and application are easy.
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Paragraph 0042
(2018/07/30)
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- AMIDE-LINKED EP4 AGONIST-BISPHOSPHONATE COMPOUNDS AND USES THEREOF
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The present invention relates to EP4 agonist-bisphosphonate conjugates or related compounds and uses thereof. Said conjugates or related compounds may be used to provide delivery of an EP4 agonist or related compound to a desired site of action, such as a bone. Bisphosphonate moieties, linked to the EP4 agonists via amide linkers, have been implicated in the inhibition of bone resorption and bone targeting.
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Paragraph 00127-00128
(2017/01/31)
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- Isoflavone amide type derivative, preparation method and medical application thereof
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The invention relates to the field of medicinal chemistry, and relates to an isoflavone amide type derivative, a preparation method and a medical application thereof, in particular to an isoflavone amide type derivative with the general formula (I), a preparation method thereof, medicine compositions including the isoflavone amide type derivative and a medical application thereof, especially an application of the isoflavone amide type derivative as a medicine for preventing or curing hyperlipemia, obesity or type II diabetes. The general formula (I) is shown in the description.
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Paragraph 0015; 0056; 0057; 0058
(2016/10/10)
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- SELECTIVE HDAC6 INHIBITORS
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The present invention provides hydroxamic acids of the formula described herein, that have activity toward inhibiting histone deacetylases, and in particular HDAC6. Also contemplated are pharmaceutical compositions and methods of use of an effective amount of the hydroxamic acid compounds provided, for treating a disease in a subject. In certain embodiments, the subject is afflicted with cancer, neurodegenerative disease, or HIV infection.
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- TRISUBSTITUTED HETEROCYCLIC DERIVATIVES AS ROR GAMMA MODULATORS
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The present invention provides trisubstituted heterocyclic derivatives of formula (I), which may be therapeutically useful, more particularly as RORγ modulators; (I) in which R1, R2, R3, Ra, X, L, m and ring A have the meanings given in the specification, and pharmaceutically acceptable salts thereof that are useful in the treatment and prevention of diseases or disorder, in particular their use in diseases or disorder where there is an advantage in modulating RORγ receptor. The present invention also provides preparation of the compounds and pharmaceutical formulations comprising at least one of the trisubstituted heterocyclic derivatives of formula (I) together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
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Page/Page column 39; 40
(2014/09/03)
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- CHROMONE INHIBITORS OF S-NITROSOGLUTATHIONE REDUCTASE
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The present invention is directed to inhibitors of S-nitrosoglutathione reductase (GSNOR), pharmaceutical compositions comprising such GSNOR inhibitors, and methods of making and using the same.
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- Discovery of hydrolytic catalysts in a peptidocalixarene library by binding assay with a transition state analogue for the hydrolysis
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Hydrolytic catalysts were found in a peptidocalixarene library by binding assay with a transition state analogue for the hydrolysis. The rate of the reaction can be specifically enhanced up to 50-fold in the presence of the discovered catalyst. The Royal
- Hioki, Hideaki,Nishimoto, Ryosuke,Kawaguchi, Kota,Kubo, Miwa,Harada, Kenichi,Fukuyama, Yoshiyasu
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supporting information; experimental part
p. 7194 - 7196
(2010/03/25)
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- Multicyclic bis-amide MMP inhibitors
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The present invention relates generally to bis-amide group containing pharmaceutical agents, and in particular, to multicyclic bis-amide MMP-13 inhibitor compounds. More particularly, the present invention provides a new class of MMP-13 inhibiting compounds, containing a pyrimidinyl bis-amide group in combination with a heterocyclic moiety, that exhibit an increased potency and solubility in relation to currently known bis-amide group containing MMP-13 inhibitors.
