cas 75178-87-9, TERT-BUTYL N-(4-HYDROXYBUTYL)CARBAMATE

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Biomimetic enterobactin analogue mediates iron-uptake and cargo transport intoE. coliandP. aeruginosa
The design, synthesis and biological evaluation of the artificial enterobactin analogueEntKLand several fluorophore-conjugates thereof are described.EntKLprovides an attachment point for cargos such as fluorophores or antimicrobial p
Coetzee, Janetta,Grunenberg, J?rg,Herrmann, Jennifer,Klahn, Philipp,Müller, Rolf,Vornweg, Johannes,Zscherp, Robert
p. 10179 - 10190
(2021)
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Hyperbranched Copolymers Based on Glycidol and Amino Glycidyl Ether: Highly Biocompatible Polyamines Sheathed in Polyglycerols
Functional hyperbranched polyglycerols (PGs) have recently garnered considerable interest due to their potential in biomedical applications. Here, we present a one-pot synthesis of hyperbranched PGs possessing amine functionality using a novel amino glycidyl ether monomer. A Boc-protected butanolamine glycidyl ether (BBAG) monomer was designed and polymerized with glycidol (G) through anionic ring-opening multibranching polymerization to yield a series of hyperbranched P(G-co-BBAG) with controlled molecular weights (4800-16700 g/mol) and relatively low molecular weight distributions (1.2-1.6). The copolymerization and subsequent deprotection chemistry allow the incorporation of an adjustable fraction of primary amine moieties (typically, 5-20% monomer ratio) within the hyperbranched PG backbones, thus providing potentials for varying charge densities and functionality in PGs. The copolymerization kinetics of G and BBAG was also evaluated using a quantitative in situ 13C NMR spectroscopic analysis, which revealed gradient copolymerization between the comonomers. The free amine groups within the deprotected P(G-co-BAG) copolymer were further utilized for a facile conjugation chemistry with a model molecule in a quantitative manner. Furthermore, the superior biocompatibility of the prepared P(G-co-BAG) polymers was demonstrated via cell viability assays, outperforming many existing polyamines possessing relatively high cytotoxicity. Taken together, the biocompatibility with facile conjugation chemistry of free amine groups sheathed within the framework of hyperbranched PGs holds the prospect of advancing biological and biomedical applications.
Song, Suhee,Lee, Joonhee,Kweon, Songa,Song, Jaeeun,Kim, Kyuseok,Kim, Byeong-Su
p. 3632 - 3639
(2016)
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The synthesis of lysine α-ketoamide thrombin inhibitors via an epoxy amide ring opening
We describe a novel route for the preparation of substituted α-ketoamides of lysine. These compounds, due to the presence of an electrophilic carbonyl, display submicromolar activity toward the enzyme thrombin.
Cacciola, Joseph,Alexander, Richard S.,Fevig, John M.,Stouten, Pieter F.W.
p. 5741 - 5744
(1997)
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De-novo designed β-lysine derivatives can both augment and diminish the proliferation rates of E. coli through the action of Elongation Factor P
An investigation into the effect of modified β-lysines on the growth rates of eubacterial cells is reported. It is shown that the effects observed are due to the post translational modification of Elongation Factor P (EFP) with these compounds catalysed b
Connon, Stephen J.,Ghanim, Magda,Kelly, Vincent P.,McDonnell, Ciara M.,Mike Southern, J.
supporting information

(2022/01/24)

Novel Labelled Cannabinergic Ligands and Related Analogs
Novel cannabinoid ligands represented by the general formulas I, II, and III and methods for preparation and use within which one or more of a fluorescent ligand, nitroxide spin label, metal chelate, biotin moiety, or group with enhanced polarity may be incorporated. The compounds can bind to and modulate the cannabinoid CB1 and CB2 receptors and thereby considered specific ligands for these receptors. Some of the disclosed compounds that bind to cannabinoid CB1 and CB2 receptors can exhibit tight or irreversible binding characteristics for these receptors. Due to the presence of the imaging/diagnostic and/or therapeutic functional groups including fluorescent groups, nitroxide spin labels, metal chelates, biotin moieties, and groups with enhanced polarity, the disclosed compounds may be useful as imaging/diagnostic tools and/or therapeutic agents.
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Paragraph 0170; 0174

(2021/10/02)

Application of bioorthogonal hetero-Diels-Alder cycloaddition of 5-arylidene derivatives of 1,3-dimethylbarbituric acid and vinyl thioether for imaging inside living cells
New bioorthogonal cycloaddition of 5-arylidene derivatives of 1,3-dimethylbarbituric acid as 1-oxa-1,3-butadienes and vinyl thioether as a dienophile has been applied to imaging inside living cells. The reaction is high yielding, selective, and fast in aqueous media. The proposed 1-oxa-1,3-butadiene derivative conjugated to a FITC fluorochrome selectively and rapidly labels the cancer cells pretreated with the dienophile-taxol. The second order rate constants k2 for various proposed bioorthogonal cycloadditions were estimated to be in the range from 0.9 × 10-2 M-1 s-1 to 1.4 M-1 s-1, which is much better than in the case of the first generation TQ-ligation (o-quinolinone quinone methide and vinyl thioether ligation, k2 = 1.5 × 10-3 M-1 s-1) and comparable or better to that for the second generation TQ-ligation (k2 = 2.8 × 10-2 M-1 s-1). The reaction rate constants k2 of proposed ligation reactions are in the range of the rate constants k2 for tetrazines and norbornenes or tetrazines and cyclopropenes. These findings indicate that this chemistry is suitable for in vitro imaging experiments.
Bazan, Bart?omiej,Pa?asz, Aleksandra,Skalniak, ?ukasz,Cie?, Dariusz,Buda, Szymon,J?drzejowska, Katarzyna,G?omb, Sonia,Kamzol, Daniel,Czarnota, Kinga,Latos, Krystian,Kozie?, Krzysztof,Musielak, Bogdan
supporting information
p. 6045 - 6058
(2021/07/25)

