- Synthesis, Biological Evaluation, and Computational Analysis of Biaryl Side-Chain Analogs of Solithromycin
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There is an urgent need for new antibiotics to mitigate the existential threat posed by antibiotic resistance. Within the ketolide class, solithromycin has emerged as one of the most promising candidates for further development. Crystallographic studies of bacterial ribosomes and ribosomal subunits complexed with solithromycin have shed light on the nature of molecular interactions (π-stacking and H-bonding) between from the biaryl side-chain of the drug and key residues in the 50S ribosomal subunit. We have designed and synthesized a library of solithromycin analogs to study their structure-activity relationships (SAR) in tandem with new computational studies. The biological activity of each analog was evaluated in terms of ribosomal affinity (Kd determined by fluorescence polarization), as well as minimum inhibitory concentration assays (MICs). Density functional theory (DFT) studies of a simple binding site model identify key H-bonding interactions that modulate the potency of solithromycin analogs.
- Daher, Samer S.,Lee, Miseon,Jin, Xiao,Teijaro, Christiana N.,Wheeler, Steven E.,Jacobson, Marlene A.,Buttaro, Bettina,Andrade, Rodrigo B.
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p. 3368 - 3373
(2021/09/06)
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- Synthesis and fundamental evaluation of radioiodinated rociletinib (CO-1686) as a probe to lung cancer with L858R/T790M mutations of Epidermal Growth Factor Receptor (EGFR)
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Rociletinib (CO-1686), a 2,4-diaminopyrimidine derivative, is a highly potent tyrosine kinase inhibitor (TKI) that acts on epidermal growth factor receptor (EGFR) with L858R/T790M mutations. We supposed radioiodinated CO-1686 would function as a useful tool for monitoring EGFR L858R/T790M mutations. To aid in patient selection before therapy with EGFR-TKIs, this study aimed to develop a 125I-labeled derivative of CO-1686, N-{3-[(2-{[4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl]amino}-5-(trifluoromethyl)pyrimidine-4-yl] amino}-5-([125I]iodophenyl)acrylamide ([125I]ICO1686) and evaluate its selectivity toward EGFR L858R/T790M. Radiosynthesis was performed by iododestannylation of the corresponding tributylstannyl precursor with [125I]NaI and N-chlorosuccinimide. The selectivity of the tracer for detecting EGFR L858R/T790M was evaluated using three relevant non-small cell lung cancer (NSCLC) cell lines—H1975, H3255 and H441 overexpressing the dual mutation EGFR L858R/T790M, active mutant EGFR L858R and wild-type EGFR, respectively. The nonradioactive ICO1686 and the precursor compound were successfully synthesized. A novel radiolabeled probe, [125I]ICO1686, was prepared with high radiochemical yield (77%) and purity (>99%). ICO1686 exhibited high cytotoxicity toward H1975 (IC50 0.20 ± 0.05 μM) and H3255 (IC50 0.50 ± 0.21 μM), which is comparable to that of CO-1686. In contrast, the cytotoxicity of ICO1686 toward H441 was 10-fold lower than that toward H1975. In the cell uptake study, the radioactivity uptake of [125I]ICO1686 in H1975 was 101.52% dose/mg, whereas the uptakes in H3255 and H441 were 33.52 and 8.95% dose/mg, respectively. The uptake of [125I]ICO1686 in H1975 was greatly reduced to 45.61% dose/mg protein by treatment with excess CO-1686. In vivo biodistribution study of the radiotracer found that its accumulation in H1975 tumor (1.77 ± 0.43% ID/g) was comparable to that in H3255 tumor (1.63 ± 0.23% ID/g) and the accumulation in H1975 tumor was not reduced by pretreatment with an excess dose of CO-1686. Although this radiotracer exhibited highly specific in vitro uptake in target cancer cells, structural modification is required to improve in vivo biodistribution.
- Fawwaz, Muammar,Kinuya, Seigo,Mishiro, Kenji,Nishii, Ryuichi,Ogawa, Kazuma,Sawazaki, Izumi,Shiba, Kazuhiro
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- MLKL INHIBITORS
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Purine derivatives that inhibit cellular necroptosis and/or human MLKL, pharmaceutical compositions thereof, and methods of treating an MLKL-mediated disorder with an effective amount of the compound or composition. Said MLKL-mediated disorder is pathology associated necroptosis, including ischemia-reperfusion damage, neurodegeneration, and inflammatory diseases such as acute pancreatitis, multiple sclerosis, inflammatory bowel disease, and allergic colitis.
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Paragraph 0880-0882
(2018/09/26)
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- Metal chelating crosslinkers form nanogels with high chelation stability
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We present a series of hydrogel nanoparticles (nanogels) incorporating either acyclic or cyclic gadolinium chelates as crosslinkers. These crosslinkers are used to formulate polyacrylamide-based nanogels (diameter 50 to 85 nm) yielding contrast agents with enhanced relaxivities (up to 6-fold greater than Dotarem), because the nanogel structure slows the chelator's tumbling frequency and allows fast water exchange. Importantly, these nanogels also stabilize Gd3+ within the chelator thermodynamically and kinetically against metal displacement through transmetallation, which should reduce toxicity associated with release of free Gd3+. This chelation stability suggests that the chelate crosslinker strategy may prove useful for other applications of metal-chelating nanoparticles in medicine, including other imaging modalities and radiotherapy.
