- Revised Structure of Anthelvencin A and Characterization of the Anthelvencin Biosynthetic Gene Cluster
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Anthelvencins A and B are pyrrolamide metabolites produced by Streptomyces venezuelae ATCC 14583 and 14585. Isolated in 1965, they were reported to exhibit anthelmintic and moderate antibacterial activities. In this study, we revise the structure of anthelvencin A and identify a third anthelvencin metabolite, bearing two N-methylated pyrrole groups, which we named anthelvencin C. We sequenced the genome of S. venezuelae ATCC 14583 and identified a gene cluster predicted to direct the biosynthesis of anthelvencins. Functional analysis of this gene cluster confirmed its involvement in anthelvencin biosynthesis and allowed us to propose a biosynthetic pathway for anthelvencins. In addition to a nonribosomal peptide synthetase (NRPS), the assembly of anthelvencins involves an enzyme from the ATP-grasp ligase family, Ant23. We propose that Ant23 uses a PCP-loaded 4-aminopyrrole-2-carboxylate as substrate. As observed for the biosynthesis of the other pyrrolamides congocidine (produced by Streptomyces ambofaciens ATCC 25877) and distamycin (produced by Streptomyces netropsis DSM 40846), the NRPS assembling anthelvencins is composed of stand-alone domains only. Such NRPSs, sometimes called type II NRPSs, are less studied than the classical multimodular NRPSs. Yet, they constitute an interesting model to study protein-protein interactions in NRPSs and are good candidates for combinatorial biosynthesis approaches.
- Aubry, Céline,Clerici, Paolo,Gerbaud, Claude,Lautru, Sylvie,Micouin, Laurent,Pernodet, Jean-Luc
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p. 945 - 951
(2020/05/19)
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- Design and Synthesis of 56 Shape-Diverse 3D Fragments
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Fragment-based drug discovery is now widely adopted for lead generation in the pharmaceutical industry. However, fragment screening collections are often predominantly populated with flat, 2D molecules. Herein, we describe a workflow for the design and synthesis of 56 3D disubstituted pyrrolidine and piperidine fragments that occupy under-represented areas of fragment space (as demonstrated by a principal moments of inertia (PMI) analysis). A key, and unique, underpinning design feature of this fragment collection is that assessment of fragment shape and conformational diversity (by considering conformations up to 1.5 kcal mol?1 above the energy of the global minimum energy conformer) is carried out prior to synthesis and is also used to select targets for synthesis. The 3D fragments were designed to contain suitable synthetic handles for future fragment elaboration. Finally, by comparing our 3D fragments with six commercial libraries, it is clear that our collection has high three-dimensionality and shape diversity.
- Atobe, Masakazu,Blakemore, David C.,Bond, Paul S.,Chan, Ngai S.,De Fusco, Claudia,Downes, Thomas D.,Firth, James D.,Hubbard, Roderick E.,Jones, S. Paul,Klein, Hanna F.,O'Brien, Peter,Roughley, Stephen D.,Vidler, Lewis R.,Waddelove, Laura,Whatton, Maria Ann,Wheldon, Mary C.,Woolford, Alison J.-A.,Wrigley, Gail L.
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supporting information
(2020/07/13)
-
- 2-PYRROLIDINE PHENYLHYDRAZIDES ANTIBACTERIAL AGENTS
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2-Pyrrolidine phenylhydrazides antibacterial agents The present invention relates to 2-pyrrolidine phenylhydrazide compounds of formula (I), which are selective antibacterials specifically agalnstAcineto barter baumannii.The invention also relates to their therapeutic use as antibacterials, to a process for their preparation and to pharmaceutical compositions containing them.
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Page/Page column 54
(2018/02/28)
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- Zirconium-catalysed N-acylation of lactams using unactivated carboxylic acids
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A large number of chemicals including surfactants, nootropic drugs and pesticides contain an N-acylated lactam moiety in their molecular structure. In this work, the direct, catalytic N-acylation of a number of lactams with various unactivated carboxylic
- Hulsbosch, Joris,Claes, Laurens,De Vos, Dirk E.