TARGET PROTEIN EED DEGRADATION-INDUCING DEGRADUCER, PREPARATION METHOD THEREOF, AND PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING DISEASES RELATED TO EED, EZH2, OR PRC2, COMPRISING SAME AS ACTIVE INGREDIENT
The present invention relates to a target protein degradation-inducing Degraducer, a preparation method thereof, and a pharmaceutical composition for preventing or treating diseases related to EED, EZH2, or PRC2 comprising same as an active ingredient. A novel compound represented by formula 1, according to the present invention is a Degraducer compound that induces degradation of a target protein, i.e., embryonic ectoderm development (EED) or polycomb repressive complex 2 (PRC2), utilizing cereblon E3 ubiquitin ligase, von Hippel-Lindau tumor suppressor (VHL) E3 ubiquitin ligase, mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase, and cellular inhibitor of apoptosis protein 1 (cIAP) E3 ubiquitin ligase, wherein the compound has an aspect of remarkably achieving target protein degradation-inducing activity through a ubiquitin proteasome system (UPS), and therefore there is a useful effect in that it is possible to provide a pharmaceutical composition for preventing or treating diseases or conditions related to a target protein, and a functional health food composition for preventing or improving same, comprising said compound as an active ingredient.
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Paragraph 0477-0479; 0513-0515; 0534-0536; 0579-0581

(2021/12/23)

Synthesis and Pharmacological Evaluation of σ2 Receptor Ligands Based on a 3-Alkoxyisoxazole Scaffold: Potential Antitumor Effects against Osteosarcoma
Since its initial discovery as the basis for nicotinic acetylcholine receptor ligands, the 3-alkoxyisoxazole scaffold has been shown to be a versatile platform for the development of potent σ1 and σ2 receptor ligands. Herein we report a further SAR exploration of the 3-alkoxyisoxazole scaffold with the aim of obtaining potent σ2 receptor ligands. Various substitutions on the benzene ring and at the basic amino regions resulted in a total of 21 compounds that were tested for their binding affinities for the σ2 receptor. In particular, compound 51 [(2S)-1-(4-ammoniobutyl)-2-(((5-((3,4-dichlorophenoxy)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-ium chloride] was identified as one of the most potent σ2 ligands within the series, with a Ki value of 7.9 nM. It demonstrated potent antiproliferative effects on both osteosarcoma cell lines 143B and MOS?J (IC50 values of 0.89 and 0.71 μM, respectively), relative to siramesine (IC50 values of 1.81 and 2.01 μM). Moreover, compound 51 inhibited clonal formation of osteosarcoma 143B cells at 1 μM, corresponding to half the dose required of siramesine for similar effects. The general cytotoxicity profile of compound 51 was assessed in a number of normal cell lines, including HaCaT, HAF, and LO2 cells. Furthermore, FACS analysis showed that compound 51 likely inhibits osteosarcoma cell growth by disruption of the cell cycle and promotion of apoptosis.
Shi, Jun-Jie,Jia, Kun-Hang,Sun, Hao,Gunosewoyo, Hendra,Yang, Fan,Tang, Jie,Luo, Jian,Yu, Li-Fang
p. 524 - 536
(2020/11/02)

Preparation method of 4-(BOC-amino)-1-butanol
The invention discloses a preparation method of 4-(BOC-amino)-1-butanol. The method comprises the following steps: reacting a proper amount of 2, 3-dihydrofuran with an acidic solution to obtain 2, 3-dihydro-5-methyl furan; mixing the obtained 2, 3-dihydro-5-methyl furan with hydrochloride, and then adding the mixture into an alkaline solution for reaction to obtain isobutyl nitrite; reacting isobutyl nitrite under the action of a reducing agent to generate 4-amino-1-butyl alcohol; and reacting 4-amino-1-butyl alcohol with di-tert-butyl dicarbonate in tetrahydrofuran to generate 4-(BOC-amino)-1-butyl alcohol; according to the preparation method of the 4-(BOC-amino)-1-butanol, the total yield of the product is as high as 70%, the reaction temperature is low, and the safety coefficient is high), the reducing agent is cheaper than that in the prior art, the experimental operation method is simple, the steps are short, and the method is suitable for large-scale production.
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Paragraph 0051; 0055-0058; 0062-0065; 0069-0071

(2021/01/28)

COMPOUNDS AND USES THEREOF
The present disclosure features compounds and methods useful for the treatment of BAF complex-related disorders.
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Page/Page column 152

(2021/08/06)

COMPOUNDS AND USES THEREOF
The present disclosure features compounds useful for the treatment of BAF complex-related disorders.
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Page/Page column 137; 143

(2021/10/15)

Chemoselective Cleavage of Si-C(sp3) Bonds in Unactivated Tetraalkylsilanes Using Iodine Tris(trifluoroacetate)
Organosilanes are synthetically useful reagents and precursors in organic chemistry. However, the typical inertness of unactivated Si-C(sp3) bonds under conventional reaction conditions has hampered the application of simple tetraalkylsilanes in organic synthesis. Herein we report the chemoselective cleavage of Si-C(sp3) bonds of unactivated tetraalkylsilanes using iodine tris(trifluoroacetate). The reaction proceeds smoothly under mild conditions (-50 °C to room temperature) and tolerates various polar functional groups, thus enabling subsequent Tamao-Fleming oxidation to provide the corresponding alcohols. NMR experiments and density functional theory calculations on the reaction indicate that the transfer of alkyl groups from Si to the I(III) center and the formation of the Si-O bond proceed concertedly to afford an alkyl-λ3-iodane and silyl trifluoroacetate. The developed method enables the use of unactivated tetraalkylsilanes as highly stable synthetic precursors.
Matsuoka, Keitaro,Komami, Narumi,Kojima, Masahiro,Mita, Tsuyoshi,Suzuki, Kimichi,Maeda, Satoshi,Yoshino, Tatsuhiko,Matsunaga, Shigeki
p. 103 - 108
(2021/01/13)

