- Unraveling the Self-Assembly Modes in Multicomponent Supramolecular Gels Using Single-Crystal X-ray Diffraction
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The control and prediction of the self-assembly process in multicomponent supramolecular gels are challenging because the structure and properties rely mostly on the geometry and spatial arrangement of the building blocks. The understanding of noncovalent
- Damodaran, Krishna K.,Farahani, Abbas D.,Ghosh, Dipankar,Martin, Adam D.,Thordarson, Pall
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- ANTICANCER AGENT DELIVERY MOLECULE
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PROBLEM TO BE SOLVED: To provide a compound which can be used as an anticancer agent targeting a cancer cell that highly expresses Lysine-specific demethylase 1 (LSD1) or salt thereof. SOLUTION: The present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, where Ar, R1, R2, L, Z, p, q, *1 and *2 are as defined in the specifications. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT
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Paragraph 0183-0184; 0188
(2017/08/04)
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- Development of amidine-based sphingosine kinase 1 nanomolar inhibitors and reduction of sphingosine 1-phosphate in human leukemia cells
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Sphingosine 1-phosphate (S1P) is a bioactive lipid that has been identified as an accelerant of cancer progression. The sphingosine kinases (SphKs) are the sole producers of S1P, and thus, SphK inhibitors may prove effective in cancer mitigation and chemosensitization. Of the two SphKs, SphK1 overexpression has been observed in a myriad of cancer cell lines and tissues and has been recognized as the presumptive target over that of the poorly characterized SphK2. Herein, we present the design and synthesis of amidine-based nanomolar SphK1 subtype-selective inhibitors. A homology model of SphK1, trained with this library of amidine inhibitors, was then used to predict the activity of additional, more potent, inhibitors. Lastly, select amidine inhibitors were validated in human leukemia U937 cells, where they significantly reduced endogenous S1P levels at nanomolar concentrations.
- Kennedy, Andrew J.,Mathews, Thomas P.,Kharel, Yugesh,Field, Saundra D.,Moyer, Morgan L.,East, James E.,Houck, Joseph D.,Lynch, Kevin R.,MacDonald, Timothy L.
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experimental part
p. 3524 - 3548
(2011/07/07)
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- Synthesis and biological activity of optimized belactosin C congeners
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Successful biochemical studies of the natural products belactosin A and C as well as their more stable acylated derivatives have proved them to be powerful proteasome inhibitors and thereby potential candidates as pharmacologically relevant active compoun
- Korotkov, Vadim S.,Ludwig, Antje,Larionov, Oleg V.,Lygin, Alexander V.,Groll, Michael,De Meijere, Armin
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scheme or table
p. 7791 - 7798
(2011/12/05)
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- Creation of superior carboxyfluorescein dyes by blocking donor-excited photoinduced electron transfer
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(Chemical Equation Presented) Carboxyfluoresceins are widely utilized as fluorescence labeling reagents, but we recently found that their emission intensity is markedly decreased after esterification. On the basis of our hypothesis that the fluorescence d
- Mineno, Tomoko,Ueno, Tasuku,Urano, Yasuteru,Kojima, Hirotatsu,Nagano, Tetsuo
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p. 5963 - 5966
(2007/10/03)
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- Process for preparation of dicarboxylic acid monoesters
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A process for producing a dicarboxylic acid monoester which comprises subjecting a dicarboxylic acid monoester or an alkali metal salt of a dicarboxylic acid monoester and a metal alkoxide to transesterification in the presence of an organic solvent, or a process for producing a dicarboxylic acid monoester which comprises subjecting a dicarboxylic acid monoester or an alkali metal salt of a dicarboxylic acid monoester and an alcohol to transesterification in the presence of a metal alkoxide.