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supporting information
p. 1646 - 1650
(2018/04/06)
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- FUSED MORPHOLINOPYRIMIDINES AND METHODS OF USE THEREOF
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The present disclosure relates to Fused Morpholinopyrimidines, pharmaceutical compositions comprising an effective amount of a Fused Morpholinopyrimidine and methods for using a Fused Morpholinopyrimidine in the treatment of a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a Fused Morpholinopyrimidine.
- -
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Paragraph 1803
(2017/05/14)
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- BIS-HETEROARYL DERIVATIVES AS MODULATORS OF PROTEIN AGGREGATION
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The present invention relates to certain bis-heteroaryl compounds, pharmaceutical compositions containing them, and methods of using them, including methods for preventing, reversing, slowing, or inhibiting protein aggregation, and methods of treating diseases that are associated with protein aggregation, including neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Lewy body disease, Parkinson's disease with dementia, fronto- temporal dementia, Huntington's Disease, amyotrophic lateral sclerosis, and multiple system atrophy, and cancer including melanoma.
- -
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Paragraph 0156
(2017/02/24)
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- Impact of Functional Groups on the Copper-Initiated N-Arylation of 5-Functionalized Pyrrolidin-2-ones and Their Vinylogues
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The electronic effects governing the N-arylation of pyrrolidone were investigated. The generalization of our preliminary findings on a copper(I)-catalyzed Csp2-N coupling process was first improved with a wide variety of aryl and heteroaryl halides and methyl pyroglutamate. The optimized protocol was further extended to pyrrolidin-2-ones substituted at the C5-position with an aryl group bearing an electron-donating or electron-withdrawing group as well as to some of their substituted enaminoester vinylogues. The impact of substituents at the N- and C5-position on these coupling processes seemed to be pivotal for determining both the reaction profiles and yields.
- Baudelet, Davy,Da?ch, Adam,Rigo, Beno?t,Lipka, Emmanuelle,Gautret, Philippe,Homerin, Germain,Claverie, Christelle,Rousseau, Jolanta,Abuhaie, Cristina-Maria,Ghinet, Alina
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supporting information
p. 2226 - 2244
(2016/07/15)
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- FUSED MORPHOLINOPYRIMIDINES AND METHODS OF USE THEREOF
-
The present disclosure relates to Fused Morpholinopyrimidines, pharmaceutical compositions comprising an effective amount of a Fused Morpholinopyrimidine and methods for using a Fused Morpholinopyrimidine in the treatment of a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a Fused Morpholinopyrimidine.
- -
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Paragraph 1238
(2015/08/03)
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- Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan analogues as opioid receptor ligands
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A series of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan (NAQ) analogues were synthesized and pharmacologically characterized to study their structure-activity relationship at the mu opioid receptor (MOR). The competition binding assay showed two-atom spacer and aromatic side chain were optimal for MOR selectivity. Meanwhile, substitutions at the 1′- and/or 4′-position of the isoquinoline ring retained or improved MOR selectivity over the kappa opioid receptor while still possessing above 20-fold MOR selectivity over the delta opioid receptor. In contrast, substitutions at the 6′- and/or 7′-position of the isoquinoline ring reduced MOR selectivity as well as MOR efficacy. Among this series of ligands, compound 11 acted as an antagonist when challenged with morphine in warm-water tail immersion assay and produced less significant withdrawal symptoms compared to naltrexone in morphine-pelleted mice. Compound 11 also antagonized the intracellular Ca2+ increase induced by DAMGO. Molecular dynamics simulation studies of 11 in three opioid receptors indicated orientation of the 6′-nitro group varied significantly in the different 'address' domains of the receptors and played a crucial role in the observed binding affinities and selectivity. Collectively, the current findings provide valuable insights for future development of NAQ-based MOR selective ligands.
- Yuan, Yunyun,Zaidi, Saheem A.,Stevens, David L.,Scoggins, Krista L.,Mosier, Philip D.,Kellogg, Glen E.,Dewey, William L.,Selley, Dana E.,Zhang, Yan
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supporting information
p. 1701 - 1715
(2015/03/30)
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- FUSED RING COMPOUNDS AS HEPATITIS C VIRUS INHIBITORS, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
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Provided are fused tricyclic compounds effective to inhibit the function of the NS5A protein of formula (I), wherein X, X', Y, Y', A, A',Q1, Q2, R1-R4, X4, R5a, f and W are defined as in the description. Also provided herein are pharmaceutical compositions thereof, and uses in the manufacture of a medicament for treating HCV infection or a HCV disorder thereof.
