- New MT2 melatonin receptor-selective ligands: Agonists and partial agonists
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The search for melatonin receptor agonists and antagonists specific towards one of the receptor subtypes will extend our understanding of the role of this system in relaying circadian information to the body. A series of compounds derived from a hit compound discovered in a screening process led to powerful agonists specific for one of the isoform of the melatonin receptor namely, MT2. The compounds are based on a poorly explored skeleton in the molecular pharmacology of melatonin. By changing the steric hindrance of one substituent (i.e., from a hydrogen atom to a tributylstannyl group), we identified a possible partial agonist that could lead to antagonist analogues. The functionalities of these compounds were measured with a series of assays, including the binding of GTPγS, the inhibition of the cyclic AMP production, the β-arrestin recruitment, and the cell shape changes as determined by cellular dielectric spectroscopy (CellKey). The variations between the compounds are discussed.
- Boutin, Jean A.,Bonnaud, Anne,Brasseur, Chantal,Bruno, Olivier,Lepretre, Nolwenn,Oosting, Peter,Coumailleau, Sophie,Delagrange, Philippe,Nosjean, Olivier,Legros, Céline
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- Synthesis and biological evaluation of new carbohydrate-substituted indenoisoquinoline topoisomerase I inhibitors and improved syntheses of the experimental anticancer agents indotecan (LMP400) and indimitecan (LMP776)
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Carbohydrate moieties were strategically transported from the indolocarbazole topoisomerase I (Top1) inhibitor class to the indenoisoquinoline system in search of structurally novel and potent Top1 inhibitors. The syntheses and biological evaluation of 20 new indenoisoquinolines glycosylated with linear and cyclic sugar moieties are reported. Aromatic ring substitution with 2,3-dimethoxy-8,9-methylenedioxy or 3-nitro groups exerted strong effects on antiproliferative and Top1 inhibitory activities. While the length of the carbohydrate side chain clearly correlated with antiproliferative activity, the relationship between stereochemistry and biological activity was less clearly defined. Twelve of the new indenoisoquinolines exhibit Top1 inhibitory activity equal to or better than that of camptothecin. An advanced synthetic intermediate from this study was also used to efficiently prepare indotecan (LMP400) and indimitecan (LMP776), two anticancer agents currently under investigation in a Phase I clinical trial at the National Institutes of Health.
- Beck, Daniel E.,Agama, Keli,Marchand, Christophe,Chergui, Adel,Pommier, Yves,Cushman, Mark
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p. 1495 - 1512
(2014/03/21)
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- Cyclic nucleotide phosphodiesterase inhibitors, preparation and uses thereof
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The invention concerns novel benzodiazepine derivatives and their uses in the field of therapeutics particularly for treating pathologies involving the activity of a cyclic nucleotide phosphodiesterase. It also concerns methods for preparing them and novel synthesis intermediates. The inventive compounds more particularly correspond to general formula (I):
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Page/Page column 16-17
(2010/02/08)
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- Preparation of Novel 4-Substituted 6-Methoxy, 6,7-Dimethoxy-, and 6,7-(Methylenedioxy)isochroman-3-ones. 2
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The title compounds 20, 21, and 22 have been prepared in modest yields by a two-step reaction involving first the reaction of bromoarenes 3, 7, and 8 with lithioalkyl- and lithioarylacetonitriles under aryne-forming conditions.The cyano products 10, 14, and 16 so formed were then converted to the corresponding isochroman-3-ones by acidic hydrolysis.
- Khanapure, Subhash P.,Biehl, Edward R.
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p. 1471 - 1475
(2007/10/02)
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- STUDIES ON THE SYNTHESIS OF BENZOLACTAM RINGS. II SYNTHESIS OF 1,4-DIHYDRO-3(2H)-ISOQUINOLINONE DERIVATIVES
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A new synthesis of 1,4-dihydro-3(2H)-isoquinolinones by the amidomethylation with acrylacetamide or acrylacetonitrile and paraformaldehyde in some acid-catalysts is described.