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- Design, synthesis, and proposed active site binding analysis of monocyclic 2-azetidinone inhibitors of prostate specific antigen
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A homology derived molecular model of prostate specific antigen (PSA) was created and refined. The active site region was investigated for specific interacting functionality and a binding model postulated for the novel 2-azetidinone acyl enzyme inhibitor 1 (IC50 = 8.98 ± 0.90 μM) which was used as a lead compound in this study. A single low energy conformation structure II (Figure 2) was adopted as most likely to represent binding after minimization and dynamics calculations. Systematic analysis of the binding importance of all three side chains appended to the 2-azetidinone was conducted by the synthesis of several analogues. A proposed salt bridge to Lys-145 with 4 (IC50 = 5.84 ± 0.92 μM) gave improved inhibition, but generally the binding of the N-1 side chain in a specific secondary aromatic binding site did not tolerate much structural alteration. A hydrophobic interaction of the C-4 side chain afforded inhibitor 6 (IC50 = 1.43 ± 0.19 μM), and polar functionality could also be added in a proposed interaction with Gln-166 in 5 (IC50 = 1.34 ± 0.05 μM). Reversal of the C-4 ester connectivity furnished inhibitors 7 (IC50 = 1.59 ± 0.15 μM), 11 IC50 = 3.08 ± 0.41 μM) and 13 (IC50 = 2.19 ± 0.36 Mμ) which were perceived to bind to PSA by a rotation of 180° relative to the C-4 ester of normal connectivity. Incorporation of hydroxyl functionality into the C-3 side chain provided 16 IC50 = 348 ± 50 nM) with the greatest increase in PSA inhibition by a single modification. Multiple copy simultaneous search (MCSS) analysis of the PSA active site further supported our model and suggested that 18 would bind strongly. Asymmetric synthesis yielded 18 (IC50 = 226 ± 10 nM) as the most potent inhibitor of PSA reported to date. It is concluded that our design approach has been successful in developing PSA inhibitors and could also be applied to the inhibition of other enzymes, especially in the absence of crystallographic information.
- Adlington,Baldwin,Becker,Chen,Cheng,Cooper,Hermann,Howe,McCoull,McNulty,Neubauer,Pritchard
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p. 1491 - 1508
(2007/10/03)
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- Computational predictions of binding affinities to dihydrofolate reductase: Synthesis and biological evaluation of methotrexate analogues
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The relative binding affinities to human dihydrofolate reductase of four new potential antifolates, containing ester linkages between the two aromatic systems, were estimated by free energy perturbation simulations. The ester analogue, predicted to exhibi
- Graffner-Nordberg,Marelius,Ohlsson,Persson,Swedberg,Andersson,Andersson,Aqvist,Hallberg
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p. 3852 - 3861
(2007/10/03)
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- Retinoid-like compounds
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The present invention relates to a compound of formula I STR1 or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, in whichX is --O--CO--, --NH--CO--, --CS--NH--, --CO--O--, --CO--NH--, --COS--, --SCO--, --SCH 2 --, --CH 2 --CH 2 --, --C C--, --CH 2 --NH--, --COCH 2 --, --NHCS--, --CH 2 S--, --CH 2 O--, --OCH 2 --, --NHCH 2 -- or --CR 5 CR 6 --;R m and R k are independently hydrogen, halogen, C 1-6 alkyl, hydroxy, C 1-6 alkyloxy or nitro;n is zero or one;R 4 is --(CH 2) t --Y, C 1-6 alkyl, or C 3-6 cycloalkyl;R 1 is --CO 2 Z, C 1-6 alkyl, CH 2 OH, --CONHR y, or CHO;R 2 and R 3 are independently hydrogen or C 1-6 alkyl;R a and R b are independently hydrogen or C 1-6 alkyl; but when n is one, R a and R b together can form a radical of the formula STR2 Y is naphthyl or phenyl, both radicals can be optionally substituted with one to three same or different C 1-6 alkyl or halogen;Z is hydrogen or C 1-6 alkyl;R 5, R 6 and R y are independently hydrogen or C 1-6 alkyl; andt is zero to six.
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- Retinoid-like compounds
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The present invention relates to a compound of formula STR1 or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, in which X is --O--CO--, --NH--CO--, --CS--NH--, --CO--O--, --CO--NH--, --COS--, --SCO--, --SCH2 --, --CH2 --CH2 --, --C C--, --CH2 --NH--, --COCH2 --, --NHCS--, --CH2 S--, --CH2 O--, --OCH2 --, --NHCH2 -- or --CR5 =CR6 --; Rm and Rk are independently hydrogen, halogen, C1-6 alkyl, hydroxy, C1-6 alkyloxy or nitro; n is zero or one; R4 is --(CH2)t --Y, C1-6 alkyl, or C3-6 cycloalkyl; R1 is --CO2 Z, C1-6 alkyl, CH2 OH, --CONHRy, or CHO; R2 and R3 are independently hydrogen or C1-6 alkyl; Ra and Rb are independently hydrogen or C1-6 alkyl; but when n is one, Ra and Rb together can form a radical of the formula STR2 Y is naphthyl or phenyl, both radicals can be optionally substituted with one to three same or different C1-6 alkyl or halogen; Z is hydrogen or C1-6 alkyl; R5, R6 and Ry are independently hydrogen or C1-6 alkyl; and t is zero to six.
