Implications For Design Of Ligands Research Articles

Chiral Discrimination in Rhodium(I) Catalysis by 2,5-Disubstituted 1,3a,4,6a-Tetrahydropenatalene Ligands—More Than Just a Twist of the Olefins?

Chiral dienes are useful ligands in a number of asymmetric transition-metal-catalyzed reactions. Here, we evaluate the efficiency of 2,5-disubstituted 1,3a,4,6a-tetrahydropentalenes as ligands to rhodium(I). 2,5-Dibenzyl and diphenyl tetrahydropentalenes were synthesized in two steps and resolved, either chromatographically, or through fractional crystallization of diastereomeric rhodium(I) salts. When evaluated in a 1,4-arylation reaction, the 2,5-dibenzyl ligand gave up to 99% ee. The use of a well-defined rhodium complex as catalyst, Cs2CO3 as the base, and toluene/water as solvent was found to have a pronounced beneficial effect on the selectivity of the reaction. The homologous 2,5-diphenyl ligand on the other hand proved to be highly prone to racemization/loss of chirality during catalysis. Control experiments reveal that this rearrangement proceeds via a rhodium-mediated 1,3-hydride shift. Implications for ligand design and catalysis are discussed.

Structured Water Molecules in the Binding Site of Bromodomains Can Be Displaced by Cosolvent

Bromodomains are α-helical bundles of approximately 110 residues that recognize acetylated lysine side chains mainly on histone tails. Bromodomains are known to play an important role in cancer and inflammation, and as such, significant efforts are being made to identify small-molecule inhibitors of these epigenetic reader proteins. Here, explicit solvent molecular dynamics (MD) simulations of two bromodomains (BAZ2B and CREBBP) are used to analyze the water molecules that seem to be conserved at the bottom of the acetyl-lysine binding site in most crystal structures of bromodomains. The MD runs suggest that the occupancy of the structured water molecules is influenced by conformational transitions of the loop that connects helices Z and A. Additional simulations in the presence of 50 molecules of cosolvent (i.e., 440 mM of dimethylsulfoxide, methanol, or ethanol) indicate that some of the structured water molecules can be displaced transiently. The residence time in the acetyl-lysine binding site is calculated to be about 1 ns, 2-5 ns, and 10-30 ns for methanol, ethanol, and dimethylsulfoxide, respectively, while the affinity of the three cosolvents for BAZ2B and CREBBP is in the range of 50-500 mM. The results described have implications for ligand design, suggesting that only structured water molecules that do not exchange with cosolvent should be maintained in crystal structures used for docking campaigns, and that hydroxy substituents should be incorporated in the ligand so as to map the structured water molecules replaced by (m)ethanol.

Mechanism of “Turn-on” Fluorescent Sensors for Mercury(II) in Solution and Its Implications for Ligand Design

