- Bivalent Ligand Aiming Putative Mu Opioid Receptor and Chemokine Receptor CXCR4 Dimers in Opioid Enhanced HIV-1 Entry
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A bivalent compound 1a featuring both a mu opioid receptor (MOR) and a CXCR4 antagonist pharmacophore (naltrexone and IT1t) was designed and synthesized. Further binding and functional studies demonstrated 1a acting as a MOR and a CXCR4 dual antagonist wi
- Ma, Hongguang,Wang, Huiqun,Li, Mengchu,Barreto-De-Souza, Victor,Reinecke, Bethany A.,Gunta, Rama,Zheng, Yi,Kang, Guifeng,Nassehi, Nima,Zhang, Huijun,An, Jing,Selley, Dana E.,Hauser, Kurt F.,Zhang, Yan
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- Novel bivalent ligands carrying potential antinociceptive effects by targeting putative mu opioid receptor and chemokine receptor CXCR4 heterodimers
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The functional interactions between opioid and chemokine receptors have been implicated in the pathological process of chronic pain. Mounting studies have indicated the possibility that a MOR-CXCR4 heterodimer may be involved in nociception and related ph
- Li, Mengchu,Ma, Hongguang,Nassehi, Nima,Pagare, Piyusha P.,Santos, Edna J.,Selley, Dana E.,Stevens Negus, S.,Wang, Huiqun,Zhang, Yan
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- Platform to Discover Protease-Activated Antibiotics and Application to Siderophore-Antibiotic Conjugates
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Here we present a platform for discovery of protease-activated prodrugs and apply it to antibiotics that target Gram-negative bacteria. Because cleavable linkers for prodrugs had not been developed for bacterial proteases, we used substrate phage to discover substrates for proteases found in the bacterial periplasm. Rather than focusing on a single protease, we used a periplasmic extract of E. coli to find sequences with the greatest susceptibility to the endogenous mixture of periplasmic proteases. Using a fluorescence assay, candidate sequences were evaluated to identify substrates that release native amine-containing payloads. We next designed conjugates consisting of (1) an N-terminal siderophore to facilitate uptake, (2) a protease-cleavable linker, and (3) an amine-containing antibiotic. Using this strategy, we converted daptomycin - which by itself is active only against Gram-positive bacteria - into an antibiotic capable of targeting Gram-negative Acinetobacter species. We similarly demonstrated siderophore-facilitated delivery of oxazolidinone and macrolide antibiotics into a number of Gram-negative species. These results illustrate this platform's utility for development of protease-activated prodrugs, including Trojan horse antibiotics.
- Boyce, Jonathan H.,Dang, Bobo,Ary, Beatrice,Edmondson, Quinn,Craik, Charles S.,Degrado, William F.,Seiple, Ian B.
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p. 21310 - 21321
(2021/01/11)
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- From Inhibition to Degradation: Targeting the Antiapoptotic Protein Myeloid Cell Leukemia 1 (MCL1)
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Protein-protein interactions (PPIs) have emerged as significant targets for therapeutic development, owing to their critical nature in diverse biological processes. An ideal PPI-based target is the protein myeloid cell leukemia 1 (MCL1), a critical prosurvival factor in cancers such as multiple myeloma where MCL1 levels directly correlate to disease progression. Current strategies for halting the antiapoptotic properties of MCL1 revolve around inhibiting its sequestration of proapoptotic factors. Existing inhibitors disrupt endogenous regulatory proteins; however, this strategy actually leads to an increase of MCL1 protein levels. Here, we show the development of hetero-bifunctional small molecules capable of selectively targeting MCL1 using a proteolysis targeting chimera (PROTAC) methodology leading to successful degradation. We have confirmed the involvement of the E3 ligase CUL4A-DDB1 cereblon ubiquitination pathway, making these PROTACs a first step toward a new class of antiapoptotic B-cell lymphoma 2 family protein degraders.
- Papatzimas, James W.,Gorobets, Evgueni,Maity, Ranjan,Muniyat, Mir Ishruna,Maccallum, Justin L.,Neri, Paola,Bahlis, Nizar J.,Derksen, Darren J.