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Page/Page column 118-119
(2008/06/13)
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- 5-AMIDINO-2-HYDROXYBENZENESULFONAMIDE DERIVATIVES, MEDICINAL COMPOSITIONS CONTAINING THE SAME, MEDICINAL USE THEREOF AND INTERMEDIATES IN THE PRODUCTION THEREOF
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The present invention relates to a 5-amidino-2-hydroxybenzenesulfonamide derivative represented by the general formula: wherein R1 is an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted lower alkenyl group, a cycloalkyl group or a lower acyl group etc.; Q is a hydrogen atom or an optionally substituted lower alkyl group; and Z is a hydrogen atom or a hydroxy group etc., or a pharmaceutically acceptable salt thereof, which exert a potent and selective activated blood coagulation factor X inhibitory activity and is useful as an agent for the prevention or treatment of a disease occurred associating an activated blood coagulation factor X, a pharmaceutical composition comprising the same and an intermediate thereof. These compounds are useful as preventives or remedies for various diseases such as brain infarction, cerebral thrombosis, cerebral embolism, TIA, cerebral vascular jerk, Alzheimer's diseases, myocardial infarction, heart attack, heart failure, thrombosis, pulmonary infarction and pulmonary embolism.
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- 6-substituted pyrazolo[3,4-d]pyrimidin-4-ones useful as cyclin dependent kinase inhibitors
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The present invention relates to the synthesis of a novel class of pyrazolo[3,4-d]pyrimidin-4-ones of formula (I), alternatively represented by the tautomer (II): that are potent inhibitors of the class of enzymes known as cyclin dependent kinases, which relate to the catalytic subunits cyclin dependent kinase 1-8 and their regulatory subunits know as cyclins A-H, K, N, and T. This invention also provides a novel method of treating cancer or other proliferative diseases by administering a therapeutically effective amount of one of these compounds or a pharmaceutically acceptable salt form thereof. Alternatively, one can treat cancer or other proliferative diseases by administering a therapeutically effective combination of one of the compounds of the present invention and one or more other known anti-cancer or anti-proliferative agents.
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- Development of new palladium catalysts for the alkoxycarbonylation of aryl chlorides
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The alkoxycarbonylation of different aryl chlorides was studied. Studies of the butoxycarbonylation of 4-chlorobenzotrifluoride and chlorobenzene using chelating ferrocenylphosphines reveal the advantages of these ligands compared to the well-known tricyc
- M?gerlein, Wolfgang,Indolese, Adriano F,Beller, Matthias
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- Synthesis and photophysical characterization of a new, highly hydrophilic caging group
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o-Nitrobenzyl-protected bioactive compounds are useful tools in biophysics, allowing controlled photorelease of biologically active compounds with high temporal and spatial precision. Thus, it is possible to study biological processes, such as neurotransmitter-receptor interaction, and many other processes, in much more detail than before. In this respect, these caged compounds have become established as extremely useful tools. In some cases, however, their biological properties (the caged compound should not interact with the biological system), their photochemical properties (quantum yield and kinetics of the photorelease), and their physical properties (high hydrophilicity) are not satisfactory. In order to address the last problem, we examined means to increase the hydrophilicity of caged compounds based on the o-nitrobenzyl moiety. Here, we report the synthesis and the photochemical and biological characterization of a new caged Daspartate derivative with vastly improved hydrophilicity, compared to derivatives reported previously, and satisfactory photophysical properties. Caged compounds with this improved o-nitrobenzyl group may thus represent a valuable new tool for different kinds of biophysical investigations. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.
- Schaper, Klaus,Abdollah Madani Mobarekeh,Grewer, Christof
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p. 1037 - 1046
(2007/10/03)
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- An efficient method for one-carbon elongation of aryl aldehydes via their dibromoalkene derivatives
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Various aryl aldehydes were efficiently converted into one-carbon extended aryl acetamides or aryl acetic acids through the reaction of their dibromoalkene derivatives with pyrrolidine in the presence of water under very mild conditions.
- Huh, Dal Ho,Jeong, Ji Sang,Lee, Hee Bong,Ryu, Hoejin,Kim, Young Gyu
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p. 9925 - 9932
(2007/10/03)
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- Advances in the carbonylation of aryl halides using palladium catalysts
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The palladium-catalyzed carbonylation of aryl halides is shown to be a versatile tool for the synthesis of various benzoic and heteroaromatic acid derivatives. Recent developments from our laboratories in this area are presented.
