- High Throughput Experimentation and Continuous Flow Validation of Suzuki–Miyaura Cross-Coupling Reactions
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Traditional methods to discover optimal reaction conditions for small molecule synthesis is a time-consuming effort that requires large quantities of material and a significant expenditure of labor. High-throughput techniques are a potentially transformative approach for reaction condition screening, however, rapid validation of the reaction hotspots under continuous flow conditions remains necessary to build confidence in high throughput screening hits. Continuous flow technology offers the opportunity to upscale the screening hotspots and optimize their output of the target compounds due to the exceptional heat and mass transfer ability of flow reactions that are conducted in a smaller and safer reaction volume. We report a robotic high throughput technique to execute reactions in multi-well plates that were coupled with fast mass spectrometric analysis using an autosampler to accelerate the reaction screening process. Palladium-catalyzed Suzuki–Miyaura cross-coupling reactions were screened in this system and a heat map was generated to identify the best reaction conditions for downstream scale-up under continuous flow. Here, high throughput experimentation reactions in 96-well plates were performed for 1 h at 50 °C, 100 °C, 150 °C, and 200 °C before diluting them into 384-well plates for mass analysis. With the aid of high throughput tools, 648 unique experiments were conducted in duplicate. The cross-coupling reactions were evaluated as a function of stoichiometry, temperature, concentration, order of addition, and substrate type. The hotspots from high throughput experimentation were examined using a microfluidic Chemtrix system that confirmed the positive reaction leads as true positives. Negative outcomes identified by these experiments were found to be true negatives by microfluidic reaction evaluation. Quantitation of product yields was performed using high-performance liquid chromatography-mass spectrometry (HPLC/MS-MS).
- Jaman, Zinia,Mufti, Ahmed,Sah, Samyukta,Avramova, Larisa,Thompson, David H.
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- Substituent effects on the in vitro and in vivo genotoxicity of 4-aminobiphenyl and 4-aminostilbene derivatives
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4-Amino-4'-substituted biphenyls and 4-aminostilbenes substituted in the 3' or 4' position were studied for their in vitro and in vivo genotoxicity. The in vitro mutagenicity of the biphenyls with and without S9 activation was established with Salmonella strains TA98 and TA100 and that of the stilbenes with the same strains plus TA98/1,8-DNP6. The in vivo genotoxicity assay with both series of compounds was for chromosomal aberrations in the bone-marrow cells of mice following intraperitoneal administration of the chemicals. Hammett values of substituents, partition coefficients and frontier orbital energies (E(LUMO) and E(HOMO) of the compounds were used for correlations with mutagenicity. The Salmonella mutagenicity in TA98 and TA98/1,8-DNP6 with S9 was correlated to Hammett σ+ values for the 4-aminostilbene substituents, showing a strong trend of increasing mutagenicity with an increase in the electron-withdrawing capability of the substituent. Hydrophobicity of the stilbenes, however, had little effect on their relative mutagenicity. The 4-aminobiphenyls showed a correlation between their mutagenicity and Hammett σ+ values of their 4'-substituents in stain TA98 with S9, although the trend was not as strong as for the stilbenes. But unlike the stilbenes, TA98 mutagenicity of the biphenyls could also be correlated to hydrophobicity, and structure-activity correlations for the biphenyls was substantially improved when both σ+ and hydrophobicity data were included. For strain TA100 with S9, little correlation was found between mutagenicity of the stilbenes and any of the parameters. However, a limited orrelation did exist between the mutagenicity of the biphenyls and their hydrophobicity. There was also limited correlations of the mutagenicity for the stilbenes in TA98 and TA98/1,8-DNP6 with S9 to E(LUMO) or E(HOMO). The in vivo genotoxicity results for the biphenyls and stilbenes could not be correlated to electronic effects as for the in vivo results, nor could they be explained by hydrophobicity. However, it is interesting to note that 3'-substituted 4-aminostilbenes were all substantially more genotoxic in vivo than their corresponding 4'-substituted counterparts. The most genotoxic compound in vivo in either series was 4-aminostilbene which would not have been predicted from the in vitro results.
- You,Brezzell,Das,Hooberman,Sinsheimer
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- Catalysis of the Photo-Fries Reaction: Antibody-Mediated Stabilization of High Energy States
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A conformationally constrained hapten is presented that is capable of catalyzing the first antibody-mediated photo-Fries rearrangement. In this reaction, absorption of light energy by a diphenyl ether substrate results in homolytic C-O bond cleavage followed by recombination to yield biphenyl-derived products. The most proficient antibody studied converts 4-phenoxyaniline 15 into 2-hydroxy-5-aminobiphenyl 16 under high-intensity irradiation at a rate of 8.6 μM/min. These results support a recent hypothesis stating that immunization with conformationally constrained haptens provides higher titers for the acquisition of simple binding antibodies; however, in this case, conformational constraint does not ensure the development of more efficient catalysts. Using the obtained antibodies, the presence of products resulting from escape of free radicals from the solvent cage can be suppressed, altering the excited state energy surface such that free radicals are funneled into the formation of the desired biphenyl product. However, studies also show the inactivation of the antibodies as a result of photodecay of the biphenyl product. Using an isocyanate scavenging resin, the photodecay product could be removed and the inactivation of the antibody drastically reduced. Furthermore, despite the observed photodecay, turnover of the antibody was present; this represents the first case in which true turnover of a photochemical reaction using a catalytic antibody could be observed.