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p. 5522 - 5540
(2019/06/17)
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- ANTIBACTERIAL SIDEROMYCINS
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A compound, comprising: an Fe(III)-binding and/or Fe(III)-bound siderophore; one or more optional linker covalently bound to the siderophore; and daptomycin covalently bound to the linker, or, if no linker is present, then to the siderophore; or pharmaceu
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- Novel pseudo[2]rotaxanes constructed by the self-assembly of dibenzyl tetramethylene bis-carbamate derivatives and per-ethylated pillar[5]arene
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Novel neutral guest molecules, G1-G7, are studied for their host-guest complexation with per-ethylated pillar[5]arene (EtP[5]A). Among them, G1 and G7, dibenzyl tetramethylene bis-carbamate derivatives, are found to afford a novel stable pseudo[2]rotaxane
- Xiong, Shuhan,Zhang, Xiaoning,Meng, Lu-Bo,Jiang, Juli,Lin, Chen,Wang, Leyong
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supporting information
p. 6504 - 6507
(2015/04/14)
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- Synthesis and preliminary investigations into norbornane-based amphiphiles and their self-assembly
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A range of norbornane based amphiphiles, which possess a rigid 'kink' in the centre of amphiphiles, were accessed via a concise four step synthesis. The self-assembly properties of these novel compounds were then investigated and the critical aggregation
- Squire, Jennifer S.,Sutti, Alessandra,Durand, Gregory,Conlan, Xavier A.,Henderson, Luke C.
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p. 1895 - 1905
(2013/10/08)
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- Role of the guanidine group in the N-terminal fragment of PTH(1-11)
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A series of PTH hybrids containing a diamine [NH2(CH 2) n NH2; n = 4, 5, 6] in the C-terminal position was synthesized based on the H-Aib-Val-Aib-Glu-Ile-Gln-Leu-Nle-His-Gln- Har-NH2 (Har = homoargini
- Caporale, Andrea,Woznica, Iwona,Schievano, Elisabetta,Mammi, Stefano,Peggion, Evaristo
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experimental part
p. 1269 - 1275
(2010/07/16)
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- Degradable PEG-folate coated poly(DMAEA-co-BA)phosphazene-based polyplexes exhibit receptor-specific gene expression
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A new cationic biodegradable polyphosphazene was developed, bearing both pendant primary and tertiary amine side groups, poly(2-dimethylaminoethylamine-co-diaminobutane)phosphazene (poly(DMAEA-co-BA)phosphazene). PEG and PEG-folate were coupled to polyple
- Luten,van Steenbergen,Lok,de Graaff,van Nostrum,Talsma,Hennink
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p. 241 - 251
(2008/04/01)
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- New fluorescent adenosine A1-receptor agonists that allow quantification of ligand-receptor interactions in microdomains of single living cells
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Fluorescence spectroscopy is becoming a valuable addition to the array of techniques available for scrutinizing ligand-receptor interactions in biological systems. In particular, scanning confocal microscopy and fluorescence correlation spectroscopy (FCS) allow the noninvasive imaging and quantification of these interactions in single living cells. To address the emerging need for fluorescently labeled ligands to support these technologies, we have developed a series of red-emitting agonists for the human adenosine A1-receptor that, collectively, are N6-aminoalkyl derivatives of adenosine or adenosine 5′-N-ethyl carboxamide. The agonists, which incorporate the commercially available fluorophore BODIPY [630/650], retain potent and efficacious agonist activity, as demonstrated by their ability to inhibit cAMP accumulation in chinese hamster ovary cells expressing the human adenosine A1-receptor. Visualization and confirmation of ligand-receptor interactions at the cell membrane were accomplished using confocal microscopy, and their suitability for use in FCS was demonstrated by quantification of agonist binding in small areas of cell membrane.
- Middleton, Richard J.,Briddon, Stephen J.,Cordeaux, Yolande,Yates, Andrew S.,Dale, Clare L.,George, Michael W.,Baker, Julian G.,Hill, Stephen J.,Kellam, Barrie
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p. 782 - 793
(2008/01/27)
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- Stereoselective synthesis of E-64 and related cysteine proteases inhibitors from 2,3-epoxyamides
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The stereoselective synthesis of cathepsin inhibitors from indoline type epoxyamides is described. The use of this type of epoxyamides permitted the preparation of E-64 and CA-074 related compounds depending on the order in which the key steps, the oxidat
- Sarabia, Francisco,Sanchez-Ruiz, Antonio,Chammaa, Samy
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p. 1691 - 1705
(2007/10/03)
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- Efficient preparation of organic substrate-RNA conjugates via in vitro transcription
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A concise synthetic way has been developed for the preparation of guanosine monophosphate derivatives carrying a decaethylene glycol spacer at their 5′-oxygen to which are attached a range of organic substrates. The four different compounds, prepared via a convergent synthetic strategy, carry a tethered benzylallyl ether residue (1a), an anthracene (1b), a benzyl carbamate residue (1c), or a primary amino group (1d), respectively. All four compounds have been successfully incorporated at the 5′-end of a 25-mer long RNA transcript via T7 RNA polymerase, and no inhibition of chain elongation could be observed. Under proper conditions, 1a and 1b can be incorporated up to 90-95% and 1c up to 68%. The amino-terminated initiator 1d is incorporated less efficiently although still up to 49%. These results show that the more hydrophobic the guanosine monophosphate derivative is, the higher is its enzymatic incorporation.
