- Synthesis and Characterization of Azido Aryl Analogs of IBNtxA for Radio-Photoaffinity Labeling Opioid Receptors in Cell Lines and in Mouse Brain
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Mu opioid receptors (MOR-1) mediate the biological actions of clinically used opioids such as morphine, oxycodone, and fentanyl. The mu opioid receptor gene, OPRM1, undergoes extensive alternative splicing, generating multiple splice variants. One type of splice variants are truncated variants containing only six transmembrane domains (6TM) that mediate the analgesic action of novel opioid drugs such as 3′-iodobenzoylnaltrexamide (IBNtxA). Previously, we have shown that IBNtxA is a potent analgesic effective in a spectrum of pain models but lacks many side-effects associated with traditional opiates. In order to investigate the targets labeled by IBNtxA, we synthesized two arylazido analogs of IBNtxA that allow photolabeling of mouse mu opioid receptors (mMOR-1) in transfected cell lines and mMOR-1 protein complexes that may comprise the 6TM sites in mouse brain. We demonstrate that both allyl and alkyne arylazido derivatives of IBNtxA efficiently radio-photolabeled mMOR-1 in cell lines and MOR-1 protein complexes expressed either exogenously or endogenously, as well as found in mouse brain. In future, design and application of such radio-photolabeling ligands with a conjugated handle will provide useful tools for further isolating or purifying MOR-1 to investigate site specific ligand–protein contacts and its signaling complexes.
- Grinnell, Steven G.,Uprety, Rajendra,Varadi, Andras,Subrath, Joan,Hunkele, Amanda,Pan, Ying Xian,Pasternak, Gavril W.,Majumdar, Susruta
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p. 977 - 993
(2020/05/29)
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- Disassembly of polymeric nanoparticles with enzyme-triggered polymer unzipping: Polyelectrolyte complexes: Vs. amphiphilic nanoassemblies
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Alkaline phosphatase (ALP) responsive polymers, which can unzip from head to tail are reported. Hydrophilic and hydrophobic modification of the polymer was carried out for the formation of a polyelectrolyte complex and an amphiphilic nanoassembly, respect
- Kumar, Vikash,Munkhbat, Oyuntuya,Secinti, Hatice,Thayumanavan
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supporting information
p. 8456 - 8459
(2020/08/13)
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- Photopromoted Entry to Benzothiophenes, Benzoselenophenes, 3H-Indoles, Isocoumarins, Benzosultams, and (Thio)flavones by Gold-Catalyzed Arylative Heterocyclization of Alkynes
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Visible light-promoted and gold-photoredox-catalyzed reactions of heteroatom (N, S, Se, O) tethered alkynes with arenediazonium salts selectively proceeded to build vicinal diaryl-substituted 2H-benzo[e][1,2]thiazine 1,1-dioxides (benzosultams), benzoselenophenes, benzothiophenes, 4H-chromen-4-ones (flavones), 3H-indoles, 1H-isochromen-1-ones (isocoumarins), and 4H-thiochromen-4-ones (thioflavones). Moreover, the utility of functionalized 3H-indoles as precursors for further elaboration has been demonstrated with the switchable and facile preparation of 1H-indoles, 2-oxindoles, and 3-oxindolines. (Figure presented.).
- Alcaide, Benito,Almendros, Pedro,Busto, Eduardo,Herrera, Fernando,Lázaro-Milla, Carlos,Luna, Amparo
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supporting information
p. 2640 - 2652
(2017/08/16)
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- A dramatic enhancing effect of InBr3 towards the oxidative Sonogashira cross-coupling reaction of 2-ethynylanilines
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The addition of InBr3 to the oxidative Sonogashira cross-coupling reaction of 2-ethynylaniline with (E)-trimethyl(3,3,3-trifluoroprop-1-enyl)silane led to a dramatic increase in the reactivity to afford the corresponding 1,3-enynes bearing a trifluoromethyl group on their terminal sp2 carbon. The subsequent cyclization of these 1,3-enynes under palladium catalysis provides access to the corresponding indoles bearing a 3,3,3-trifluoroprop-1-enyl group at their 2-position.