Target protein degradation inducing compound, preparation method thereof and pharmaceutical composition for preventing or treating targeted protein related diseases containing the same as an active ingredient
The present invention relates to a degraducer for inducing the decomposition of target protein, a producing method thereof, and a pharmaceutical composition for preventing or treating target protein-related diseases by containing the degraducer as an active ingredient. A novel compound represented by chemical formula 1, ULB-L-PTM, by the present invention, as a degraducer compound inducing the decomposition of target protein using cereblon E3 ubiquitin ligase, is able to significantly achieve a target protein degradation-inducing activity with an excellent binding activity of a cereblon E3 ubiquitin ligase binder thereby, being able to achieve an excellent protein degradation activity by targeting protein or polypeptide related to various diseases. The bromodomain-containing pharmaceutical composition for preventing or treating protein-related diseases or conditions contains the novel compound represented by chemical formula 1 as an active ingredient and has a useful effect of providing a health functional food composition for prevention or improvement.(AA) Example 22 (nM, 24h)COPYRIGHT KIPO 2020
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Paragraph 1061; 1063-1065

(2020/05/01)

Azido-Desferrioxamine Siderophores as Functional Click-Chemistry Probes Generated in Culture upon Adding a Diazo-Transfer Reagent
This work aimed to undertake the in situ conversion of the terminal amine groups of bacterial desferrioxamine (DFO) siderophores, including desferrioxamine B (DFOB), to azide groups to enable downstream click chemistry. Initial studies trialed a precursor-directed biosynthesis (PDB) approach. Supplementing Streptomyces pilosus culture with blunt-end azido/amine non-native substrates designed to replace 1,5-diaminopentane as the native diamine substrate in the terminal amine position of DFOB did not produce azido-DFOB. Addition of the diazo-transfer reagent imidazole-1-sulfonyl azide hydrogen sulfate to spent S. pilosus medium that had been cultured in the presence of 1,4-diaminobutane, as a viable native substrate to expand the suite of native DFO-type siderophores, successfully generated the cognate suite of azido-DFO analogues. CuI-mediated or strain-promoted CuI-free click chemistry reactions between this minimally processed mixture and the appropriate alkyne-bearing biotin reagents produced the cognate suite of 1,4-disubstituted triazole-linked DFO-biotin compounds as potential molecular probes, detected as FeIII-loaded species. The amine-to-azide transformation of amine-bearing natural products in complex mixtures by the direct addition of a diazo-transfer reagent to deliver functional click chemistry reagents adds to the toolbox for chemical proteomics, chemical biology, and drug discovery.
Gotsbacher, Michael P.,Codd, Rachel
p. 1433 - 1445
(2020/02/27)

Preparation method of target BTK protein degradation compound, and application of compound in treating autoimmune diseases and tumors
The invention provides a compound, the compound is a compound represented by a formula I, and a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceuticallyacceptable salt and prodrug of the compound represented by the formula I. The compound has a strong degradation effect on wild-type BTK, has no inhibition or degradation effects on other targets suchas EGFR, ITK, TEC, and the like, and has an effect of specific targeted degradation of BTK proteins. The formula I is X-Y-Z.
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Paragraph 0209; 0213-0215

(2020/02/14)

Applications of targeted BTK degradation compound in treatment of autoimmune system diseases
The invention discloses application of a targeted BTK degradation compound in treatment of autoimmune system diseases and in preparation of medicines which are used for treating or preventing autoimmune diseases. The targeted BTK degradation compound is a compound shown as formula I or a stereoisomer, a geometrical isomer, a tautomer, a nitric oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and the targeted BTK degradation compound has good treatment and prevention effects on the autoimmune diseases. X-Y-Z is as shown in formula I which is disclosed in the specification.
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Paragraph 0207-0209

(2020/03/12)

Cooperativity of Catechols and Amines in High-Performance Dry/Wet Adhesives
The outstanding adhesive performance of mussel byssal threads has inspired materials scientists over the past few decades. Exploiting the amino-catechol synergy, polymeric pressure-sensitive adhesives (PSAs) have now been synthesized by copolymerizing tra
Delparastan, Peyman,Gerst, Matthias,Messersmith, Phillip B.,Ney, Max R.,Tiu, Brylee David B.
supporting information
p. 16616 - 16624
(2020/08/03)

Design and Synthesis of Fluorescent Methylphenidate Analogues for a FRET-Based Assay of Synapsin III Binding
We previously described synapsin III (Syn III) as a synaptic phosphoprotein that controls dopamine release in cooperation with α-synuclein (aSyn). Moreover, we found that in Parkinson's disease (PD), Syn III also participates in aSyn aggregation and toxic
Casiraghi, Andrea,Longhena, Francesca,Straniero, Valentina,Faustini, Gaia,Newman, Amy H.,Bellucci, Arianna,Valoti, Ermanno
p. 1330 - 1337
(2020/06/25)

Chemical Targeting of Voltage Sensitive Dyes to Specific Cells and Molecules in the Brain
Voltage sensitive fluorescent dyes (VSDs) are important tools for probing signal transduction in neurons and other excitable cells. The impact of these highly lipophilic sensors has, however, been limited due to the lack of cell-specific targeting methods in brain tissue or living animals. We address this key challenge by introducing a nongenetic molecular platform for cell- and molecule-specific targeting of synthetic VSDs in the brain. We employ a dextran polymer particle to overcome the inherent lipophilicity of VSDs by dynamic encapsulation and high-affinity ligands to target the construct to specific neuronal cells utilizing only native components of the neurotransmission machinery at physiological expression levels. Dichloropane, a monoamine transporter ligand, enables targeting of dense dopaminergic axons in the mouse striatum and sparse noradrenergic axons in the mouse cortex in acute brain slices. PFQX in conjunction with ligand-directed acyl imidazole chemistry enables covalent labeling of AMPA-type glutamate receptors in the same brain regions. Probe variants bearing either a classical electrochromic ANEP dye or state-of-the-art VoltageFluor-type dye respond to membrane potential changes in a similar manner to the parent dyes, as shown by whole-cell patch recording. We demonstrate the feasibility of optical voltage recording with our probes in brain tissue with one-photon and two-photon fluorescence microscopy and define the signal limits of optical voltage imaging with synthetic sensors under a low photon budget determined by the native expression levels of the target proteins. This work demonstrates the feasibility of a chemical targeting approach and expands the possibilities of cell-specific imaging and pharmacology.
Fiala, Tomas,Wang, Jihang,Dunn, Matthew,?ebej, Peter,Choi, Se Joon,Nwadibia, Ekeoma C.,Fialova, Eva,Martinez, Diana M.,Cheetham, Claire E.,Fogle, Keri J.,Palladino, Michael J.,Freyberg, Zachary,Sulzer, David,Sames, Dalibor
supporting information
p. 9285 - 9301
(2020/06/04)