- -
-
Paragraph 00353; 00354; 00487; 00488; 00679; 00680; 00681
(2014/06/23)
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- Total reflection fluorescent observation device
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A device and method for fluorescence observation have good operability, high sensitivity, and high acid reliability. The device is used for fluorescence observation using evanescent light. The angle of incidence of the excitation light is adjusted so that the excitation light is totally reflected from the surface of a substrate irrespective of the angle of the substrate surface. The method includes a step of shining the excitation light on the observation substrate while continuously varying the angle of the excitation light with respect to the observation substrate. In addition, the method includes a step of sensing the shone excitation light via optical sensors, and a step of setting the angle of total reflection according to the result of the sensing by the optical sensors. In the present device and method, the direction in which the shone excitation light travels varies with the angle of incidence.
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-
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- Structure activity relationship studies of 17-cyclopropylmethyl-3,14β- dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido) morphinan (NAQ) analogues as potent opioid receptor ligands: Preliminary results on the role of electronic characteristics for affinity and function
-
17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α- (isoquinoline-3′-carboxamido)morphinan (NAQ) was previously designed following the 'message-address' concept and was identified as a potent and highly selective mu opioid receptor (MOR) ligand based on its pharmacological profile. We here report the preliminary structure activity relationship (SAR) studies of this novel lead compound. For the new ligands synthesized as NAQ analogues, their binding assay results showed that a longer spacer and a saturated ring system of the side chain were unfavorable for their MOR selectivity over the kappa and delta opioid receptors. In contrast, substitutions with different electronic properties at either 1′- or 4′-position of the isoquinoline ring of the side chain were generally acceptable for reasonable MOR selectivity. The majority of NAQ analogues retained low efficacy at the MOR compared to NAQ in the 35S- GTP[γS] binding assays while electron-withdrawing groups at 1′-position of the isoquinoline ring induced higher MOR stimulation than electron-donating groups did. In summary, the electronic characteristics of substituents at 1′- or 4′-position of the isoquinoline ring in NAQ seem to be critical and need to be further tuned up to achieve higher MOR selectivity and lower MOR stimulation.
- Yuan, Yunyun,Elbegdorj, Orgil,Beletskaya, Irina O.,Selley, Dana E.,Zhang, Yan
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supporting information
p. 5045 - 5048
(2013/09/12)
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- Remote chiral induction in vinyl sulfonium salt-mediated ring expansion of hemiaminals into epoxide-fused azepines
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The planet of the azepines: Epoxy-fused azepines have been synthesized in a highly selective reaction with hemiaminals and vinyl sulfonium salts. Stereochemistry is controlled by the substituent at the four- or five-position of the hemiaminal. The key step involves ring-opening of the hemiaminal, conjugate addition onto a vinyl sulfonium salt, and epoxidation of the aldehyde by the in situ formed sulfur ylide. Copyright
- Yar, Muhammad,Unthank, Matthew G.,McGarrigle, Eoghan M.,Aggarwal, Varinder K.
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supporting information; experimental part
p. 372 - 375
(2011/10/09)
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- A remarkably simple protocol for the N -formylation of amino acid esters and primary amines
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A simple, convenient, and wide scope protocol for the N-formylation of amino acid esters and primary amines has been developed utilizing only imidazole in warm DMF.
- Suchy, Mojmir,Elmehriki, Adam A. H.,Hudson, Robert H. E.
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supporting information; experimental part
p. 3952 - 3955
(2011/09/19)
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- Nitrogen-containing bicyclic compounds active on chronic pain conditions
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The invention refers to compounds of general formula (I) wherein the R groups are, independently, H, C1-6alkyl, aryl, CF3; Y is CH2, C=O; X is bond, C=O, SO2, or C=N-CN; m is 0, 1; n is 0, 1; A is a heterocycle, or a phenyl group optionally substituted. The compounds are active on chronic pain conditions of different origin; they can be administered alone or with other drugs. Most of these compounds are new. The invention include a process to prepare said compounds, and pharmaceutical compositions suitable for their administration to a patient.