The tendency of a Hg(II) ion to strongly quench fluorescence of potential fluorescent sensors is explored. Fluorescence measurements show the expected order of the chelation-enhanced fluorescence (CHEF) effect of Zn(II) > Cd(II) >> Hg(II) ~ Cu(II), which is interpreted as (1) unpaired electrons causing the weak CHEF effect for Cu(II) and (2) the order Zn(II) > Cd(II) >> Hg(II) reflecting the "heavy atom" effect, which may be due to increasing spin-orbit coupling constants (ζ) for Zn(II) < Cd(II) << Hg(II). The structures of mercury(II) complexes of N-(9-anthracenylmethyl)-N-(2-pyridinylmethyl)-2-pyridinemethanamine (ADPA) are reported. [Hg(ADPA)Cl(2)HgCl(2)] (1) has one Hg(II) held by two bridging chlorides, while the other Hg(II) is coordinated to the ADPA ligand. The latter Hg(II) has a nearest π contact of 3.215 Å with a C atom from the anthracenyl group, which falls in the range of reported Hg-C π contacts with aromatic groups. This contact may be important in quenching the fluorescence of the Hg(II)/ADPA complex. A density functional theory study shows that the Hg-C interaction is strong enough to prevent a simple HOMO → LUMO transition of the fluorophore. In fact, the S(0) → S(1) and S(2) transitions in the Hg(II)/ADPA complex have significant charge-transfer character to mercury. An important aspect of the coordination geometry of Hg(II) is illustrated by 1, where Hg(II) tends to form a few (often only two) short bonds to the more covalently binding donor atoms present, with much longer bonds to other donor atoms. The Hg-N bonds to the two pyridyl N-donor atoms of ADPA in 1 are relatively short at 2.212(8) and 2.224(8) Å, while that to the central saturated N-donor atom of ADPA is long at 2.603(8) Å. The latter long Hg-N bond may allow a photoinduced electron-transfer (PET) effect, quenching the fluorescence of the anthracenyl fluorophore. The structure of [Hg(ADPA)Br(2)] (2) reflects the more covalent binding of the two bromine ligands compared to the clorine ligands of 1, with much longer Hg-C contacts with the anthracenyl fluorophore and a Hg-N contact with the saturated N atom of ADPA of 2.917 Å. The latter long Hg-N contact is related to the nearly negligible fluorescence of the ADPA complex in the presence of added Br(-). The addition of extra ligands to the Hg(II)/ADPA complex produces a weak increase in the fluorescence intensity for OH(-) ~ Cl(-) >> Br(-) > I(-), which is discussed in terms of an increasing PET effect, and to collisional quenching. The ligand design principles for generating turn-on sensors for mercury suggested by this work are discussed.

Synthesis and Evaluation of Lipophilic BTBP Ligands for An/Ln Separation in Nuclear Waste Treatment: The Effect of Alkyl Substitution on Extraction Properties and Implications for Ligand Design (Eur. J. Org. Chem. 8/2012)

AbstractThe cover picture shows four radiochemical gloveboxes used for working with plutonium and other α‐active radioactive materials as the background image. The gloveboxes contain centrifugal contactors and mixer‐settler rigs for use in laboratory‐scale solvent extraction, actinide oxide dissolution and aqueous actinide chemistry and spectroscopy. The picture is courtesy of Dr. Robin Taylor, National Nuclear Laboratory, Sellafield, Seascale, Cumbria CA20 1PG, UK. The foreground represents the selective extraction of AmIII over EuIII by new 6,6′‐bis(triazinyl)‐2,2′‐bipyridine (BTBP) ligands, a family of ligands currently under study for the separation of actinides from lanthanides in a proposed future selective actinide extraction (SANEX) process. This separation is foreseen as an important step in reducing the long‐term radiotoxicity of nuclear waste. Details are discussed in the article by F. W. Lewis, L. M. Harwood et al. on p. 1509 ff. magnified image

Synthesis and Evaluation of Lipophilic BTBP Ligands for An/Ln Separation in Nuclear Waste Treatment: The Effect of Alkyl Substitution on Extraction Properties and Implications for Ligand Design

AbstractFour new 6,6′‐bis(1,2,4‐triazin‐3‐yl)‐2,2′‐bipyridine (BTBP) ligands, which contain either additional alkyl groups on the pyridine rings or seven‐membered aliphatic rings attached to the triazine rings, have been synthesized, and the effects of the additional alkyl substitution in the 4‐ and 4′‐positions of the pyridine rings on their extraction properties with LnIII and AnIII cations in simulated nuclear waste solutions have been studied. The speciation of ligand 13 with some trivalent lanthanide nitrates was elucidated by 1H NMR spectroscopic titrations and ESI‐MS. Although 13 formed both 1:1 and 1:2 complexes with LaIII and YIII, only 1:2 complexes were observed with EuIII and CeIII. Quite unexpectedly, both alkyl‐substituted ligands 12 and 13 showed lower solubilities in certain diluents than the unsubstituted ligand CyMe4‐BTBP. Compared to CyMe4‐BTBP, alkyl‐substitution was found to decrease the rates of metal‐ion extraction of the ligands in both 1‐octanol and cyclohexanone. A highly efficient (DAm &gt; 10) and selective (SFAm/Eu &gt; 90) extraction was observed for 12 and 13 in cyclohexanone and for 13 in 1‐octanol in the presence of a phase‐transfer agent. The implications of these results for the design of improved extractants for radioactive waste treatment are discussed.