- Ikeda,Omote,Kusumoto,Komori,Tarui,Sato,Ando
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supporting information
p. 2127 - 2133
(2016/02/18)
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- ALKYNE COMPOUNDS AS S-NITROSOGLUTATHIONE REDUCTASE INHIBITORS
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Provided are compounds of formula (Ia) and pharmaceutically acceptable salts thereof, wherein A, B, R 1, R 2, m and n are as defined herein, which are active as inhibitors of S-Nitrosoglutathione reductase (GSNOR). These compounds prevent, inhibit, or suppress the action of GSNOR and are therefore useful in the treatment of GSNOR mediated diseases, disorders, syndromes or conditions such as, e.g., pulmonary hypertension, acute respiratory distress syndrome (ARDS), asthma, bronchospasm, cough, pneumonia, pulmonary fibrosis, interstitial lung diseases, cystic fibrosis and chronic obstructive pulmonary disease (COPD).
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Page/Page column 101
(2016/05/02)
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- Consecutive gold(I)-catalyzed cyclization reactions of o -(buta-1,3-diyn-1-yl-)-substituted N-aryl ureas: A one-pot synthesis of pyrimido[1,6- a ]indol-1(2 H)-ones and related systems
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Treatment of readily available o-(buta-1,3-diyn-1-yl-)-substituted N-aryl ureas such as 1 with the Au(I)-catalyst 11 affords, via a twofold cyclization process, the isomeric pyrimido[1,6-a]indol-1(2H)-one 3 in good yield.
- Sharp, Phillip P.,Banwell, Martin G.,Renner, Jens,Lohmann, Klaas,Willis, Anthony C.
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supporting information
p. 2616 - 2619
(2013/07/11)
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- Synthesis and evaluation of bidentate ligands designed to interact with PDZ domains
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We designed bidentate ligands to target PDZ domains through two binding sites: site S0, delimited by the GLGF loop, and site S1, a zone situated around loop βB/βC. A molecular docking study allowed us to design a generic S0 binder, to which was attached a variable size linker, itself linked to an amino acid aimed to interact with the S1 site of PDZ domains. A series of 15 novel bidentate ligands was prepared in 6-11 steps in good overall yield (24-43%). Some of these ligands showed an inhibitory activity against serotonin 5-HT2A receptor/PSD-95 interaction. This was assessed by pull-down assay using a synthetic decapeptide corresponding to the C-terminal residues of the receptor as a bait.
- Boucherle, Benjamin,Vogrig, Alexandre,Deokar, Hemantkumar,Bouzidi, Naoual,Ripoche, Isabelle,Thomas, Isabelle,Marin, Philippe,Ducki, Sylvie
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scheme or table
p. 4346 - 4354
(2011/08/10)
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- NOVEL CC-1065 ANALOGS AND THEIR CONJUGATES
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This invention relates to novel analogs of the DNA-alkylating agent CC-1065 and to their conjugates. Furthermore this invention concerns intermediates for the preparation of said agents and conjugates. The conjugates are designed to release their (multiple) payload after one or more activation steps and/or at a rate and time span controlled by the conjugate in order to selectively deliver and/or controllably release one or more of said DNA alkylating agents. The agents, conjugates, and intermediates can be used to treat an illness that is characterized by undesired (cell) proliferation. As an example, the agents and the conjugates of this invention may be used to treat a tumor.
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Page/Page column 140
(2010/06/17)
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- Extending helicity - Capturing the helical character of longer ortho-phenylene ethynylene oligomers
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New ortho-phenylene ethynylene oligomers are shown to fold into helices of up to two full turns. Evidence of folding is shown by both 1D NMR, where π-π stacking is explored through both solvent and temperature titrations, as well as by 2D ROESY NMR which
- Jones, Ticora V.,Slutsky, Morris M.,Tew, Gregory N.
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p. 676 - 679
(2008/09/20)
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- SELF-IMMOLATIVE POLYMERS
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Self-immolative polymers, designed to release a chemical moiety, or a plurality of chemical moieties, upon a pre-determined cleavage event, or sequences of events, are disclosed. The polymers can be simple polymers, comb polymers or branched polymers. Fur
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Page/Page column 41-42
(2008/12/05)
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- Palladium-catalyzed chloroimination of imidoyl chlorides to a triple bond: An intramolecular reaction leading to 4-chloroquinolines
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(Chemical Equation Presented) In this paper, a new type of effective chloroimination was reported. This reaction afforded 4-chloro-2-perfluoroalkyl quinolines from fluorinated imidoyl chlorides in high yields. This is the first achievement of oxidative addition-reductive elimination type C-Cl bond activation by chloropalladation.