- Kamochi, Yasuko,Watanabe, Yasuo
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p. 2385 - 2391
(2007/10/02)
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- Chloromethylation of 2-Bromo-4,5-dimethoxyphenylacetic Acid : Formation of 6,7-Dimethoxy-3-isochromanone
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Prolonged treatment of 2-bromo-4,5-dimethoxyphenylacetic acid (1) with 37percent formalin and hydrochloric acid in acetic acid affords 6,7-dimethoxy-3-isochromanone (4) resulting from the loss of the bromo substituent.The recently reported formation of 5,
- Nimgirawath, S.,Srikirin, Y.
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p. 272 - 273
(2007/10/02)
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- Synthetic Studies on Protoberberine Alkaloids
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Condensation of homoveratrylamine with substituted isochroman-3-ones (3a-c) affords N-β-(3,4-dimethoxyphenethyl)arylacetamides (4a-c).Treatment of 4a-c with POCl3 and subsequent NaBH4 reduction of the reaction products furnish (+/-)-2,3,9,10,11-pentamethoxytetrahydroprotoberberine (2a), (+/-)-12-hydroxymethyl-2,3,9,10,11-pentamethoxytetrahydroprotoberberine (2b) and (+/-) nor coralydine (2c), respectively.Oxidation of 2a with iodine furnishes 2,3,9,10,11-pentamethoxyprotoberberinium salt (1).Carbon-13 NMR assignments of 2c, 3b, 3c, 4b and 4c are also reported.
- Patra, Amarendra,Mukhopadhyay, Prabir K.,Ghosh, Gargi
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p. 173 - 175
(2007/10/02)
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- Active-Site-Directed Inhibition of &α-Chymotrypsin by Deaminatively Produced Carbonium Ions: An Example of Suicide or Enzyme-Activated-Substrate Inhibition
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N-Nitroso amides derived from phenylalanine and alanine were utilized as inhibitors of α-chymotrypsin.During the enzyme-catalyzed hydrolysis of these substrates, carbonium ions capable of alkylating nucleophilic groups are released in the active site.Nitroso lactams were also tested as substrates since they produce carbonium ions while still tethered to the enzyme at the acyl-enzyme stage.Kinetic studies indicated that at substrate/α-chymotrypsin ratios of 40:1 the acyclic substrates caused the following percent inhibition of α-chymotrypsin activity (substrate, percent inhibition): D-1a, 100; L-1a, 9; D-1c, 100; L-1c, 9.Nitroso lactams 2 and 3, in substrate/enzyme ratios of 54:1 and 20:1, respectively, caused 91 and 97percent inhibition of α-chymotrypsin activity.At low (6:1) substrate/enzyme ratios, the inhibition of nitroso lactam 3 was partially reversible.The extents of inhibition were decreased by the competitive inhibitor N-acetyl-L-tryptophan, indicating that the inhibitor substrates were acting at the active site.Radioactive analogues of D- and L-1a and of 3(14C) provided evidence that the inhibition was irreversible, since ca. 1.0 mol of the benzyl group of D-1a and ca. 1.6 mol of the aryl moiety in the case of 3 remained bound to the inhibited enzyme after dialysis or Sephadex G-25 chromatography (no alkylation occurred with L-1a).The enzymatic hydrolyses of the L isomers of phenylalanine substrates (1a,b) were faster than those of the D enantiomers, whereas in the alanine series (1c) the rate ratio was reversed.A model based on "reverse" binding of the two aromatic groups of substrates D-1a and D-1c in the enzyme active site is proposed to explain the hydrolysis rate and the preferential inhibition of α-chymotrypsin by the D antipodes.
- White, Emil H.,Jelinski, Lynn W.,Politzer, Ieva R.,Branchini, Bruce R.,Roswell, David F.
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p. 4231 - 4239
(2007/10/02)
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- Synthesis of 2-Hydroxy-3,10,11-trimethoxy-5,6,13,13a-tetrahydro-8H-dibenzoquinolizine (Govanine)
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Condensation of 6,7-dimethoxy-3-isochromanone (1) with 3-methoxy-4-benzyloxy-β-phenethylamine (2) gives N-(3-methoxy-4-benzyloxy-β-phenethyl)-4,5-dimethoxy-2-hydroxymethylphenylacetamide (3).Treatment of 3 with POCl3 followed by NaBH4 reduction and debenz
- Pandey, G. D.,Tiwari, K. P.
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