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- N-substituted amides
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N-substituted amides which inhibit hydrolysis of elastin, are described, which compounds are tri-and di- fluoromethyl ketone amide and non-naturally occurring n-substituted amino acids derivatives.
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- TETRAHYDROISOQUINOLINE AMIDES
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Tetrahydroisoquinoline amides having the general structure STR1 are disclosed, the substituents defined hereinbelow, which amides are useful in inhibiting human leukocyte and neutrophil elastaes.
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- Inhibition of human leukocyte elastase (HLE) by N-substituted peptidyl trifluoromethyl ketones
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A series of tripeptides possessing trifluoromethyl or aryl ketone residues at P1 were prepared and evaluated both in vitro and in vivo as potential inhibitors of human leukocyte elastase (HLE). Tripeptides containing non naturally occurring N-substituted glycine residues at the P2-position have been demonstrated to be potent in vitro inhibitors of HLE, with IC50 values in the submicromolar range. Sterically demanding substituents on the P2- nitrogen have no detrimental effect on in vitro potency. The inhibition process presumably acts via hemiketal formation with the active site Ser195 of HLE, and is facilitated by the strongly electron withdrawing trifluoromethyl functionality. Deletion of the amino acid at the P3-subsite region affords inactive compounds. Valine is the preferred residue at the P1-position, whereas the corresponding glycine, alanine, α,α- dimethylglycine, or phenylalanine analogues are all inactive. The compounds described herein all confer a high degree of in vitro specificity when tested against representative cysteine, aspartyl, metallo, and other serine proteases. One of the most potent in vitro inhibitors is (3RS)-N-[4[[[(4- chlorophenyl)sulfonyl]amino]carbonyl]phenyl]oxomethyl]-L-valyl-N-(2,3- dihydro-1H-inden-2-yl)glycine N-[3-(1,1,1-trifluoro-4-methyl-2- oxopentyl)amide (20i; BI-RA-260) (IC50 = 0.084 μM). Compound 20i was also tested in hamsters in an elastase-induced pulmonary hemorrhage (EPH) model. In this model, intratracheal (it.) administration of 20i, 5 min prior to HLE challenge, effectively inhibited hemorrhage in a dose-dependent manner with an ED50 of 4.8 μg. The inhibitor 20i, 20 μg administered it. 24, 48, and 72 h prior to HLE challenge, exhibits significant inhibition against hemorrhage at all time points (97%, 64% and 49%, respectively). In a 21-day chronic model of emphysema in hamsters, 200 μg of HLE administered it. caused an elastase-induced emphysema in the lungs which can be quantitated histologically utilizing image analysis. In this assay, 20i significantly inhibited pulmonary lesions associated with septal destruction and increased alveolar spaces, when dosed at 20 μg it. 5 min prior to challenge with HLE.
- Skiles,Fuchs,Miao,Sorcek,Grozinger,Mauldin,Vitous,Mui,Jacober,Chow,Matteo,Skoog,Weldon,Possanza,Keirns,Letts,Rosenthal
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p. 641 - 662
(2007/10/02)
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- PREPARATION AND PROPERTIES OF OLIGOMERS OF DEFINED CHAIN LENGTH AND STRUCTURE AS MODELS FOR TECHNICAL COPOLYMERS
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Oligomeric segments of the macromolecules with defined structure have been prepared in an attempt to answer the question whether the thermal and mechanical properties of the elastomers (polyester) are mainly influenced by the segregation or by the structu
- Seliger, H.,Bitar, M. B.,Goeldner, E.,Kittel, I.,Kilian, H. G.
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p. 171 - 186
(2007/10/03)
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- N-substituted amides
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Compounds of the formula are inhibitors of human leukocyte elastase.
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- SELECTED DIFLUORO DERIVATIVES
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The invention discloses a series of difluoroketone, mono-di-and tri-peptide derivatives of formula Ia, Ib and Ic: ______________________________________ (Formula set out on pages following Examples) Ia (Formula set out on pages following Examples) Ib (Formula set out on pages following Examples) Ic ______________________________________ and salts thereof where appropriate, and wherein the radicals are defined hereafter in the specification. The derivatives are useful in inhibiting the action of human leukocyte elastase. There are also disclosed methods and intermediates for the manufacture of, and pharmaceutical compositions comprising, the said derivatives.
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