- Unified Synthesis of Polycyclic Alkaloids by Complementary Carbonyl Activation**
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A complementary dual carbonyl activation strategy for the synthesis of polycyclic alkaloids has been developed. Successful applications include the synthesis of tetracyclic alkaloids harmalanine and harmalacinine, pentacyclic indoloquinolizidine alkaloid nortetoyobyrine, and octacyclic β-carboline alkaloid peganumine A. The latter synthesis features a protecting-group-free assembly and an asymmetric disulfonimide-catalyzed cyclization. Furthermore, formal syntheses of hirsutine, deplancheine, 10-desbromoarborescidine A, and oxindole alkaloids rhynchophylline and isorhynchophylline have been achieved. Finally, a concise synthesis of berberine alkaloid ilicifoline B was completed.
- Christmann, Mathias,He, Guoli,List, Benjamin
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supporting information
p. 13591 - 13596
(2021/05/07)
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- Tryptamine derivatives disarm colistin resistance in polymyxin-resistant gram-negative bacteria
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The last three decades have seen a dwindling number of novel antibiotic classes approved for clinical use and a concurrent increase in levels of antibiotic resistance, necessitating alternative methods to combat the rise of multi-drug resistant bacteria. A promising strategy employs antibiotic adjuvants, non-toxic molecules that disarm antibiotic resistance. When co-dosed with antibiotics, these compounds restore antibiotic efficacy in drug-resistant strains. Herein we identify derivatives of tryptamine, a ubiquitous biochemical scaffold containing an indole ring system, capable of disarming colistin resistance in the Gram-negative bacterial pathogens Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli while having no inherent bacterial toxicity. Resistance was overcome in strains carrying endogenous chromosomally-encoded colistin resistance machinery, as well as resistance conferred by the mobile colistin resistance-1 (mcr-1) plasmid-borne gene. These compounds restore a colistin minimum inhibitory concentration (MIC) below the Clinical & Laboratory Sciences Institute (CLSI) breakpoint in all resistant strains.
- Barker, William T.,Chandler, Courtney E.,Melander, Roberta J.,Ernst, Robert K.,Melander, Christian
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p. 1776 - 1788
(2019/03/21)
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- IDO inhibitors
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Presently provided are methods for (a) modulating an activity of indoleamine 2,3-dioxygenase comprising contacting an indoleamine 2,3-dioxygenase with a modulation effective amount of a compound as described in one of the aspects described herein; (b) treating indoleamine 2,3-dioxygenase (IDO) mediated immunosuppression in a subject in need thereof, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound as described in one of the aspects described herein; (c) treating a medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound as described in one of the aspects described herein; (d) enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent and a compound as described in one of the aspects described herein; (e) treating tumor-specific immunosuppression associated with cancer comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound as described in one of the aspects described herein; and (f) treating immunosuppression associated with an infectious disease, e.g., HIV-I infection, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount a compound as described in one of the aspects described herein.
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Page/Page column 319
(2018/09/02)
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- BENZOFURANE AND BENZOTHIOPHENE DERIVATIVES AS PGE2 RECEPTOR MODULATORS
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The present invention relates to benzofurane and benzothiophene derivatives of formula (I) Formula (I) wherein (R1)n, R2, R3, R4a, R4b, R5a, R5b and Ar1 are as described in the description and their use in the treatment of cancer by modulating an immune response comprising a reactivation of the immune system in the tumor. The invention further relates to novel benzofurane and benzothiophene derivatives of formula (II) and their use as pharmaceuticals, to their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of formula (I), and especially to their use as modulators of the prostaglandin 2 receptors EP2 and/or EP4.
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Page/Page column 81; 82
(2018/12/13)
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- D1-like receptors distinguishing thieno-azecine regioisomers
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Designing ligands with D1/D5 subtype selectivity is a challenge because of the high identity within the receptor helices. Based on the lead compounds 1-3, the thieno-benzazecine regioisomers 4 and 5 were synthesized and biologically evaluated for their affinity towards the five dopamine receptor subtypes utilizing a radioligand binding affinity technique. Within the D1-like family, compound 4 showed 20 fold selectivity for the D5 subtype over D1 subtype (Ki = 3 nM, D1: 60 nM), while its regioisomer, compound 5 with a reversed thiophene position, prefers the D1 subtype over the D5 subtype (Ki = 4 nM, D5: 15 nM). The benzothieno-benzazecine analog 6 was shown to be one of the few azecine derivatives with high affinity for both the D1- and the D2-like family members in the same order of magnitude (Ki = 1.5 nM for D2 and 1.9 nM for D5). Thorough analysis of the amino acid residues constituting the binding pockets of the target dopamine receptor subtypes revealed that at the D5 receptor, either serine S 6.62 and threonine T 7.33 residues or a water network, stabilized by anionic amino acids could contribute to the selectivity pattern of the synthesized compounds.
