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Reinventing Hsp90 Inhibitors: Blocking C‐Terminal Binding Events to Hsp90 by Using Dimerized Inhibitors
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Yen Chin Koay Dr. Hendra Wahyudi Prof. Shelli R. McAlpine 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(51):18572-18582
Heat shock protein 90 (Hsp90) is a molecular chaperone (90 kDa) that functions as a dimer. This protein facilitates the folding, assembly, and stabilization of more than 400 proteins that are responsible for cancer development and progression. Inhibiting Hsp90’s function will shut down multiple cancer‐driven pathways simultaneously because oncogenic clients rely heavily on Hsp90, which makes this chaperone a promising anticancer target. Classical inhibitors that block the binding of adenine triphosphate (ATP) to the N‐terminus of Hsp90 are highly toxic to cells and trigger a resistance mechanism within cells. This resistance mechanism comprises a large increase in prosurvival proteins, namely, heat shock protein 70 (Hsp70), heat shock protein 27 (Hsp27), and heat shock factor 1 (HSF‐1). Molecules that modulate the C‐terminus of Hsp90 are effective at inducing cancer‐cell death without activating the resistance mechanism. Herein, we describe the design, synthesis, and biological binding affinity for a series of dimerized C‐terminal Hsp90 modulators. We show that dimers of these C‐terminal modulators synergistically inhibit Hsp90 relative to monomers. 相似文献
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Crosslinkable high dielectric constant polymer dielectrics for low voltage organic field‐effect transistor memory devices 下载免费PDF全文
Chih‐Chien Hung Hung‐Chin Wu Yu‐Cheng Chiu Shih‐Huang Tung Wen‐Chang Chen 《Journal of polymer science. Part A, Polymer chemistry》2016,54(19):3224-3236
I n this study, we successfully synthesized water/methanol soluble random copolymers with a high dielectric constant, poly(n‐(hydroxymethyl) acrylamide‐co‐5‐(9‐(5‐(diethylamino)pentyl)?2‐(4‐vinylphenyl)?9H‐fluorene(P(NMA‐co‐F6NSt)), which contained chemical crosslinkable segment (NMA) and hole trapping building block (F6NSt). The feeding molar ratios of two monomers (NMA:F6NSt) were set as 100:0, 95:5, 80:20, and 67:33 for the copolymers of P1 , P2 , P3, and P4 , respectively. The crosslinked P(NMA‐co‐F6NSt) thin film could serve as both dielectric and charge storage layers in organic field‐effect transistor (OFET) memory device and exhibited high k (i.e., 4.91–6.47) characteristics, leading to a low voltage operation and a small power consumption. Devices based on the P1 ‐ P4 dielectrics showed excellent insulating properties and good charge storage performance under a low operating voltage in a range of ±5V because of tightly network structures and well‐dispersed trapping cites. In particular, P3 ‐based memory device exhibited a large memory window of 4.13 V with stable data retention stability over 104 s, a large on/off ratio of 104, and good endurance characteristics as high as 200 cycles. The above results suggested that a high‐performance OFET memory device could be facilely achieved using the novel crosslinkable high‐k copolymers. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 3224–3236 相似文献
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Synthesis and characterization of double hydrophilic block copolymers containing semi-rigid and flexible segments 下载免费PDF全文
Alice M. Savage Elizabeth Ullrich Stacey M. Chin Zachary Kiernan Caitlyn Kost S. Richard Turner 《Journal of polymer science. Part A, Polymer chemistry》2015,53(2):219-227
3-Methyl-(E)-stilbene (3MSti) and 4-(diethylamino)-(E)-stilbene (DEASti) monomers are synthesized and polymerized separately with maleic anhydride (MAn) in a strictly alternating fashion using reversible addition-fragmentation chain transfer (RAFT) polymerization techniques. The optimal RAFT chain transfer agents (CTAs) for each copolymerization affect the reaction kinetics and CTA compatibilities. Psuedo-first order polymerization kinetics are demonstrated for the synthesis of poly((3-methyl-(E)-stilbene)-alt-maleic anhydride) (3MSti-alt-MAn) with a thiocarbonylthio CTA (methyl 2-(dodecylthiocarbonothioylthio)−2-methylpropionate, TTCMe). In contrast, a dithioester CTA (cumyl dithiobenzoate, CDB) controls the synthesis of poly((4-(diethylamino)-(E)-stilbene)-alt-maleic anhydride) (DEASti-alt-MAn) with pseudo-first order polymerization kinetics. DEASti-alt-MAn is chain extended with 4-acryloylmorpholine (ACMO) to synthesize diblock copolymers and subsequently converted to a double hydrophilic polyampholyte block copolymers (poly((4-(diethylamino)-(E)-stilbene)-alt-maleic acid))-b-acryloylmorpholine) (DEASti-alt-MA)-b-ACMO) via acid hydrolysis. The isoelectric point and dissociation behavior of these maleic acid-containing copolymers are determined using ζ-potential and acid–base titrations, respectively. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 219–227 相似文献
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Otoikhian Kevin Shegun Akhabue Christopher E. Aghogho Mujakperuo Adeniyi Adewale George Ighalo Joshua O. 《Russian Journal of Applied Chemistry》2020,93(12):1976-1988
Russian Journal of Applied Chemistry - The study is focused on modelling and optimizing the process parameters on the production of biodiesel from Jatropha Curcas oil using achantinoidea shell... 相似文献
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Megan L. Qualls Dr. Jinchao Lou Dillon P. McBee Prof. Joshua A. Baccile Prof. Michael D. Best 《Chemistry (Weinheim an der Bergstrasse, Germany)》2022,28(45):e202201164
Liposomes are effective therapeutic delivery nanocarriers due to their ability to encapsulate and enhance the pharmacokinetic properties of a wide range of therapeutics. Two primary areas in which improvement is needed for liposomal drug delivery is to enhance the ability to infiltrate cells and to facilitate derivatization of the liposome surface. Herein, we report a liposome platform incorporating a cyclic disulfide lipid (CDL) for the dual purpose of enhancing cell entry and functionalizing the liposome membrane through thiol-disulfide exchange. In order to accomplish this, CDL-1 and CDL-2 , composed of lipoic acid (LA) or asparagusic acid (AA) appended to a lipid scaffold, were designed and synthesized. A fluorescence-based microplate immobilization assay was implemented to show that these compounds enable convenient membrane decoration through reaction with thiol-functionalized small molecules. Additionally, fluorescence microscopy experiments indicated dramatic enhancements in cellular delivery when CDLs were incorporated within liposomes. These results demonstrate that multifunctional CDLs serve as an exciting liposome system for surface decoration and enhanced cellular delivery. 相似文献
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本文对HOC2H3F可能解离通道的势能面进行从头算CCSD(T)/CBS//B3LYP/6-311G(d,p)计算,同时对速率常数进行Rice-Ramsperger-Kassel-Marcus计算. 生成主要产物CH2CHO+HF最有利的反应途径是OHC2H3F→i2→TS14→i6→TS9→i3→TS3→CH2CHO+HF,其中速率决定步骤是HF通过TS11从CO桥接位置解离,能量比反应物高3.8 kcal/mol. 借助中间态TS14,F原子从Cα迁移到Cβ位置生成CH2O+CH2F,然后通过中间态TS16,H从O迁移到Cα位置;通过中间态TS5,C-C键断裂生成产物,其能量比反应物低1.8 kcal/mol,比TS11低4.0 kcal/mol. 相似文献
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