- Fiammengo, Roberto,Musilek, Kamil,Jaeschke, Andres
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p. 9271 - 9276
(2007/10/03)
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- (POLY) AMINOACETAMIDE DERIVATIVES OF EPIPODOPHYLLOTOXIN THEIR PROCESS OF PREPARATION AND THEIR APPLICATIONS IN THERAPEUTICS AS ANTICANCER AGENTS
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The present invention relates to novel podophyllotoxin derivatives substituted in the 4-position by a substituted (poly)aminoalkylaminoacetamide chain, to their process of preparation and to their use as medicament as anticancer agents.
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Page/Page column 24
(2008/06/13)
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- Study on the Structure Activity Relationships of NPTX-594, a Spider Toxin Belonging to the Type-B Acylpolyamine Structure
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In order to elucidate the structure activity relationships of the spider toxin termed NPTX-594, eleven toxin analogs were designed and synthesized, and their paralytic activities against cricket were tested. As a result of the present study, it was clarif
- Wakamiya, Tateaki,Kinoshita, Tomohiko,Hattori, Yoshihide,Yamaguchi, Yoshihiro,Naoki, Hideo,Corzo, Gerardo,Nakajimal, Terumi
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p. 331 - 340
(2007/10/03)
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- Selective synthesis of carbamate protected polyamines using alkyl phenyl carbonates
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Utilising alkyl phenyl carbonates, an economical, practical and versatile method for selective Boc, Cbz and Alloc protection of polyamines has been developed. This method allows Boc, Cbz and Alloc protection of primary amines in the presence of secondary amines by reaction of the polyamines with the alkyl phenyl carbonates. Also, this method allows mono carbamate protection of simple symmetrical aliphatic α,ω-alkanediamines in high yields with respect to the diamine. Finally, the method allows selective carbamate protection of a primary amine located on a primary carbon in the presence of a primary amine located on a secondary or a tertiary carbon in excellent yields.
- Pittelkow, Michael,Lewinsky, Rasmus,Christensen, Jorn Bolstad
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p. 2195 - 2202
(2007/10/03)
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- REMEDIES FOR JOINT DISEASES BOUND TO HYALURONIC ACID
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The object of the present invention is to provide a conjugate of a therapeutic agent for joint diseases and hyaluronic acid, a hyaluronic acid derivative or a salt thereof which can retain the therapeutic agent for joint diseases in joint cavities. Accord
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- Syntheses of [13C,15N]-Labeled Polyamines
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[1,4-13C2, 1,4-15N2]butanediamine (1), a key compound in the syntheses of [5,8-13C2, 1,4,8-15N3]spermidine (2) and [5,8-13C2, 1,4,8,12-15N4]spermine (3), has been prepared as part of a 6-step process from 1,2-dibromoethane using potassium [13C]cyanide and potassium [15N]phthalimide. In the course of the syntheses, it was found that 1,4-dibromobutane was generated from tetrahydrofuran when bromination using triphenylphosphine and tetrabromomethane took place. A high-yield preparation of monobenzyloxycarbonyl (Z) derivative of 1, a precursor for 2, was obtained using a water-soluble Z reagent, Z-DSP, in a two-phase system of alkaline solution and chloroform. All the steps for 1, 2, and 3, were aimed at minimizing the loss of stable isotopes.
- Hara, Takeshi,Xu, Yong Ji,Sasaki, Hitomi,Niitu, Masaru,Samejima, Keijiro
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p. 1005 - 1012
(2007/10/03)
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- Practical, convergent total synthesis of polyamine amide spider toxin NSTX-3
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A practical, total synthesis of polyamine amide spider toxin NSTX-3, a potent glutamate receptor antagonist with potential as a neuroprotective agent, is reported. The unsymmetrical polyamine moiety was built by a conjugate addition to afford putreanine and regioselective acylation of L-asparaginyl-cadaverine.
- Blagbrough, Ian S.,Moya, Eduardo,Walford, Steven P.
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p. 551 - 554
(2007/10/02)
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- HETEROCYCLIC THROMBIN INHIBITORS
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Heterocyclic thrombin inhibitors are provided which have the structure STR1 wherein n, R, R 1, R 2, R 3, G, G x, R. sup.6', Ra, Xa, R 6, Rb, R 3, p, Q, A and R 4 are as defined herein.