- Abdel-Fattah, Mohamed A. O.,Abadi, Ashraf H.,Lehmann, Jochen,Schweikert, Peter M.,Enzensperger, Christoph
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p. 1679 - 1686
(2015/09/21)
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- Electron transfer reduction of nitriles using SmI2-Et 3N-H2O: Synthetic utility and mechanism
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The first general reduction of nitriles to primary amines under single electron transfer conditions is demonstrated using SmI2 (Kagan's reagent) activated with Lewis bases. The reaction features excellent functional group tolerance and represents an attractive alternative to the use of pyrophoric alkali metal hydrides. Notably, the electron transfer from Sm(II) to CN functional groups generates imidoyl-type radicals from bench stable nitrile precursors.
- Szostak, Michal,Sautier, Brice,Spain, Malcolm,Procter, David J.
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supporting information
p. 1092 - 1095
(2014/03/21)
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- PIPERAZINYL OXOALKYL TETRAHYDRO-BETA-CARBOLINES AND RELATED ANALOGUES
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Piperazinyl oxoalkyl tetrahydro-beta-carbolines and related analogues of the formula (I): are provided, as are methods for their preparation and use. Such compounds may generally be used to modulate ligand binding to histamine H3 receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of disorders in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and therapeutic methods are provided, as are methods for using such ligands for detecting histamine H3 receptors (e.g., receptor localization studies).
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Page/Page column 68
(2009/03/07)
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- BENZOHETEROCYCLYLETHYLCARBOXAMIDE DERIVATIVES
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The present invention relates to novel benzoheterocyclylethylcarboxamide derivatives of formula (I) in which the substituents are in the description, their process of preparation, their use as fungicides, particularly in the form of fungicidal compositions, methods for the control of phytopathogenic fungi of plants using these compounds or their compositions.
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Page/Page column 73
(2008/06/13)
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- FUSED HETEROCYCLIC COMPOUNDS USEFUL AS INHIBITORS OF HISTONE DEACETYLASE
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Disclosed are compounds of formula (I) that inhibit histone deacetylase (HDAC) enzymatic activity, pharmaceutical compositions comprising such compounds, as well as methods to treat conditions, particularly proliferative conditions, mediated at least in part by HDAC, wherein A, W, W1, W2, Ar2, and G are described herein.
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Page/Page column 170-172
(2008/06/13)
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- Modified ibogaine fragments: Synthesis and preliminary pharmacological characterization of 3-ethyl-5-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5- b]benzothiophenes
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Five phenyl-substituted derivatives and analogues of 1,2,3,4,5,6- hexahydroazepino[4,5-b]indole, 5, a major fragment of ibogaine (1), were synthesized and tested for binding to monoamine transporters, the NMDA receptor-coupled cation channel, and dopamine and opioid receptors. All five derivatives, 9 and 17a-d, displayed 8-10-fold higher affinity at the DA transporter than ibogaine and noribogaine (4). At the serotonin transporter, two compounds (9 and 17a) exhibited higher potency than ibogaine, while the rest had weaker binding affinities than the lead compound. In keeping with their structural similarity to ibogaine, all five compounds displayed weak to poor affinity for dopamine D1 and D2 receptors. However, two compounds, 17a,c, demonstrated moderate binding affinities at dopamine D3 receptors. All five compounds displayed weak to poor affinities for μ and κ opioid receptors and for the NMDA receptor-coupled cation channel. Despite the qualitative differences, derivatives and analogues of 5 may serve as useful substitutes for ibogaine.
- Efange, Simon M. N.,Mash, Deborah C.,Khare, Anil B.,Ouyang, Quinjie
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p. 4486 - 4491
(2007/10/03)
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- Polycyclic amines and intermediates therefor
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This invention relates to a new method for the preparation of amines containing alkylene groups by using cyclic alkylene sulphuric esters, and novel intermediates for use in the method. The new method is useful for preparation of i.a. pharmaceuticals. The novel intermediates are useful i.a. as surfactants.
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