- Beller, Matthias,Indolese, Adriano F.
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p. 684 - 687
(2007/10/03)
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- Heteroaromatic glucokinase activators
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2,3-Di-substituted N-heteroaromatic propionamides with said substitution at the 2-position being a substituted phenyl group and at the 3-position being a cycloalkyl ring, said propionamides being glucokinase activators which increase insulin secretion in the treatment of type II diabetes.
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- Analogues of methotrexate in rheumatoid arthritis. 2. Effects of 5- deazaaminopterin, 5,10-dideazaaminopterin, and analogues on type II collagen- induced arthritis in mice
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Twenty-six compounds derived from the 5-deaza- and 5,10- dideazaaminopterin series of aminopterin analogues were evaluated for antiarthritic activity in the mouse type II collagen model. New compounds in the 5-deaza series were prepared by alkylation of an appropriate N- substituted (4-aminobenzoyl)-L-glutamic acid dialkyl ester or N-(5-amino-2- thenoyl)-L-glutamate diester with a 2,4-diamino-5-alkyl-6-(bromomethyl)-5- deazapteridine. The resultant 5-deazaaminopterin diesters were saponified to provide the target 5-deaza analogues. 5,10-Dideazaaminopterins were synthesized by similar alkylation of the carbanions of appropriate 4- carboxyphenylacetic, (5-carboxy-2-thienyl)acetic, or (5-carboxy-2- pyridyl)acetic acid dimethyl esters. The diesters of the 2,4-diamino-4- deoxy-10-carboxy-5,10-dideazapteroic acid types so obtained were saponified and then readily decarboxylated by heating in Me2SO solution to provide the 2,4-diamino-5,10-dideazapteroic acid-type intermediates. Peptide coupling with diethyl L-glutamate followed by ester hydrolysis at room temperature afforded the new 5,10-dideazaaminopterin analogues. 5-Deazaaminopterins bearing an alkyl substituent at the 5-position were generally quite effective as antiinflammatory agents. Thus 5-propyl-5-deazaaminopterin, 5-methyl-10- propargyl-5-deazaaminopterin, 5-methyl-10-allyl-5-deazaaminopterin, 5-ethyl- 5-deazamethotrexate, and 2,5-disubstituted thiophene analogue of 5-methyl-5- deazaaminopterin showed potencies greater than methotrexate by intraperitoneal or oral administration and were active over a considerably broader dose range. Useful activity in the 5,10-dideaza series was only observed for 5,10-dideazaaminopterin and its 10-methyl analogue. Alkyl substitution at C-5 or C-10 was generally detrimental to antiinflammatory activity in this series.
- Piper, James R.,DeGraw, Joseph I.,Colwell, William T.,Johnson, Cheryl A.,Smith, R. Lane,Waud, William R.,Sirotnak, Francis M.
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p. 377 - 384
(2007/10/03)
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- Sunlamp-Irradiated Phase-Transfer Catalysis. 1. Cobalt Carbonyl Catalyzed SRN1 Carbonylations of Aryl and Vinyl Halides
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Cobalt carbonyl catalyzed carbonylation (1 atm) of aryl and vinyl halides may be easily achieved under phase-transfer-catalysis conditions provided that the reaction medium is irradiated.Irradiation may be achieved by a commercial sunlamp.Most of these reactions may also be performed without organic solvent and in some cases without a phase-transfer agent.Finally, this new, inexpensive carbonylation method allows very efficient synthesis of benzolactams and benzolactones.
- Brunet, Jean-Jacques,Sidot, Christian,Caubere, Paul
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p. 1166 - 1171
(2007/10/02)
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- PHASE TRANSFER CATALYSIS USING COBALT TRICARBONYL NITROSYL
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The first example of the use a mononuclear cobalt complex in a phase-transfer catalyzed process is described.The carbonylation of halides catalyzed by cobalt tricarbonyl nitrosyl gives, depending on the organic substrate, appreciably different results as compared with dicobalt octacarbonyl.
- Gambarotta, Sandro,Alper, Howard
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p. C23 - C26
(2007/10/02)
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