Computational studies of allosteric interactions have witnessed a recent renaissance fueled by growing interest in the modeling of complex molecular assemblies and biological networks. Allosteric interactions of the molecular chaperone Hsp90 with a diverse array of cochaperones and client proteins allow for molecular communication in signal transduction networks. In this review, recent developments in the understanding of allosteric interactions in the context of structural, functional, and computational studies of the Hsp90 chaperone are discussed. A comprehensive analysis of structural and network-based models of protein allostery is provided. Computational and experimental approaches and advances in the understanding of Hsp90 interactions and regulatory mechanisms are reviewed to provide a systematic and critical view of the current progress and most challenging questions in the field. The current status and future prospects for translational research, bridging the basic science of chaperones with the discovery of anti-cancer therapies, are also highlighted. 相似文献
Experimental protein structures provide spatial information at the atomic level. A further dimension, time, is supplemented by molecular dynamics. Since the pioneering work on the 58-residue inhibitor of bovine pancreatic trypsin in the group of Martin Karplus in the seventies, molecular dynamics simulations have shown that the intrinsic flexibility of proteins is essential for their function. Here, we review simulation studies of bromodomains. These protein modules are involved in the recognition of acetylated lysine side chains, a post-translational modification frequently observed in histone tails. The molecular dynamics simulations have unmasked: (i) the large plasticity of the loops lining the acetyl-lysine binding site (coupled to its self-occlusion), and (ii) multiple binding modes of acetyl-lysine. These simulation results suggest that recognition of histone tails by bromodomains is modulated by their intrinsic flexibility, and further corroborate the utility of molecular dynamics in understanding (macro)molecular recognition. 相似文献
From the law of conversation of energy, the release energy from the initiation to the Chapman–Jouguet point during the detonation of an energetic compound has been deduced as a function of initial density, detonation velocity, and detonation pressure. For C H N O energetic compounds the relative release energy per unit volume (Iv) approaches the relative specific wall kinetic energy (Ecyl/EHMX) at 19 mm wall displacement from the cylinder test with HMX as reference. A good linear relationship between Iv and Ecyl/EHMX has been regressed, implying that Ecyl/EHMX is also a function of initial density, detonation velocity, and detonation pressure. It has been concluded that Iv can reflect the driving force of detonation products of energetic compounds and is appropriate to be used for the evaluation of energy characteristics. The assessment of the energy for a series of synthesized and theoretically designed high‐energy compounds reveals that the future of C H N O energetic compounds is promising after CL‐20 and ONC. 相似文献
An extraordinarily efficient hybrid acids‐assisted, palladium‐catalyzed and chelating‐group‐assisted C H bond activation of N‐sulfonyl‐2‐aminobiaryls and their annulations with [60]fullerene via sequential C C and C N bond formation at room temperature to afford [60]fulleroazepines is demonstrated. The formation of [60]fulleroazepines is highly regioselective and tolerant to both electron‐withdrawing and electron‐donating groups on the aryl moiety and the reaction gives monofunctionalized fullerenes in good yields (up to 54% isolated yield and 92% based on converted C60). 相似文献
Zinc is the 24th most abundant element in the Earth’s crust. Since the discovery of pure zinc metal in the 18th century, the main application of zinc metal is as materials. Because zinc salts are abundant, cheap, non‐toxic, and exhibit environmentally benign properties, organic chemists have been interested in using zinc salts as catalysts in organic synthesis during the last three decades. Within this review, we have summarized the progress on applications of zinc salts in organic reactions. Our the target is to emphasize the special properties of zinc catalysts, and further promote the interest of organic chemists. 相似文献
A catalytic synthesis of selectively substituted phenanthridines is achieved through a reaction sequence involving palladium/norbornene‐catalyzed unsymmetrical aryl‐aryl and Heck couplings followed by aza‐Michael and retro‐Mannich reactions. In spite of the many steps involved the method is very simple and allows the formation of selectively substituted phenanthridines under mild conditions in a straightforward one‐pot reaction starting from readily available aryl iodides and bromides. 相似文献
The activation of benzylic C H bonds and subsequent coupling with terminal alkynes in the presence of 2,3‐dichloro‐5,6‐dicyanoquinone (DDQ) and a catalytic amount of copper(I) triflate is presented. Good to moderate yields of disubstituted alkynes are obtained for this cross‐dehydrogenative coupling (CDC) reaction between a variety of aromatic alkynes and diphenylmethane derivatives. 相似文献
Generally applicable, palladium‐catalyzed direct arylations of 1,2,3‐triazoles with aryl chlorides were accomplished through conventional heating at reaction temperatures of 105–120 °C. Thereby, intra‐ and intermolecular C H bond functionalizations were achieved with a variety of differently substituted chlorides as electrophiles, bearing numerous valuable functional groups. 相似文献
By using N,N‐dimethylformamide (DMF) as a methylenating reagent, the copper‐catalyzed C H activation of indole was demonstrated as an efficient and facile protocol for synthesizing 3,3′‐diindolylmethane (DIM) and its derivatives. The results indicate that copper chloride was the best catalyst among the investigated transition metal salts, which affords an excellent regioselectivity and good yield when tert‐butyl hydroperoxide (TBHP) was used as an oxidant.