ANTIESTROGEN COMPOUNDS
A genus of proteolysis-targeting chimeras (PROTACs)-type compounds/antiestrogens has now been found that act as selective estrogen receptor degraders (SERDs) and estrogen receptor antagonists by degrading and antagonizing ERa in breast cancer cells. The compounds are of the following genus: The compounds described herein exhibit anti-proliferative effects, and are potentially useful, alone or in combination with other therapies, for the treatment of breast cancer. In general, these compounds combine a tight binding ERa targeting ligand tethered to a recognition motif or degron. Once bound, the degron recruits destructive cellular components and the targeted receptor (i.e., ERa) is degraded (i.e., destroyed) or antagonized.
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Paragraph 0085-0086

(2020/01/08)

Design, Synthesis, and Conformational Analysis of Oligobenzanilides as Multifacial α-Helix Mimetics
The design, synthesis, and conformational analysis of an oligobenzanilide helix mimetic scaffold capable of simultaneous mimicry of two faces of an α-helix is reported. The synthetic methodology provides access to diverse monomer building blocks amenable to solid-phase assembly in just four synthetic steps. The conformational flexibility of model dimers was investigated using a combination of solid and solution state methodologies supplemented with DFT calculations. The lack of noncovalent constraints allows for significant conformational plasticity in the scaffold, thus permitting it to successfully mimic residues i, i+2, i+4, i+6, i+7, and i+9 of a canonical α-helix.
Flack, Theo,Romain, Charles,White, Andrew J. P.,Haycock, Peter R.,Barnard, Anna
supporting information
p. 4433 - 4438
(2019/06/27)

Rapid Assembly of Saturated Nitrogen Heterocycles in One-Pot: Diazo-Heterocycle “Stitching” by N–H Insertion and Cyclization
Methods that provide rapid access to new heterocyclic structures in biologically relevant chemical space provide important opportunities in drug discovery. Here, a strategy is described for the preparation of 2,2-disubstituted azetidines, pyrrolidines, pi
Boddy, Alexander J.,Affron, Dominic P.,Cordier, Christopher J.,Rivers, Emma L.,Spivey, Alan C.,Bull, James A.
supporting information
p. 1458 - 1462
(2019/01/04)

CLASS OF BIFUNCTIONAL COMPOUNDS WITH QUATERNARY AMMONIUM SALT STRUCTURE
The invention provides a class of compounds represented by formula (I), having bifunctional active quaternary ammonium salt structure of a β2-adrenoreceptor agonist and an M receptor antagonist, a pharmaceutically acceptable salt, solvate, and optical isomer thereof. A pharmaceutical composition comprising such a compound with quaternary ammonium salt structure, a method for preparing such a compound with quaternary ammonium salt structure and an intermediate thereof, and uses thereof in treating pulmonary disorders are also provided. The compounds of the invention have high selectivity to the M receptor subtype, and have less adverse reaction and lower toxic and side effects in the treatment of pulmonary diseases such as COPD and asthma.
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Paragraph 0205

(2019/11/11)

COMPOUNDS AND METHODS FOR TRANS-MEMBRANE DELIVERY OF MOLECULES
The Invention provides a novel delivery system for delivery of drugs across biological membranes. It provides novel chemical conjugates that comprise said delivery system, methods for synthesis of said compounds, and methods for utilization of said delivery system, among others, for delivery of genetic drugs into tissues and cells, in vitro, ex vivo, and in vivo, for the treatment of various medical disorders.
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Paragraph 00205

(2019/07/17)

Molecular-Dynamics-Simulation-Directed Rational Design of Nanoreceptors with Targeted Affinity
Here, we demonstrate the possibility of rationally designing nanoparticle receptors with targeted affinity and selectivity for specific small molecules. We used atomistic molecular-dynamics (MD) simulations to gradually mutate and optimize the chemical structure of the molecules forming the coating monolayer of gold nanoparticles (1.7 nm gold-core size). The MD-directed design resulted in nanoreceptors with a 10-fold improvement in affinity for the target analyte (salicylate) and a 100-fold decrease of the detection limit by NMR-chemosensing from the millimolar to the micromolar range. We could define the exact binding mode, which features prolonged contacts and deep penetration of the guest into the monolayer, as well as a distinct shape of the effective binding pockets characterized by exposed interacting points.
Sun, Xiaohuan,Riccardi, Laura,De Biasi, Federico,Rastrelli, Federico,De Vivo, Marco,Mancin, Fabrizio
supporting information
p. 7702 - 7707
(2019/05/15)

Specificity of extended O-aryloxycarbonyl hydroxamates as inhibitors of a class C β-lactamase
Class C β-lactamases have previously been shown to be efficiently inactivated by O-aryloxycarbonyl hydroxamates. O-Phenoxycarbonyl-N-benzyloxycarbonylhydroxylamine (1) and O-phenoxycarbonyl-N-(R)-[(4-amino-4-carboxy-1-butyl)oxycarbonyl]hydroxylamine (2),
Malico, Alexandra A.,Dave,Adediran,Pratt
p. 1430 - 1436
(2019/02/24)

Agent for Preventing or Ameliorating Hearing Impairment
It is to provide an agent for preventing or improving hearing loss, which comprises a low molecular compound which can be produced relatively easily and inexpensively as an active ingredient. One or more compounds selected from the group consisting of compounds represented by the following formulas (I0), (II), and (III) and a pharmaceutically acceptable salt of the compounds when R3 is OH are used as an agent for preventing or improving hearing loss.
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Paragraph 0093; 0094; 0159-0160

(2019/08/02)