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- α-Methyl polyamines: Metabolically stable spermidine and spermine mimics capable of supporting growth in cells depleted of polyamines
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In order to assess the tolerance of the target enzyme spermine synthase for α-substituents on the aminopropyl moiety of the substrate spermidine, 1- methylspermidine (MeSpd, 2) was synthesized. It was determined that MeSpd is a poor substrate for spermine synthase and is not a substrate for spermidine N1-acetyltransferase, suggesting that α-methylated polyamines might be metabolically stable and therefore useful tools for studying polyamine effects in intact cells. On the basis of initial cellular results with 2, 1- methylspermine (MeSpm, 3) and 1,12-dimethylspermine (Me2Spm, 4) were also synthesized. When added to cells (L1210, SV-3T3, or HT29) depleted of both putrescine and spermidine by prior treatment with α- (difluoromethyl)ornithine (DFMO), these α-methylated polyamines were able to restore cell growth to that observed in the absence of DFMO. In accord with the enzyme data noted above, metabolic studies indicated a slow conversion of 2 to 3, but no metabolism of 4 in these cells. It was concluded from these results that the α-methylated polyamines are able to substitute for the natural polyamines spermidine and spermine in critical biochemical processes which involve polyamines for continued cell growth. In accord with the hypothesis, preliminary data indicate that MeSpd and Me2Spm are as effective as spermidine and spermine, respectively, in promoting the conversion of B- DNA to Z-DNA.
- Lakanen,Coward,Pegg
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p. 724 - 734
(2007/10/02)
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- Acylated amine compounds which are useful fungicigal agents
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A compound selected from the group consisting of a compound of the formula STR1 wherein R1 is selected from the group consisting of Ar-O- and aryl, polyaryl and condensed polyaryl unsubstituted or substituted and heterocycle unsubstituted or substituted, Ar is aryl of 6 to 14 carbon atoms unsubstituted or substituted, heteroaryl unsubstituted or substituted and heterocyclic unsubstituted or substituted, W is selected from the group comsisting of --(CH2)n1 --or --(CH2)n2 --NY--(CH2)n3, n1, n2 and n3 are individually integers from 2 to 6, Y is selected from the group consisting of hydrogen, alkyl of 1 to 12 carbon atoms, aryl of 6 to 12 carbon atoms and aralkyl of 7 to 14 carbon atoms unsubstituted or substituted, --COOAlk and --COR2, Alk is alkyl of 1 to 12 carbon atoms, R2 is selected from the group consisting of alkyl of 1 to 12 carbon atoms, alkenyl and alkynyl of 2 to 12 carbon atoms, aryl of 6 to 14 carbon atoms, aralkyl of 7 to 18 carbon atoms unsubstituted or substituted and heterocyclic unsubstituted or substituted, Z is selected from the group consisting of hydrogen, STR2 R2 is alkyl of 1 to 12 carbon atoms or aralkyl of 7 to 18 carbon atoms, Alk' is alkyl of 1 to 12 carbon atoms, ArAlk is aralkyl of 7 to 18 carbon atoms, R2 ' is R2, R3 and R3 ' are selected from the group consisting of aryl substituted or unsubstituted, heteroaryl substituted or unsubstituted, heterocyclic unsubstituted or substituted and R1 with the proviso that Z is not hydrogen when W is --(CH2)3 --and R1 is 2,4-dichlorophenoxy and their non-toxic, pharmaceutically acceptable acid addition salts having fungicidal activity.
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- 1-(carbamyl, thiocarbamyl, and iminocarbamyl)-indoline derivatives
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1-(Carbamyl, thiocarbamyl, and iminocarbamyl)-indoline derivatives of the formula STR1 where each R1 is independently alkyl, alkoxy, acyloxy, hydroxy, halo or trifluoromethyl, n is 0, 1, 2 or 3, R2 and R3 are independently hydroxy, alkoxy, amino or substituted amino, R4 and R5 are independently hydrogen, alkyl or substituted alkyl, R6 is hydrogen, alkyl or substituted alkyl, and Y is O, S or N--R7 where R7 is hydrogen, alkyl, cyano or substituted alkyl, and salts thereof, which are useful as antihypertensive and cardioactive agents, methods of preparing the same, and pharmaceutical compositions thereof, are provided.
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- N-[4-[(3-aminopropyl)amino]butyl]-2,2-dihydroxyethanamide
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N-[4-[(3-aminopropyl)amino]butyl]-2,2-dihydroxyethanamide is an immunostimulant in animals and an intermediate for synthesis of the antibiotic BMG162-aF2.
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- N-[4-(3-aminopropyl)-aminobutyl]-2-(ω-guanidino-fatty-acid-amido)-2-substituted-ethanamide and salt thereof
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N-[4-(3-Aminopropyl)aminobutyl]-2-(ω-guanidino-fatty acid-amido)-2-substituted-ethanamides represented by the general formula STR1 wherein Y represents --(CH2 --CH2 --, --CH=CH or STR2 R represents a hydrogen atom, an alkyl group of 1 to 4 carbon atoms which may have a hydroxyl group as substituent, or a benzyl group, and n is an integer of from 1 to 8, provided that when Y is STR3 and n is 4, R represents the groups other than the hydrogen atom; a salt thereof having antitumor activity in experimental animal tumors and a process for the preparation thereof is provided.
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