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Page/Page column 13
(2009/09/26)
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- ARYLOXY-SUBSTITUTED BENZIMIDAZOLE DERIVATIVES
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A glucokinase activator is provided; and a treatment and/or a preventive for diabetes, or a treatment and/or a preventive for diabetes such as retinopathy, nephropathy, neurosis, ischemic cardiopathy, arteriosclerosis, and further a treatment and/or a preventive for obesity are provided. The invention relates to a compound of a formula (I): [wherein R1 and R2 represent a hydrogen, etc.; R3 represents a hydrogen atom, a halogen atom, etc.; R4 each independently represents a hydrogen atom, a lower alkyl group, etc.; Q represents a carbon atom, a nitrogen atom or a sulfur atom (the sulfur atom may be mono- or di-substituted with an oxo group); R5 and R6 each represent a hydrogen atom, a lower alkyl group, etc.; X1, X2, X3 and X4 each independently represent a carbon atom or a nitrogen atom; Z represents an oxygen atom, a sulfur atom or a nitrogen atom; Ar represents an aryl or heteroaryl group optionally mono to tri-substituted with a group selected from the substituent group β; ring A represents a 5- or 6-membered nitrogen-containing heteroaromatic group; m indicates an integer of from 1 to 6; n indicates an integer of from 0 to 3; p indicates an integer of from 0 to 2 (provided that at least two of X1 to X4 are carbon atoms); q indicates 0 or 1] or its pharmaceutically-acceptable salt, which has an effect of glucokinase activation and is useful as a treatment for diabetes.
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Page/Page column 39
(2010/11/28)
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- 2,5-Disubstituted pyrrolidine carboxylates as potent, orally active sphingosine-1-phosphate (S1P) receptor agonists
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A series of 2,5-cis-disubstituted pyrrolidines were synthesized and evaluated as S1P receptor agonists. Compounds 15-21 were identified with good selectivity over S1P3 which lowered circulating lymphocytes after oral administration in mice.
- Colandrea, Vincent J.,Legiec, Irene E.,Huo, Pei,Yan, Lin,Hale, Jeffrey J.,Mills, Sander G.,Bergstrom, James,Card, Deborah,Chebret, Gary,Hajdu, Richard,Keohane, Carol Ann,Milligan, James A.,Rosenbach, Mark J.,Shei, Gan-Ju,Mandala, Suzanne M.
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p. 2905 - 2908
(2008/09/20)
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- Syntheses of seven-membered rings: Ruthenium-catalyzed intramolecular [5+2] cycloadditions
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The Ru-catalyzed intramolecular [5+2] cycloaddition of cyclopropylenynes is investigated with respect to the regio- and diastereoselectivity as well as the functional group compatibility of the reaction. Evidence for the mechanism as occurring through a ruthenacyclopentene intermediate is elucidated from 1) the study of the diastereoselectivity of the cycloaddition; 2) the effect of variation of substituents on the regioselectivity of cyclopropyl bond cleavage in 1,2-trans- and 1,2-cis-disubstituted cyclopropanes and 3) examples that clearly do not involve ruthenacyclohexene as intermediates as products still incorporate the cyclo propyl moiety. The scope and limitations of the Ru-catalyzed cycloaddition are discussed and compared with the Rh-catalyzed reaction. The potential power of this methodology towards natural product total synthesis is demonstrated by the formation of several polycyclic systems with the chosen reaction conditions and readily available cyclopropylenyne substrates.
- Trost, Barry M.,Shen, Hong C.,Horne, Daniel B.,Toste, F. Dean,Steinmetz, Bernhard G.,Koradin, Christopher
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p. 2577 - 2590
(2007/10/03)
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- Substituted diazabicycloalkane derivatives
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Compounds of formula (I) [in-line-formulae]Z-Ar1—Ar2??(I) [/in-line-formulae] wherein Z is a diazabicyclic amine, Ar1 is a 5- or 6-membered aromatic ring, and Ar2 is selected from the group consisting of an unsubstituted or substituted 5- or 6-membered heteroaryl ring; unsubstituted or substituted bicyclic heteroaryl ring; 3,4-(methylenedioxy)phenyl; carbazolyl; tetrahydrocarbazolyl; naphthyl; and phenyl; wherein the phenyl is substituted with 0, 1, 2, or 3 substituents in the meta- or para-positions. The compounds are useful in treating conditions or disorders prevented by or ameliorated by α7 nAChR ligands. Also disclosed are pharmaceutical compositions comprising compounds of formula (I) and methods for using such compounds and compositions.