New Class of Selective Estrogen Receptor Degraders (SERDs): Expanding the Toolbox of PROTAC Degrons
An effective endocrine therapy for breast cancer is to selectively and effectively degrade the estrogen receptor (ER). Up until now, there have been largely only two molecular scaffolds capable of doing this. In this study, we have developed new classes of scaffolds that possess selective estrogen receptor degrader (SERD) and ER antagonistic properties. These novel SERDs potently inhibit MCF-7 breast cancer cell proliferation and the expression of ER target genes, and their efficacy is comparable to Fulvestrant. Unlike Fulvestrant, the modular protein-targeted chimera (PROTAC)-type design of these novel SERDs should allow easy diversification into a library of analogs to further fine-tune their pharmacokinetic properties including oral availability. This work also expands the pool of currently available PROTAC-type scaffolds that could be beneficial for targeted degradation of various other therapeutically important proteins.
Wang, Lucia,Guillen, Valeria S.,Sharma, Naina,Flessa, Kevin,Min, Jian,Carlson, Kathryn E.,Toy, Weiyi,Braqi, Sara,Katzenellenbogen, Benita S.,Katzenellenbogen, John A.,Chandarlapaty, Sarat,Sharma, Abhishek
supporting information
p. 803 - 808
(2018/07/21)

Discovery of Novel Nonsteroidal Anti-Inflammatory Drugs and Carbonic Anhydrase Inhibitors Hybrids (NSAIDs-CAIs) for the Management of Rheumatoid Arthritis
Herein we report the design as well as the synthesis of a new series of dual hybrid compounds consisting of the therapeutically used nonsteroidal-anti-inflammatory drugs (NSAIDs; i.e., indometacin, sulindac, ketoprofen, ibuprofen, diclofenac, ketorolac, etc., cyclooxygenase inhibitors) and the carbonic anhydrase inhibitor (CAIs) fragments of the sulfonamide type. Such compounds are proposed as new tools for the management of ache symptoms associated with rheumatoid arthritis (RA) and related inflammation diseases. The majority of the hybrids reported were effective in inhibiting the ubiquitous human (h) CA I and II as well as the RA overexpressed hCAs IX and XII isoforms, with KI values comprised of the low-medium nanomolar ranges. The antihyperalgesic activity of selected compounds was assessed by means of the paw-pressure and incapacitance tests using an in vivo RA model, and among them the hybrids 6B and 8B showed potent antinociceptive effects lasting up to 60 min after administration.
Akgul, Ozlem,Di Cesare Mannelli, Lorenzo,Vullo, Daniela,Angeli, Andrea,Ghelardini, Carla,Bartolucci, Gianluca,Alfawaz Altamimi, Abdulmalik Saleh,Scozzafava, Andrea,Supuran, Claudiu T.,Carta, Fabrizio
p. 4961 - 4977
(2018/05/23)

Exploiting Peptidomimetics to Synthesize Compounds That Activate Ryanodine Receptor Calcium Release Channels
Ryanodine receptor (RyR) Ca2+-release channels are essential for contraction in skeletal and cardiac muscle and are prime targets for modification of contraction in disorders that affect either the skeletal or heart musculature. We designed and synthesized a number of compounds with structures based on a naturally occurring peptide (A peptides) that modifies the activity of RyRs. In total, 34 compounds belonging to eight different classes were prepared. The compounds were screened for their ability to enhance Ca2+ release from isolated cardiac sarcoplasmic reticulum (SR) vesicles, with 25 displaying enhanced Ca2+ release. Competition studies with the parent peptides indicated that the synthetic compounds act at a competing site. The activity of the most effective of the compounds, BIT 180, was further explored using Ca2+ release from skeletal SR vesicles and contraction in intact skeletal muscle fibers. The compounds did not alter tension in intact fibers, indicating that (as expected) they are not membrane permeable, but importantly, that they are not toxic to the intact cells. Proof in principal that the compounds would be effective in intact muscle fibers if rendered membrane permeable was obtained with a structurally related membrane-permeable scorpion toxin (imperatoxin A), which was found to enhance contraction.
Robinson, Ken,Easton, Christopher J.,Dulhunty, Angela F.,Casarotto, Marco G.
p. 1957 - 1971
(2018/09/11)

Ruthenium-Pincer-Catalyzed Hydrogenation of Lactams to Amino Alcohols
By using the commercially available ruthenium pincer complex (Ru-MACHO-BH) as a catalyst, the challenging direct hydrogenation of lactams and analogues has been successfully accomplished to deliver corresponding value-added amino alcohols in good-to-excellent yields under mild reaction conditions. Remarkably, in addition to N-protected lactams, unprotected ones could also be readily reduced in the presence of a catalytic amount of weak base or even under neutral reaction conditions, which further highlights the broad substrate scope and the protocol efficiency.
Chen, Jiangbo,Wang, Jiaquan,Tu, Tao
p. 2559 - 2565
(2018/07/30)

Exploiting Chromophore-Protein Interactions through Linker Engineering to Tune Photoinduced Dynamics in a Biomimetic Light-Harvesting Platform
Creating artificial systems that mimic and surpass those found in nature is one of the great challenges of modern science. In the context of photosynthetic light harvesting, the difficulty lies in attaining utmost control over the energetics, positions and relative orientations of chromophores in densely packed arrays to transfer electronic excitation energy to desired locations with high efficiency. Toward achieving this goal, we use a highly versatile biomimetic protein scaffold from the tobacco mosaic virus coat protein on which chromophores can be attached at precise locations via linkers of differing lengths and rigidities. We show that minor linker modifications, including switching chiral configurations and alkyl chain shortening, lead to significant lengthening of the ultrafast excited state dynamics of the system as the linkers are shortened and rigidified. Molecular dynamics simulations provide molecular-level detail over how the chromophore attachment orientations, positions, and distances from the protein surface lead to the observed trends in system dynamics. In particular, we find that short and rigid linkers are able to sandwich water molecules between chromophore and protein, leading to chromophore-water-protein supracomplexes with intricately coupled dynamics that are highly dependent on their local protein environment. In addition, cyclohexyl-based linkers are identified as ideal candidates to retain rotational correlations over several nanoseconds and thus lock relative chromophore orientations throughout the lifetime of an exciton. Combining linker engineering with judicious placement of chromophores on the hydrated protein scaffold to exploit different chromophore-bath couplings provides a clear and effective path to producing highly controllable artificial light-harvesting systems that can increasingly mimic their natural counterparts, thus aiding to elucidate natural photosynthetic mechanisms.
Delor, Milan,Dai, Jing,Roberts, Trevor D.,Rogers, Julia R.,Hamed, Samia M.,Neaton, Jeffrey B.,Geissler, Phillip L.,Francis, Matthew B.,Ginsberg, Naomi S.
supporting information
p. 6278 - 6287
(2018/06/01)