- Dickerson, Tobin J.,Tremblay, Martin R.,Hoffman, Timothy Z.,Ruiz, Diana I.,Janda, Kim D.
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- Selective primary aniline synthesis through supported Pd-catalyzed acceptorless dehydrogenative aromatization by utilizing hydrazine
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By utilizing hydrazine (N2H4) as the nitrogen source in the presence of a hydroxyapatite-supported Pd nanoparticle catalyst (Pd/HAP), various primary anilines can be selectively synthesized from cyclohexanonesviaacceptorless dehydrogenative aromatization. The strong nucleophilicity of N2H4and the stability of the hydrazone intermediates can effectively suppress the formation of the undesired secondary aniline byproducts.
- Lin, Wei-Chen,Yatabe, Takafumi,Yamaguchi, Kazuya
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supporting information
p. 6530 - 6533
(2021/07/07)
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- Selective Synthesis of Primary Anilines from NH3 and Cyclohexanones by Utilizing Preferential Adsorption of Styrene on the Pd Nanoparticle Surface
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Dehydrogenative aromatization is one of the attractive alternative methods for directly synthesizing primary anilines from NH3 and cyclohexanones. However, the selective synthesis of primary anilines is quite difficult because the desired primary aniline products and the cyclohexanone substrates readily undergo condensation affording the corresponding imines (i.e., N-cyclohexylidene-anilines), followed by hydrogenation to produce N-cyclohexylanilines as the major products. In this study, primary anilines were selectively synthesized in the presence of supported Pd nanoparticle catalysts (e.g., Pd/HAP, HAP=hydroxyapatite, Ca10(PO4)6(OH)2) by utilizing competitive adsorption unique to heterogeneous catalysis; in other words, when styrene was used as a hydrogen acceptor, which preferentially adsorbs on the Pd nanoparticle surface in the presence of N-cyclohexylidene-anilines, various structurally diverse primary anilines were selectively synthesized from readily accessible NH3 and cyclohexanones. The Pd/HAP catalyst was reused several times though its catalytic performance gradually declined.
- Koizumi, Yu,Jin, Xiongjie,Yatabe, Takafumi,Miyazaki, Ray,Hasegawa, Jun-ya,Nozaki, Kyoko,Mizuno, Noritaka,Yamaguchi, Kazuya
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supporting information
p. 10893 - 10897
(2019/07/12)
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- Selective synthesis of primary anilines from cyclohexanone oximes by the concerted catalysis of a Mg-Al layered double hydroxide supported Pd catalyst
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Although the selective conversion of cyclohexanone oximes to primary anilines would be a good complement to the classical synthetic methods for primary anilines, which utilize arenes as the starting materials, there have been no general and efficient methods for the conversion of cyclohexanone oximes to primary anilines until now. In this study, we have successfully realized the efficient conversion of cyclohexanone oximes to primary anilines by utilizing a Mg-Al layered double hydroxide supported Pd catalyst (Pd(OH)x/LDH) under ligand-, additive-, and hydrogen-acceptor-free conditions. The substrate scope was very broad with respect to both cyclohexanone oximes and cyclohexenone oximes, which gave the corresponding primary anilines in high yields with high selectivities (17 examples, 75% to >99% yields). The reaction could be scaled up (gram-scale) with a reduced amount of the catalyst (0.2 mol %). Furthermore, the one-pot synthesis of primary anilines directly from cyclohexanones and hydroxylamine was also successful (five examples, 66-99% yields). The catalysis was intrinsically heterogeneous, and the catalyst could be reused for the conversion of cyclohexanone oxime to aniline at least five times with keeping its high catalytic performance. Kinetic studies and several control experiments showed that the high activity and selectivity of the present catalyst system were attributed to the concerted catalysis of the basic LDH support and the active Pd species on LDH. The present transformation of cyclohexanone oximes to primary anilines proceeds through a dehydration/dehydrogenation sequence, and herein the plausible reaction mechanism is proposed on the basis of several pieces of experimental evidence.