- Isobe, Akira,Takagi, Jun,Katagiri, Toshimasa,Uneyama, Kenji
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supporting information; scheme or table
p. 2657 - 2659
(2009/05/27)
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- Formation of arenes via diallylarenes: Strategic utilization of Suzuki-Miyaura cross-coupling, Claisen rearrangement and ring-closing metathesis
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Two new synthetic strategies for benzoannulation are reported. The first strategy is based on the Suzuki-Miyaura cross-coupling reaction. To this end, various ortho-diallylbenzene derivatives were prepared from the corrresponding diiodo derivatives by an allylation strategy using an allylboronate as coupling partner. These diallyl derivatives were subjected to a ring-closing metathesis (RCM) and one-pot dichlorodicyanoquinone (DDQ) oxidation sequence to deliver 2-substituted naphthalenes. In the second strategy, a double Claisen rearrangement and RCM protocol have been used as key steps to give highly functionalized benzoannulated quinone derivatives.
- Kotha, Sambasivarao,Shah, Vrajesh R.,Mandal, Kalyaneswar
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p. 1159 - 1172
(2008/04/03)
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- Spin system assignment of homo-o-phenylene ethynylene oligomers
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We previously reported the synthesis and solution characterization of short o-phenylene ethynylene (oPE) foldamers. Proton correlation techniques are not adequate for NMR assignment in these compounds as the ethynylene linkers interrupt proton connectivit
- Slutsky, Morris M.,Jones, Ticora V.,Tew, Gregory N.
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p. 342 - 347
(2007/10/03)
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- Rhodium-catalyzed cycloisomerization: Formation of indoles, benzofurans, and enol lactones
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(Chemical Equation Presented) Internal affairs: Indoles, benzofurans, and enol lactones are formed chemoselectively from the rhodium-catalyzed cyclo-isomerization reaction of easily prepared alkynyl aniline substrates (see scheme, cod = cycloocta-1,5-diene, DMF = N,N-dimethylformamide). The reaction may proceed by nucleophilic capture of a vinylidene intermediate. Indoles are formed under mild conditions using low catalyst loadings.
- Trost, Barry M.,McClory, Andrew
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p. 2074 - 2077
(2008/02/14)
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- Preparation of polyfunctional arylmagnesium reagents bearing a triazene moiety. A new carbazole synthesis
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(Chemical Equation Presented) The reaction of iodo- or bromo-substituted aryltriazenes with i-PrMgCl·LiCl generates the corresponding magnesiated derivatives which react with various electrophiles (acid chlorides, 3-iodoenones, allylic halides, aldehydes)
- Liu, Ching-Yuan,Knochel, Paul
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p. 2543 - 2546
(2007/10/03)
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- Solution 1H NMR confirmation of folding in short o-phenylene ethynylene oligomers
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Oligomers based on an o-phenylene ethynylene (oPE) backbone with polar substituents have been synthesized using Sonogashira methods. Folding of these extremely short oligomers was confirmed via 1D and 2D (NOESY) NMR methods. Utilizing electron-rich and el
- Jones, Ticora V.,Slutsky, Morris M.,Laos, Roberta,De Greef, Tom F. A.,Tew, Gregory N.
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p. 17235 - 17240
(2007/10/03)
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- Synthesis of polyfunctional indoles and related heterocycles mediated by cesium and potassium bases
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A general preparation of 2-substituted indoles starting from functionalized 2-alkynylanilines has been developed. This base mediated reaction has also been used to synthesize the heterocyclic core of the marine alkaloid hinckdentine A. Furthermore the reaction was successfully adapted to the solid phase. Benzofurans and isoindolones could also be prepared with this method.