ANTICANCER AGENT DELIVERY MOLECULE
PROBLEM TO BE SOLVED: To provide a compound which can be used as an anticancer agent targeting a cancer cell that highly expresses Lysine-specific demethylase 1 (LSD1) or salt thereof. SOLUTION: The present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, where Ar, R1, R2, L, Z, p, q, *1 and *2 are as defined in the specifications. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT
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Paragraph 0208-0210

(2017/08/04)

Exploring endoperoxides as a new entry for the synthesis of branched azasugars
A new class of nitrogen-containing endoperoxides were synthesised by a photochemical [4 + 2]-cycloaddition between a diene and singlet oxygen. The endoperoxides were dihydroxylated and protected to provide a series of endoperoxide building blocks for organic synthesis, with potential use as precursors for the synthesis of branched azasugars. Preliminary exploration of the chemistry of these building blocks provided access to a variety of derivatives including tetrahydrofurans, epoxides and protected amino-tetraols.
Domeyer, Svenja,Bjerregaard, Mark,Johansson, Henrik,Pedersen, Daniel Sejer
supporting information
p. 644 - 647
(2017/06/20)

MULTIVALENT RAS BINDING COMPOUNDS
Described herein are compounds that modulate Ras signaling, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with altered Ras signaling. Further described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds and methods of using such compounds in the treatment of cell proliferative disorders, including cancer.
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Paragraph 00883

(2017/07/23)

Amidoalkylindoles as Potent and Selective Cannabinoid Type 2 Receptor Agonists with in Vivo Efficacy in a Mouse Model of Multiple Sclerosis
Selective CB2 agonists represent an attractive therapeutic strategy for the treatment of a variety of diseases without psychiatric side effects mediated by the CB1 receptor. We carried out a rational optimization of a black market designer drug SDB-001 that led to the identification of potent and selective CB2 agonists. A 7-methoxy or 7-methylthio substitution at the 3-amidoalkylindoles resulted in potent CB2 antagonists (27 or 28, IC50 = 16-28 nM). Replacement of the amidoalkyls from 3-position to the 2-position of the indole ring dramatically increased the agonist selectivity on the CB2 over CB1 receptor. Particularly, compound 57 displayed a potent agonist activity on the CB2 receptor (EC50 = 114-142 nM) without observable agonist or antagonist activity on the CB1 receptor. Furthermore, 57 significantly alleviated the clinical symptoms and protected the murine central nervous system from immune damage in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis.
Shi, Ying,Duan, Yan-Hui,Ji, Yue-Yang,Wang, Zhi-Long,Wu, Yan-Ran,Gunosewoyo, Hendra,Xie, Xiao-Yu,Chen, Jian-Zhong,Yang, Fan,Li, Jing,Tang, Jie,Xie, Xin,Yu, Li-Fang
p. 7067 - 7083
(2017/09/07)

Design, synthesis and evaluation of bitopic arylpiperazinephenyl-1,2,4-oxadiazoles as preferential dopamine D3 receptor ligands
The dopamine D3 receptor (D3R) was proposed as a therapeutic target for drug development to treat drug abuse and addiction and neuropsychiatric disorders. Several D3R-selective modulators over the dopamine D2 receptor (D2R) can avoid extrapyramidal sympto
Cao, Yongkai,Min, Chengchun,Acharya, Srijan,Kim, Kyeong-Man,Cheon, Seung Hoon
p. 191 - 200
(2015/12/31)

Photoactivatable platinum(II) terpyridine derivatives for G-quadruplex DNA double anchoring
Platinum(II) tolylterpyridine (ttpy) complexes, have been shown to generate monofunctional adducts with various G-quadruplex DNA forming sequences resulting from an efficient π-stacking mode on the top of the quadruplex structure. To further explore the p
Morel, Elodie,Poyer, Florent,Vaslin, Laurence,Bombard, Sophie,Teulade-Fichou, Marie-Paule
supporting information
p. 152 - 158
(2016/10/05)

α-Amino Acid-Isosteric α-Amino Tetrazoles
The synthesis of all 20 common natural proteinogenic and 4 otherα-amino acid-isosteric α-amino tetrazoles has been accomplished, whereby the carboxyl group is replaced by the isosteric 5-tetrazolyl group. The short process involves the use of the key Ugi tetrazole reaction followed by deprotection chemistries. The tetrazole group is bioisosteric to the carboxylic acid and is widely used in medicinal chemistry and drug design. Surprisingly, several of the common α-amino acid-isosteric α-amino tetrazoles are unknown up to now. Therefore a rapid synthetic access to this compound class and non-natural derivatives is of high interest to advance the field.
Zhao, Ting,Kurpiewska, Katarzyna,Kalinowska-T?us?cik, Justyna,Herdtweck, Eberhardt,D?mling, Alexander
supporting information
p. 3009 - 3018
(2016/03/26)

CONTROLLED RELEASE PREPARATION
A controlled release preparation wherein the release of active ingredient is controlled, which releases an active ingredient for an extended period of time by staying or slowly migrating in the gastrointestinal tract, is provided by means such as capsulating a tablet, granule or fine granule wherein the release of active ingredient is controlled and a gel-forming polymer. Said tablet, granule or fine granule has a release-controlled coating-layer formed on a core particle containing an active ingredient.
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Paragraph 0486; 0487; 0488

(2016/06/06)