- Jin, Xiongjie,Koizumi, Yu,Yamaguchi, Kazuya,Nozaki, Kyoko,Mizuno, Noritaka
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p. 13821 - 13829
(2017/11/06)
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- 3-Hydroxypyrimidine-2,4-diones as Selective Active Site Inhibitors of HIV Reverse Transcriptase-Associated RNase H: Design, Synthesis, and Biochemical Evaluations
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Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains an unvalidated antiviral target. A major challenge of specifically targeting HIV RNase H arises from the general lack of selectivity over RT polymerase (pol) and integrase (IN) strand transfer (ST) inhibitions. We report herein the synthesis and biochemical evaluations of three novel 3-hydroxypyrimidine-2,4-dione (HPD) subtypes carefully designed to achieve selective RNase H inhibition. Biochemical studies showed the two subtypes with an N-1 methyl group (9 and 10) inhibited RNase H in low micromolar range without siginificantly inhibiting RT polymerase, whereas the N-1 unsubstituted subtype 11 inhibited RNase H in submicromolar range and RT polymerase in low micromolar range. Subtype 11 also exhibited substantially reduced inhibition in the HIV-1 INST assay and no significant cytotoxicity in the cell viability assay, suggesting that it may be amenable to further structure-activity relationship (SAR) for identifying RNase H inhibitors with antiviral activity.
- Tang, Jing,Liu, Feng,Nagy, Eva,Miller, Lena,Kirby, Karen A.,Wilson, Daniel J.,Wu, Bulan,Sarafianos, Stefan G.,Parniak, Michael A.,Wang, Zhengqiang
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p. 2648 - 2659
(2016/04/10)
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- Structure-activity relationship study of E6 as a novel necroptosis inducer
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Necroptosis inducers represent a promising potential treatment for drug-resistant cancer. We herein describe the structure modification of E6, which was identified recently as a potent and selective necroptosis inducer. The studies described herein demonstrate for the first time that functionalized biphenyl derivatives possess necroptosis inducer activity. Furthermore, these studies have led to the identification of two promising compounds (5h and 5j) that can be used for further optimization studies as well as mechanism of action investigations.
- Mou, Jianfeng,Park, Ann,Cai, Yu,Yuan, Junying,Yuan, Chengye
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supporting information
p. 3057 - 3061
(2015/06/22)
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- Design and synthesis of potent carboxylic acid DGAT1 inhibitors with high cell permeability
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A series of potent carboxylic acid DGAT1 inhibitors with high permeability were developed from a virtual screening hit. Strategies were employed to reduce Pgp substrate recognition and increase passive permeability, resulting in the discovery of a series showing good inhibition of cellular triglyceride synthesis. The mutagenic potential of prospective metabolites was evaluated in the Ames assay, and one aniline was shown to be devoid of mutagenicity.
- Bali, Ustav,Barba, Oscar,Dawson, Graham,Gattrell, William T.,Horswill, James G.,Pan, David A.,Procter, Martin J.,Rasamison, Chrystelle M.,Sambrook Smith, Colin P.,Taylor-Warne, Amanda,Wong-Kai-In, Philippe
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scheme or table
p. 824 - 828
(2012/03/26)
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- A Gd3+-based magnetic resonance imaging contrast agent sensitive to β-Galactosidase activity utilizing a receptor-induced magnetization enhancement (RIME) phenomenon
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Magnetic resonance imaging (MRI) permits noninvasive three-dimensional imaging of opaque organisms. Gadolinium (Gd3+) complexes have become important imaging tools as MRI contrast agents for MRI studies, though most of them are nonspecific and report solely on anatomy. Recently, MRI contrast agents have been reported whose ability to relax water protons is triggered or greatly enhanced by recognition of a particular biomolecule. This new class of MRI contrast agents could open up the possibility of reporting on the physiological state or metabolic activity deep within living specimens. One possible strategy for this purpose is to utilize the increase in the longitudinal water proton r1 relaxivity that occurs upon slowing the molecular rotation of a small paramagnetic complex, a phenomenon which is known as receptor-induced magnetization enhancement (RIME), by either binding to a macro-molecule or polymerization of the agent itself. Here we describe the design and synthesis of a novel β-galactosidase-activated MRI contrast agent, the Gd3+ complex [Gd-5], by using the RIME approach. β-Galactosidase is commonly used as a marker gene to monitor gene expression. This newly synthesized compound exhibited a 57% increase in the r1 relaxivity in phosphate-buffered saline (PBS) with 4.5% w/v human serum albumin (HSA) in the presence of β-galactosidase. Detailed investigations revealed that RIME is the dominant factor in this increase of the observed r1 relaxivity, based on analysis of Gd3+ complexes [Gd-5] and [Gd-8], which is generated from [Gd-5] by the activity of β-galactosidase, and spectroscopic analysis of their corresponding Tb3+ complexes, [Tb-5] and [Tb-8].
- Hanaoka, Kenjiro,Kikuchi, Kazuya,Terai, Takuya,Komatsu, Toru,Nagano, Tetsuo
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p. 987 - 995
(2008/09/21)
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