Carbodiphosphorane Analogues E(PPh3)2 with E=C–Pb: A Theoretical Study with Implications for Ligand Design

Quantum-chemical calculations at the BP86/TZVPP level have been carried out for the heavy Group 14 homologues of carbodiphosphorane E(PPh(3))(2), where E=Si, Ge, Sn, Pb, which are experimentally unknown so far. The results of the theoretical investigation suggest that the tetrelediphosphoranes E(PPh(3))(2) (1E) are stable compounds that could become isolated in a condensed phase. The molecules possess donor-acceptor bonds Ph(3)P→E←PPh(3) to a bare tetrele atom E, which retains its four valence electrons as two electron lone pairs. The analysis of the bonding situation and the calculation of the chemical reactivity indicate that the molecules 1E belong to the class of divalent E(0) compounds (ylidones). All molecules 1C-1Pb have very large first but also very large second proton affinities, which distinguishes them from the N-heterocyclic carbene homologues, in which the donor atom is a divalent E(II) species that possesses only one electron lone pair. Compounds 1E are powerful double donors that strongly bind Lewis acids such as BH(3) and AuCl in the complexes 1E(BH(3))(n) and 1E(AuCl)(n) (n=1, 2). The bond dissociation energies (BDEs) of the second BH(3) and AuCl molecules are only slightly less than the BDE of the first BH(3) and AuCl. The results of this work are a challenge for experimentalists.

Comparative study of calix[4]arene derivatives: implications for ligand design

The first comparative theoretical study of three parent calix[4]arene analogues (calix[4]arene, thiacalix[4]arene, and homooxacalix[4]arene) has been performed using molecular dynamic simulations and density functional theory (MPWB1K/6-311G ∗∗//B3LYP/6-311G ∗∗) methods. The theoretical observations herein including optimized geometry, polarity, and atomic charge data provide that homooxacalix[4]arene would offer more efficient platform for metal ion recognition compared to thiacalix[4]arene or calix[4]arene.

Structural Origins of a Dramatic Variation in Catalyst Efficiency in Enantioselective Alkene Aziridination: Implications for Design of Ligands Based on Chiral Biaryldiamines

ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTStructural Origins of a Dramatic Variation in Catalyst Efficiency in Enantioselective Alkene Aziridination: Implications for Design of Ligands Based on Chiral BiaryldiaminesChristopher J. Sanders, Kevin M. Gillespie, David Bell, and Peter ScottView Author Information Department of Chemistry, University of Warwick Coventry, CV4 7AL, UK SmithKline Beecham Pharmaceuticals Harlow, Essex, CM19 5AW, UK Cite this: J. Am. Chem. Soc. 2000, 122, 29, 7132–7133Publication Date (Web):July 11, 2000Publication History Received13 December 1999Published online11 July 2000Published inissue 26 July 2000https://doi.org/10.1021/ja994353dCopyright © 2000 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views705Altmetric-Citations79LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (96 KB) Get e-AlertsSupporting Info (3)»Supporting Information Supporting Information SUBJECTS:Aziridines,Bimetals,Catalysts,Ligands,Molecular structure Get e-Alerts

Anatomy of protein pockets and cavities: measurement of binding site geometry and implications for ligand design.