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Page/Page column 25
(2010/02/11)
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- Acylase I in the alcoholysis of α-substituted dicarboxylic acid esters and derivatives: Enantio- and regioselectivity
-
Enantio- and regioselective butanolyses of α-substituted dimethyl succinates (substituents: Me-, MeO2CCH2-, NH2-, AcHN-, PrCOHN-, HO-, MeO-, PrO-, AcO-, PrCO2-, HepCO2-, Cl- and Br-) and glutarates (substituents: PrCONH- and CbzNH-) and that of methyl pyroglutamate with acylase I enzymes have been studied. Acylase I-catalyzed reactions were totally regioselective proceeding exclusively at the sterically more hindered methyl ester group α to the substituent. High enantioselectivities (E from 50 to >>100) were observed only for the substrates containing CONH functionality in the substituent although the C-N bond was unreactive. The nature of the substituent influenced which of the two enantiomers reacted faster. Copyright (C) 2000 Elsevier Science Ltd.
- Liljeblad, Arto,Lindborg, Jutta,Kanerva, Liisa T.
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p. 3957 - 3966
(2007/10/03)
-
- Studies on pyrrolidinones. Synthesis and reactivity of some N-protected pyroglutamic derivatives
-
The synthesis of pyroglutamoyl chloride N-protected by a methoxycarbonyl or a trifluoroacetyl group is described. Some aspects of the reactivity of these compounds and intermediates have been studied.
- Rigo,Erb,El Ghammarti,Gautret,Couturier
-
p. 1599 - 1604
(2007/10/03)
-
- γ-allenyl-γ-aminobutyric acids
-
This invention is for γ-allenyl-γ-aminobutyric acid derivatives which are γ-aminobutyric acid transaminase inhibitors.
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-
- Chemie der α-Aminonitrile. 1. Mitteilung. Einleitung und Wege zu Uroporphyrinogen-octanitrilen
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Chemistry of α-Aminonitriles I: Introduction and Pathways to Uroporphyrinogen-octanitriles.An introduction to experimental studies on the chemistry of α-aminonitriles potentially relevant to the problems of prebiotic chemistry is presented.The framework of conditions wherein the investigations is chosen to be carried out implies both molecular oxygen and - whenever feasible - water to be excluded from reaction conditions.This study focusses on 2-amino-2-propenenitrile (3) (Scheme 6) as central starting material of reaction sequences which aim at the nitrile forms of proteinogenic amino acids as well as at the aza forms of building blocks of biological cofactor molecules as their targets (Scheme 5).Schemes 13, 16, 23 as well as 25, and 26 summarize reaction sequences by which 3 is tranformed within the definied framework of conditions into the thermodynamic (statistically controlled) mixture of the four isomeric uroporphyrinogen-octanitriles 57-60.HPLC's of such mixtures document the dominance of the least symmetrical isomer whose constitutional pattern of peripheral substituents happens to be the one present in all biological porphinoids.Preparative procedures for the synthesis of 3 (Scheme 9), the β,β-disubstututed pyrrol-nitriles 30, 53, and 54 (Scheme 19) as well as the porphyrinogen-octakis(propionitrile) and -octakis(acetonitrile) 65 and 66, respectively (Scheme 24) are given.
- Ksander, Gary,Bold, Guido,Lattmann, Rene,Lehmann, Christian,Frueh, Thomas,et al.
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p. 1115 - 1172
(2007/10/02)
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- ALKYLATION OF SHIFF BASE ANIONS WITH ω-HALOGENO ESTERS: A LACTAM SYNTHESIS.
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Imine anions of α-aminoesters, obtained from NaH/DMSO are alkylated with ω-halogenoesters.Thermolysis of the alkylated compounds lead to functionnalized lactams.
- Mkhairi, A,Hamelin, J.
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p. 4435 - 4436
(2007/10/02)
-