Synthesis of fluorescent molecular probes based on cis-cinnamic acid and molecular imaging of lettuce roots
We synthesized azo dye- and fluorescence-labeled cis-cinnamic acid analogues possessing inhibitory activity against lettuce root growth and a trans-isomer without bioactivity as a control probe. The radicles incubated with the azo dye-labeled analogue were stained red, with their tips especially deeply dyed. The fluorescent images of the radicles incubated with each of these molecular probes depicted that the root cap was fluorescence-stained. However, images of the control radicles prepared by staining with the trans-isomer fluorescent probe did not show emission at the root cap. These contrasts suggest specific localization of the cis-cinnamate analogue at the columella cells.
Fukuda, Hiroshi,Nishikawa, Keisuke,Fukunaga, Yukihiro,Okuda, Katsuhiro,Kodama, Kozue,Matsumoto, Kenji,Kano, Arihiro,Shindo, Mitsuru
supporting information
p. 6492 - 6498
(2016/09/23)

Structure-Activity Study of N -((trans)-4-(2-(7-Cyano-3,4-dihydroisoquinolin-2(1 H)-yl)ethyl)cyclohexyl)-1 H -indole-2-carboxamide (SB269652), a Bitopic Ligand That Acts as a Negative Allosteric Modulator of the Dopamine D2 Receptor
We recently demonstrated that SB269652 (1) engages one protomer of a dopamine D2 receptor (D2R) dimer in a bitopic mode to allosterically inhibit the binding of dopamine at the other protomer. Herein, we investigate structural determinants for allostery, focusing on modifications to three moieties within 1. We find that orthosteric "head" groups with small 7-substituents were important to maintain the limited negative cooperativity of analogues of 1, and replacement of the tetrahydroisoquinoline head group with other D2R "privileged structures" generated orthosteric antagonists. Additionally, replacement of the cyclohexylene linker with polymethylene chains conferred linker length dependency in allosteric pharmacology. We validated the importance of the indolic NH as a hydrogen bond donor moiety for maintaining allostery. Replacement of the indole ring with azaindole conferred a 30-fold increase in affinity while maintaining negative cooperativity. Combined, these results provide novel SAR insight for bitopic ligands that act as negative allosteric modulators of the D2R.
Shonberg, Jeremy,Draper-Joyce, Christopher,Mistry, Shailesh N.,Christopoulos, Arthur,Scammells, Peter J.,Lane, J. Robert,Capuano, Ben
p. 5287 - 5307
(2015/08/03)

Erythropoietin Expression Promoter
The present invention provides an erythropoietin expression-enhancing agent that can cancel the suppression of erythropoietin production or promote erythropoietin production, and a therapeutic or preventive drug for anemia, a liver function-improving agent, an ischemic injury-improving agent, a renal protective agent, and an insulin secretagogue comprising the erythropoietin expression-enhancing agent. The erythropoietin expression-enhancing agent of the present invention comprises one or more compounds selected from the group consisting of compounds represented by the following general formulas (I), (II), and (III) and pharmaceutically acceptable salts thereof when R3 is OH.
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Paragraph 0070; 0181; 0182

(2015/12/30)

Discovery of a Novel Class of Negative Allosteric Modulator of the Dopamine D2 Receptor Through Fragmentation of a Bitopic Ligand
Recently, we have demonstrated that N-((trans)-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652) (1) adopts a bitopic pose at one protomer of a dopamine D2 receptor (D2R) dimer to negatively modulate the binding of dopamine at the other protomer. The 1H-indole-2-carboxamide moiety of 1 extends into a secondary pocket between the extracellular ends of TM2 and TM7 within the D2R protomer. To target this putative allosteric site, we generated and characterized fragments that include and extend from the 1H-indole-2-carboxamide moiety of 1. N-Isopropyl-1H-indole-2-carboxamide (3) displayed allosteric pharmacology and sensitivity to mutations of the same residues at the top of TM2 as was observed for 1. Using 3 as an "allosteric lead", we designed and synthesized an extensive fragment library to generate novel SAR and identify N-butyl-1H-indole-2-carboxamide (11d), which displayed both increased negative cooperativity and affinity for the D2R. These data illustrate that fragmentation of extended compounds can expose fragments with purely allosteric pharmacology.
Mistry, Shailesh N.,Shonberg, Jeremy,Draper-Joyce, Christopher J.,Klein Herenbrink, Carmen,Michino, Mayako,Shi, Lei,Christopoulos, Arthur,Capuano, Ben,Scammells, Peter J.,Lane, J. Robert
p. 6819 - 6843
(2015/09/22)

Synthesis of Actinomycetes natural products JBIR-94, JBIR-125, and related analogues
The synthesis of the natural products JBIR-94, DCP, DFP, and CFP is reported. A strategy for the coupling of ferulic or coumaric acid to putrescine is described. We determined that EDCI was the most effective coupling agent for this synthesis. In addition amide coupling with saturated cinnamic acids derivatives provided the best yield. The synthesis of JBIR-125 is accomplished through a novel synthesis of differentially protected spermidine. Preliminary bioassay data demonstrated that all five compounds were active against Pseudomonas aeruginosa.
Taj, Rafiq,Sorensen, John L.
supporting information
p. 7108 - 7111
(2015/12/01)

Structure-activity relationships of privileged structures lead to the discovery of novel biased ligands at the dopamine D2 receptor
Biased agonism at GPCRs highlights the potential for the discovery and design of pathway-selective ligands and may confer therapeutic advantages to ligands targeting the dopamine D2 receptor (D2R). We investigated the determinants of efficacy, affinity, and bias for three privileged structures for the D2R, exploring changes to linker length and incorporation of a heterocyclic unit. Profiling the compounds in two signaling assays (cAMP and pERK1/2) allowed us to identify and quantify determinants of biased agonism at the D2R. Substitution on the phenylpiperazine privileged structures (2-methoxy vs 2,3-dichloro) influenced bias when the thienopyridine heterocycle was absent. Upon inclusion of the thienopyridine unit, the substitution pattern (4,6-dimethyl vs 5-chloro-6-methoxy-4-methyl) had a significant effect on bias that overruled the effect of the phenylpiperazine substitution pattern. This latter observation could be reconciled with an extended binding mode for these compounds, whereby the interaction of the heterocycle with a secondary binding pocket may engender bias.
Szabo, Monika,Klein Herenbrink, Carmen,Christopoulos, Arthur,Lane, J. Robert,Capuano, Ben
p. 4924 - 4939
(2014/07/07)