- Koradin, Christopher,Dohle, Wolfgang,Rodriguez, Alain L.,Schmid, Bertram,Knochel, Paul
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p. 1571 - 1587
(2007/10/03)
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- Viral polymerase inhibitors
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An isomer, enantiomer, diastereoisomer, or tautomer of a compound, represented by formula I: wherein: A is O, S, NR1, or CR1, wherein R1 is defined herein; ---- represents either a single or a double bond; R2 is selected from: H, halogen, R21, OR21, SR21, COOR21, SO2N(R22)2, N(R22)2, CON(R22)2, NR22C(O)R22 or NR22C(O)NR22 wherein R21 and each R22 is defined herein; B is NR3 or CR3, with the proviso that one of A or B is either CR1 or CR3, wherein R3 is defined herein; K is N or CR4, wherein R4 is defined herein; L is N or CR5, wherein R5 has the same definition as R4 defined above; M is N or CR7, wherein R7 has the same definition as R4 defined above; Y1 is O or S; Z is N(R6a)R6 or OR6, wherein R6a is H or alkyl or NR61R62 wherein R61 and R62 are defined herein; a salt or a derivative thereof, as an inhibitor of HCV NS5B polymerase.
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- Substituted phenyl farnesyltransferase inhibitors
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Compounds of formula (I) or pharmaceutically acceptable salts thereof, inhibit farnesyltransferase. Methods for making the compounds, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds are disclosed.
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- Preparation and reactions of functionalized arylmagnesium reagents
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Functionalized magnesium reagents have been prepared via an iodine-magnesium exchange. These reagents can be either trapped directly with aldehydes or transmetallated to copper or zinc to participate in cross-coupling reactions. The iodine-magnesium exchange, represent a unique method for the preparation of aryl and heteroaryl magnesium reagents.
- Jensen, Anne Eeg,Dohle, Wolfgang,Sapountzis, Ioannis,Lindsay, David M.,Vu, Viet Anh,Knochel, Paul
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p. 565 - 569
(2007/10/03)
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- Preparation of Polyfunctional Heterocycles Using Highly Functionalized Aminated Arylmagnesium Reagents as Versatile Scaffolds
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(Equation Presented) Functionalized Grignard reagents, derived from readily available o-iodoaniline derivatives and obtained via a straightforward iodine-magnesium exchange, can be used to prepare a wide range of polyfunctional indoles, quinolines, and quinazolinones.
- Lindsay, David M.,Dohle, Wolfgang,Jensen, Anne Eeg,Kopp, Felix,Knochel, Paul
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p. 1819 - 1822
(2007/10/03)
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- Substituted quinolinecarboxamides as antiviral agents
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The present invention discloses disubstiuted 4-oxo-1,4-dihydro-3-quinolinecarboxamide derivatives. The compounds are useful as antiviral agents, in particular, as agents against viruses of the herpes family.
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- Pyrroloquinolones as antiviral agents
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The present invention provides a compound of formula I which is useful as antiviral agents, in particular, as agents against viruses of the herpes family.
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- 1N-ALKYL-N-ARYLPYRIMIDINAMINES AND DERIVATIVES THEREOF
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The present invention provides novel compounds, compounds and pharmaceutical compositions thereof, and methods of using same in the treatment of affective disorders, anxiety, depression, post-traumatic stress disorders, eating disorders, supranuclear palsy, irritable bowel syndrome, immune suppression, Alzheimer'disease, gastrointestinal diseases, anorexia nervosa, drug and alcohol withdrawal symptoms, drug addiction, inflammatory disorders, or fertility problems. The novel compounds provided by this invention are those of formula: wherein R 1, R 3, R 4, R 5, Z, Y, V, X, X', J, K, L, and M are as defined herein.
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- 1N-alkyl-N-arylpyrimidinamines and derivatives thereof
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The present invention provides novel compounds, compounds and pharmaceutical compositions thereof, and methods of using same in the treatment of affective disorders, anxiety, depression, post-traumatic stress disorders, eating disorders, supranuclear palsy, irritable bowel syndrome, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa, drug and alcohol withdrawal symptoms, drug addiction, inflammatory disorders, or fertility problems. The novel compounds provided by this invention are those of formula: wherein R1, R3, R4, R5, Z, Y, V, X, X', J, K, L, and M are as defined herein.