Identification and size characterization of surface pockets and occluded cavities are initial steps in protein structure-based ligand design. A new program, CAST, for automatically locating and measuring protein pockets and cavities, is based on precise computational geometry methods, including alpha shape and discrete flow theory. CAST identifies and measures pockets and pocket mouth openings, as well as cavities. The program specifies the atoms lining pockets, pocket openings, and buried cavities; the volume and area of pockets and cavities; and the area and circumference of mouth openings. CAST analysis of over 100 proteins has been carried out; proteins examined include a set of 51 monomeric enzyme-ligand structures, several elastase-inhibitor complexes, the FK506 binding protein, 30 HIV-1 protease-inhibitor complexes, and a number of small and large protein inhibitors. Medium-sized globular proteins typically have 10-20 pockets/cavities. Most often, binding sites are pockets with 1-2 mouth openings; much less frequently they are cavities. Ligand binding pockets vary widely in size, most within the range 10(2)-10(3)A3. Statistical analysis reveals that the number of pockets and cavities is correlated with protein size, but there is no correlation between the size of the protein and the size of binding sites. Most frequently, the largest pocket/cavity is the active site, but there are a number of instructive exceptions. Ligand volume and binding site volume are somewhat correlated when binding site volume is < or =700 A3, but the ligand seldom occupies the entire site. Auxiliary pockets near the active site have been suggested as additional binding surface for designed ligands (Mattos C et al., 1994, Nat Struct Biol 1:55-58). Analysis of elastase-inhibitor complexes suggests that CAST can identify ancillary pockets suitable for recruitment in ligand design strategies. Analysis of the FK506 binding protein, and of compounds developed in SAR by NMR (Shuker SB et al., 1996, Science 274:1531-1534), indicates that CAST pocket computation may provide a priori identification of target proteins for linked-fragment design. CAST analysis of 30 HIV-1 protease-inhibitor complexes shows that the flexible active site pocket can vary over a range of 853-1,566 A3, and that there are two pockets near or adjoining the active site that may be recruited for ligand design.

ChemInform Abstract: Crown Thioether Chemistry: Structural and Conformational Studies of Tetrathia‐12‐crown‐4, Pentathia‐15‐crown‐5, and Hexathia‐18‐crown‐6. Implications for Ligand Design

ChemInformVolume 18, Issue 44 Physical Organic Chemistry ChemInform Abstract: Crown Thioether Chemistry: Structural and Conformational Studies of Tetrathia-12-crown-4, Pentathia-15-crown-5, and Hexathia-18-crown-6. Implications for Ligand Design R. E. JUN. WOLF, R. E. JUN. WOLF Inorg. Chem. Lab., Oxford Univ., Oxford OX1 3QR, UKSearch for more papers by this authorJ. R. HARTMAN, J. R. HARTMAN Inorg. Chem. Lab., Oxford Univ., Oxford OX1 3QR, UKSearch for more papers by this authorJ. M. E. STOREY, J. M. E. STOREY Inorg. Chem. Lab., Oxford Univ., Oxford OX1 3QR, UKSearch for more papers by this authorB. M. FOXMAN, B. M. FOXMAN Inorg. Chem. Lab., Oxford Univ., Oxford OX1 3QR, UKSearch for more papers by this authorS. R. COOPER, S. R. COOPER Inorg. Chem. Lab., Oxford Univ., Oxford OX1 3QR, UKSearch for more papers by this author R. E. JUN. WOLF, R. E. JUN. WOLF Inorg. Chem. Lab., Oxford Univ., Oxford OX1 3QR, UKSearch for more papers by this authorJ. R. HARTMAN, J. R. HARTMAN Inorg. Chem. Lab., Oxford Univ., Oxford OX1 3QR, UKSearch for more papers by this authorJ. M. E. STOREY, J. M. E. STOREY Inorg. Chem. Lab., Oxford Univ., Oxford OX1 3QR, UKSearch for more papers by this authorB. M. FOXMAN, B. M. FOXMAN Inorg. Chem. Lab., Oxford Univ., Oxford OX1 3QR, UKSearch for more papers by this authorS. R. COOPER, S. R. COOPER Inorg. Chem. Lab., Oxford Univ., Oxford OX1 3QR, UKSearch for more papers by this author First published: November 3, 1987 https://doi.org/10.1002/chin.198744056Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume18, Issue44November 3, 1987 RelatedInformation