An expedient cleavage of the C S bond of dimethyl sulfoxide (DMSO) has been developed for the preparation of substituted pyridines from ketones. In this transformation, the co‐product formic acid was formed from ammonium formate, which acted as an important catalyst for the reaction. Notably, this transformation exhibited a broad substrate scope towards a wide variety of different ketones to give the corresponding substituted pyridines in high yields. Mechanistic studies suggested that dimethyl sulfoxide delivered a methylene fragment, which was subsequently captured in situ to give a pyridine.
The last decades have seen a tremendous expanse in the application of C H activation of many different substrate classes, including the invaluable indole scaffold. Following the exciting emergence of C H activation as a multi‐faceted platform for functionalization, a versatile tool box has been developed for the preparation of structurally diverse indoles. This review article discusses recent advances and strategies for transition metal‐catalyzed C H activation of indoles.
An in‐depth mechanistic study on the palladium‐catalyzed direct arylation of imidazoles at the C‐5 position is presented. The interactions of triphenylphosphine (PPh3)‐ligated aryl‐Pd species with 1,2‐dimethyl‐1H‐imidazole (dmim) have been studied in detail. In contrast with previous suggestions, phosphine‐ligated organo‐Pd species are not active and the reaction proceeds through imidazole‐ligated organo‐Pd intermediates. The kinetics of the oxidative addition of aryl halides with dmim‐ligated Pd(0) species have been characterized in a Pd(dba)2/dmim model system. A thorough study of the equilibria involving novel [ArPd(dmim)2X] complexes (X=I, OAc) and the unexpected cationic [ArPd(dmim)3]+ is also reported. The ability of these species to effect the C H arylation of dmim at room temperature in the presence of acetate is also demonstrated.
It appears that transition metal catalysts are not necessary to perform the direct arylation of electron‐rich heterocycles with aryl iodides and bromides. Lithium tert‐butoxide in DMF promotes this reaction for a variety of N‐alkyl‐ and N‐arylpyrroles as well as for benzofuran and some other electron‐rich aromatic compounds and provides the desired products in moderate to high yields. In contrast to all previous reports on the Pd‐catalyzed direct arylation of indolizine, the reaction mediated by lithium tert‐butoxide proceeds selectively at position 5. 相似文献
A new approach for the synthesis of novel annulated‐pyrazoles is presented. This protocol includes an intermolecular condensation followed by a copper‐mediated intramolecular C N or C O coupling reaction. The method is applied to a range of substituted 4‐iodopyrazolecarbaldehydes which react with 1,2‐phenylenediamines or 2‐aminophenols to yield substituted 2,4‐ or 1,4‐dihydrobenzo[b]pyrazolo[4,3‐e][1,4]diazepines or substituted‐2H‐ or 1H‐benzo[b]pyrazolo[3,4‐f][1,4]oxazepines, respectively. 相似文献
A directed cyclization‐dehydration cascade of α‐aryloxy ketones and α‐arylamino ketones was efficiently catalyzed by a cationic iridium‐BINAP complex, which afforded various types of 4‐substituted benzofurans and indoles in high yields with complete regioselectivity. The newly developed protocol also enabled the enantioselective preparation of chiral 4‐acetyloxindole using a chiral iridium catalyst. 相似文献
We report an improved synthesis of α,β‐unsaturated imides, a class of compounds that has been identified as broadly useful in (salen)aluminum‐catalyzed asymmetric conjugate addition reactions. An efficient, scaleable procedure for the synthesis of phosphonate imide reagent 4 is described, as well as a DBU‐mediated Horner Wadsworth Emmons reaction that affords the target compounds in high yield and (E)‐selectivity and with good functional group tolerance. 相似文献
Pyrroles, ubiquitous bioactive heterocycles in nature, are readily prepared via a palladium‐catalyzed oxidative annulation of cyclic trans‐enamines to various internal alkynes in the absence of a directing group.