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- Non-peptide corticotropin-releasing hormone antagonists: Syntheses and structure activity relationships of 2-anilinopyrimidines and -triazines
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Screening of our chemical library using a rat corticotropin-releasing hormone (CRH) receptor assay led to the discovery that 2-anilinopyrimidine 15-1 weakly displaced [125I]-0-Tyr-oCRH from rat frontal cortex homogenates when compared to the known peptide antagonist α-helical CRH(9- 41) (K(i) = 5700 nM vs 1 nM). Furthermore, 15-1 weakly inhibited CRH- stimulated adenylate cyclase activity in the same tissue, but it was less potent than α-helical CRH(9-41) (IC50 = 20 000 nM vs 250 nM). Systematic structure-activity relationship studies, using the cloned human CRH1 receptor assay, defined the pharmacophore for optimal binding to hCRH1 receptors. Several high-affinity 2-anilinopyrimidines and -triazines were discovered, some of which had superior pharmacokinetic profiles in the rat. This paper describes the structure-activity studies which improved hCRH1 receptor binding affinity and pharmacokinetic parameters in the rat. Compound 28-17 (mean hCRH(1)K(1) = 32 nM) had a significantly improved pharmacokinetic profile in the rat (19% oral bioavailability at 30 mg/kg) as well as in the dog (20% oral bioavailability at 5 mg/kg) relative to the early lead structures.
- Arvanitis, Argyrios G.,Gilligan, Paul J.,Chorvat, Robert J.,Cheeseman, Robert S.,Christos, Thomas E.,Bakthavatchalam, Rajagopal,Beck, James P.,Cocuzza, Anthony J.,Hobbs, Frank W.,Wilde, Richard G.,Arnold, Charles,Chidester, Dennis,Curry, Matthew,He, Liqi,Hollis, Andrea,Klaczkiewicz, John,Krenitsky, Paul J.,Rescinito, Joseph P.,Scholfield, Everett,Culp, Steven,De Souza, Errol B.,Fitzgerald, Lawrence,Grigoriadis, Dimitri,Tam, S. William,Wong, Y. Nancy,Huang, Shiew-Mei,Shen, Helen L.
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p. 805 - 818
(2007/10/03)
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- Iodoaminopotentidine and related compounds: A new class of ligands with high affinity and selectivity for the histamine H2 receptor
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The synthesis and biological evaluation of a new class of histamine H2 antagonists with N-cyano-N'-[ω-[3-(1- piperidinylmethyl)phenoxy]alkyl]guanidine partial structure are described as part of an extensive research program to find model compounds for the development of new radioligands with high H2 affinity and specific activity. High receptor affinity is achieved by an additional (substituted) aromatic ring, which is connected with the third guanidine N by a carbon chain spacer and an amine, carboxamide, ester, or sulfonamide link ('polar group'). In functional studies for H2 antagonistic activity and other pharmacological actions [e.g. H1 antihistaminic, antimuscarinic, antiadrenergic (α1, β1), 5-HT2 blocking activity] in the isolated guinea pig atrium and ileum and rat aorta and tail artery, the compounds proved to be highly potent and selective histamine H2 receptor antagonists. The H2 antagonistic activity is mainly depending on the length of both the N'-alkyl chain (chain A) and the N''-spacer (chain B). Compounds with a C3 chain A and a C2 chain B are most potent in the preferred group of substances, i.e., the carboxamide series. A wide variety of substituents at the aromatic ring is tolerated, among them iodine, amino, and azido groups. These compounds are up to 32 times more potent than cimetidine in the isolated guinea pig right atrium. The replacement of the carboxamide by an ester group (44c) is well tolerated, while replacement of the cyanoguanidine by an urea group results in nearly 100-fold decrease in activity (46c,e). The iodinated benzamides are among the most potent H2 antagonists known so far. The [125I]-labeled form of 31f ([125]iodoaminopotendine, [125I]-N-[2-(4-amino-3-iodobenzamido)ethyl]- N'-cyano-N''-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]guanidine) and its photolabile analogue 31h ([125I]iodoazidopotentidine, [125I]-N-[2-(4- azido-3-iodobenzamido)ethyl]-N'-cyano-N''-[3-[3-(1-piperidinyl- methyl)phenoxy]propyl]guanidine) proved to be useful probes for reversible and irreversible labeling of the histamine H2 receptor. Radioligand binding studies in guinea pig cerebral membranes revealed considerably higher H2 receptor affinity for 31f (pK(i) = 9.15), 31h (pK(i) = 8.58), and some analogues than functional experiments (guinea pig atrium), presumably reflecting an easier access to the H2 receptors in membranes.
- Hirschfeld,Buschauer,Elz,Schunack,Ruat,Traiffort,Schwartz
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p. 2231 - 2238
(2007/10/02)
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