- Lux, Jacques,Chan, Minnie,Vander Elst, Luce,Schopf, Eric,Mahmoud, Enas,Laurent, Sophie,Almutairi, Adah
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p. 6359 - 6364
(2013/12/04)
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- Triplex-forming ability of oligonucleotides containing 1-aryl-1,2,3- triazole nucleobases linked via a two atom-length spacer
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Phosphoramidites containing 2-propynyloxy or 1-butyn-4-yl as nucleobase precursors were synthesized and introduced into oligonucleotides using an automated DNA synthesizer. Copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition of the oligonucleotides wi
- Hari, Yoshiyuki,Nakahara, Motoi,Obika, Satoshi
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p. 5583 - 5588
(2013/09/02)
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- Polymerization of an optically active phenylacetylene derivative bearing an azide residue by click reaction and reaction with a rhodium catalyst
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A facile method for synthesizing diverse optically active polymers with different backbone structures was developed by the polymerization of an optically active aromatic azide bearing an acetylene unit with a rhodium catalyst followed by the click reaction of the pendant azides or by the click polymerization of the monomer. The Royal Society of Chemistry.
- Kobayashi, Shinzo,Itomi, Ken,Morino, Kazuhide,Iida, Hiroki,Yashima, Eiji
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supporting information; experimental part
p. 3019 - 3021
(2009/02/04)
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- Synthesis of tricyclic heterocycles via a tandem aryl alkylation/Heck coupling sequence
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(Chemical Equation Presented) A norbornene-mediated palladium-catalyzed sequence is described in which two alkyl-aryl bonds and one alkenyl-aryl bond are formed in one pot with use of microwave irradiation. A variety of symmetrical and unsymmetrical oxygen-, nitrogen-, silicon-, and sulfur-containing tricyclic heterocycles were synthesized from a Heck acceptor and an aryl iodide containing two tethered alkyl halides. This approach was further applied to the synthesis of a tricyclic mescaline analogue.
- Alberico, Dino,Rudolph, Alena,Lautens, Mark
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p. 775 - 781
(2007/10/03)
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- Synthesis of carbon dendron nano-chains with π-extended conjugation based on linear 1,4-phenylethynyl and 1,5-naphthylethynyl subunits
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A convenient and efficient synthesis of 3,5-di(trimethylsilylethynyl)phenylacetylene and p-[3,5-di(trimethylsilylethynyl)-1-phenylethynyl]phenylacetylene and the naphthylethynyl homologues terminal acetylenes of 5-(N,N-dimethylamino)naphthylethyne have been carried out. These terminal acetylene compounds serve to prepare nanometer-sized conjugated 1,3,5-tri(ethynylphenyl)benzene and 1,3,5-tri(ethynylnaphthyl)benzene oligomers, by means of heterocoupling with 1,3,5-triiodobenzene, catalysed by palladium, in excellent yields. Both the ethynylphenyl or ethynylnaphthyl homologues chains show fluorescence emission radiation, with important quantum yield.
- Rodríguez, J. Gonzalo,Tejedor, J. Luis,Esquivias, Jorge,Díaz, Cristina
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p. 6375 - 6378
(2007/10/03)
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- Synthesis of nanostructures based on 1,4- and 1,3,5-ethynylphenyl subunits with π-extended conjugation. Carbon dendron units
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Nanometer-sized conjugated 1,4- and 1,3,5-ethynylphenyl oligomers were synthesized starting from 3,5-di(trimethylsilylethynyl)phenylacetylene and p-[3,5-di(trimethylsilylethynyl)-1-ethynylphenyl]-phenyl acetylene by cross-coupling reaction with a convenient haloaryl derivative, catalyzed by palladium(II)/copper(I), in excellent yield. The terminal acetylenes were efficiently prepared by a specific protection-deprotection methodology. All ethynylphenyl homologues obtained show fluorescence emission, with the bathochromic shift of approximately 20 nm by each ethynylphenyl unit increasing the conjugate chain. Parallel conjugated ethynylphenyl chains were prepared through the insertion of a 1,5-naphthalene subunit, and the compounds exhibit fluorescence radiation emission.
- Gonzalo Rodriguez,Esquivias, Jorge,Lafuente, Antonio,Diaz, Cristina
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p. 8120 - 8128
(2007/10/03)
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- AZIDOPHENYLCYANOGUANIDINES AS PHOTOAFFINITY PROBES
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This invention comprises novel compounds that are useful and effective as photoaffinity probes useful for the identification of the biochemical components that form K ATP channels in smooth muscle cells. The probes are described by the formula below, STR1 where R. sub.1 is H, C. sub.1-3 alkyl; R 2 is H, C 1-3 alkyl; or R 1 and R 2 may be joined together to form C 3-6 cycloalkyl, or C 3-6 cycloalkyl optionally substituted with C 1-4 alkyl;R 3 is C 1-6 alkyl, or C 6-12 aryl optionally substituted with 1-3 Halogens; or suitable salts thereof.
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