A class of 4-sulfamoylphenyl-ω-aminoalkyl ethers with effective carbonic anhydrase inhibitory action and antiglaucoma effects
We report a series of 4-sulfamoylphenyl-ω-aminoalkyl ethers as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The structure-activity relationship was drawn for the inhibition of four physiologically relevant isoforms: hCA I, II, IX, and XII. Many of these compounds were highly effective, low nanomolar inhibitors of all CA isoforms, whereas several isoform-selective were also identified. X-ray crystal structures of two new sulfonamides bound to the physiologically dominant CA II isoform showed the tails of these derivatives bound within the hydrophobic half of the enzyme active site through van der Waals contacts with Val135, Leu198, Leu204, Trp209, Pro201, and Pro202 amino acids. One of the highly water-soluble compound (as trifluoroacetate salt) showed effective IOP lowering properties in an animal model of glaucoma. Several fluorescent sulfonamides incorporating either the fluorescein-thiourea (7a-c) or tetramethylrhodamine-thiourea (9a,b) moieties were also obtained and showed interesting CA inhibitory properties for the tumor-associated isoforms CA IX and XII.
Bozdag, Murat,Pinard, Melissa,Carta, Fabrizio,Masini, Emanuela,Scozzafava, Andrea,McKenna, Robert,Supuran, Claudiu T.
p. 9673 - 9686
(2015/01/09)

Structure of a complex formed by a protein and a helical aromatic oligoamide foldamer at 2.1 ? resolution
In the search of molecules that could recognize sizeable areas of protein surfaces, a series of ten helical aromatic oligoamide foldamers was synthesized on solid phase. The foldamers comprise three to five monomers carrying various proteinogenic side chains, and exist as racemic mixtures of interconverting right-handed and left-handed helices. Functionalization of the foldamers by a nanomolar ligand of human carbonic anhydrase II (HCA) ensured that they would be held in close proximity to the protein surface. Foldamer-protein interactions were screened by circular dichroism (CD). One foldamer displayed intense CD bands indicating that a preferred helix handedness is induced upon interacting with the protein surface. The crystal structure of the complex between this foldamer and HCA could be resolved at 2.1 ? resolution and revealed a number of unanticipated protein-foldamer, foldamer-foldamer, and protein-protein interactions. To design a foldamer that binds to a protein surface, a strategy is proposed that uses a known protein ligand to tether the foldamer to the protein surface. Candidates are first screened for induced circular dichroism in presence of the protein. Then, structural information about foldamer-protein interactions is collected before strong binding is established. The crystal structure of human carbonic anhydrase (A, B chains) with helical aromatic amide foldamers (stick models) is shown. Copyright
Buratto, Jérémie,Colombo, Cinzia,Stupfel, Marine,Dawson, Simon J.,Dolain, Christel,Langlois D'Estaintot, Béatrice,Fischer, Lucile,Granier, Thierry,Laguerre, Michel,Gallois, Bernard,Huc, Ivan
supporting information
p. 883 - 887
(2014/01/23)

Concise, stereodivergent and highly stereoselective synthesis of cis-and trans-2-substituted 3-hydroxypiperidines-development of a phosphite-driven cyclodehydration
A concise (5 to 6 steps), stereodivergent, highly diastereoselective (dr up to >19:1 for both stereoisomers) and scalable synthesis (up to 14 g) of cis- and trans-2-substituted 3-piperidinols, a core motif in numerous bioactive compounds, is presented. This sequence allowed an efficient synthesis of the NK-1 inhibitor L-733,060 in 8 steps. Additionally, a cyclodehydration-realizing simple triethylphosphite as a substitute for triphenylphosphine is developed. Here the stoichiometric oxidized P(V)-byproduct (triethylphosphate) is easily removed during the work up through saponification overcoming separation difficulties usually associated to triphenylphosphine oxide.
Huy, Peter H.,Westphal, Julia C.,Koskinen, Ari M.P.
supporting information
p. 369 - 383
(2014/03/21)

Synthesis and biological evaluation of RGD-Conjugated MEK1/2 kinase inhibitors for integrin-targeted cancer therapy
Two novel series of RGD-MEKI conjugates derived from a MEK1/2 kinase inhibitor-PD0325901-have been developed for integrin receptor mediated anticancer therapy. The first series, alkoxylamine analog RGD-MEKI conjugates 9a-g showed anti-proliferation activity in melanoma A375 cells by the same mechanism as that of PD0325901. PEGylation increased the IC50 value of 9f three-fold in the A375 assay, and the multi-cRGD peptide cargo significantly improved the receptor specific anti-proliferation activity of 9g in integrin-overexpressing U87 cells. In the second series, RGD-PD0325901 13 exhibited significantly increased antitumor properties compared to the alkoxylamine analogs by both inhibition of the ERK pathway activity and DNA replication of the cancer cells. Furthermore, 13 displayed more potent anti-proliferation activity in the U87 assay than PD0325901 in a dose-dependent manner. All these data demonstrate that RGD-MEKI conjugates with an ester bond linkage enhanced anticancer efficacy with improved targeting capability toward integrin-overexpressing tumor cells.
Li, Xiaoxiao,Hou, Jianjun,Wang, Chao,Liu, Xinjie,He, Hongyan,Xu, Ping,Yang, Zhenjun,Chen, Zili,Wu, Yun,Zhang, Lihe
p. 13957 - 13978
(2014/01/06)

Efficient synthesis of five and six member sultam
A robust approach for the synthesis of five and six member sultam is achieved employing commercially available starting materials and reagents. The use of simplest reactions without any critical parameter is the key strength of this route applicable on large scale synthesis.
Shewalkar, Mukesh P.,Rao, Ramakrishna,Reddy, Veer Bhadra,Shinde, Devanand B.
p. 518 - 522
(2013/08/23)