scholarly journals De novo macrolide–glycolipid macrolactone hybrids: Synthesis, structure and antibiotic activity of carbohydrate-fused macrocycles

2014 ◽  
Vol 10 ◽  
pp. 2215-2221 ◽  
Author(s):  
Richard T Desmond ◽  
Anniefer N Magpusao ◽  
Chris Lorenc ◽  
Jeremy B Alverson ◽  
Nigel Priestley ◽  
...  
Keyword(s):  
Natural Product ◽  
Dihedral Angle ◽  
Hydroxy Group ◽  
De Novo ◽  
Antibiotic Activity ◽  
Anomeric Effect ◽  
Glycosidic Linkage ◽  
Antibacterial Compounds ◽  
X Ray ◽  
X Ray Crystallography

Natural product-like macrocycles were designed as potential antibacterial compounds. The macrocycles featured a D-glucose unit fused into a 12- or 13-member macrolactone. The rings are connected via the C6’ and anomeric (C1’) positions of the monosaccharide. The new macrocycles/macrolides were characterized by X-ray crystallography. Their structures showed that, in addition to the ester and alkene units, the dihedral angle about the glycosidic linkage (exo-anomeric effect) influenced the overall shape of the molecules. Glycosylation of an available hydroxy group on the macrocycle gave a hybrid macrolide with features common to erythromycin and sophorlipid macrolactone. Weak antibiotic activity (MICs <100 μg/mL) was observed for several of the compounds.

scholarly journals A defined structural unit enables de novo design of small-molecule–binding proteins

Science ◽  
2020 ◽  
Vol 369 (6508) ◽  
pp. 1227-1233 ◽  
Author(s):  
Nicholas F. Polizzi ◽  
William F. DeGrado
Keyword(s):  
Protein Structure ◽  
Amino Acid ◽  
Small Molecules ◽  
Structural Unit ◽  
De Novo ◽  
Computational Design ◽  
De Novo Design ◽  
X Ray ◽  
X Ray Crystallography ◽  
Chemical Groups

The de novo design of proteins that bind highly functionalized small molecules represents a great challenge. To enable computational design of binders, we developed a unit of protein structure—a van der Mer (vdM)—that maps the backbone of each amino acid to statistically preferred positions of interacting chemical groups. Using vdMs, we designed six de novo proteins to bind the drug apixaban; two bound with low and submicromolar affinity. X-ray crystallography and mutagenesis confirmed a structure with a precisely designed cavity that forms favorable interactions in the drug–protein complex. vdMs may enable design of functional proteins for applications in sensing, medicine, and catalysis.

scholarly journals Synthesis and characterization of novel bioactive 1,2,4-oxadiazole natural product analogs bearing the N-phenylmaleimide and N-phenylsuccinimide moieties

2013 ◽  
Vol 9 ◽  
pp. 2202-2215 ◽  
Author(s):  
Catalin V Maftei ◽  
Elena Fodor ◽  
Peter G Jones ◽  
M Heiko Franz ◽  
Gerhard Kelter ◽  
...  
Keyword(s):  
Natural Product ◽  
Synthesis And Characterization ◽  
Aminobenzoic Acid ◽  
One Pot ◽  
X Ray ◽  
X Ray Crystallography ◽  
Quisqualic Acid ◽  
Oxobutanoic Acid

Taking into consideration the biological activity of the only natural products containing a 1,2,4-oxadiazole ring in their structure (quisqualic acid and phidianidines A and B), the natural product analogs 1-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenyl)pyrrolidine-2,5-dione (4) and 1-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenyl)-1H-pyrrole-2,5-dione (7) were synthesized starting from 4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)aniline (1) in two steps by isolating the intermediates 4-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenylamino)-4-oxobutanoic acid (3) and (Z)-4-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenylamino)-4-oxobut-2-enoic acid (6). The two natural product analogs 4 and 7 were then tested for antitumor activity toward a panel of 11 cell lines in vitro by using a monolayer cell-survival and proliferation assay. Compound 7 was the most potent and exhibited a mean IC50 value of approximately 9.4 µM. Aniline 1 was synthesized by two routes in one-pot reactions starting from tert-butylamidoxime and 4-aminobenzoic acid or 4-nitrobenzonitrile. The structures of compounds 1, 2, 4, 5 and 6 were confirmed by X-ray crystallography.

scholarly journals The S-Layer Glycome—Adding to the Sugar Coat of Bacteria

2011 ◽  
Vol 2011 ◽  
pp. 1-16 ◽  
Author(s):  
Robin Ristl ◽  
Kerstin Steiner ◽  
Kristof Zarschler ◽  
Sonja Zayni ◽  
Paul Messner ◽  
...  
Keyword(s):  
Unique Feature ◽  
Nanometer Scale ◽  
Capsular Polysaccharides ◽  
Glycosidic Linkage ◽  
Cell Surfaces ◽  
X Ray ◽  
Tyrosine Residues ◽  
X Ray Crystallography ◽  
Gram Positive Bacteria ◽  
Self Assembling

The amazing repertoire of glycoconjugates present on bacterial cell surfaces includes lipopolysaccharides, capsular polysaccharides, lipooligosaccharides, exopolysaccharides, and glycoproteins. While the former are constituents of Gram-negative cells, we review here the cell surface S-layer glycoproteins of Gram-positive bacteria. S-layer glycoproteins have the unique feature of self-assembling into 2D lattices providing a display matrix for glycans with periodicity at the nanometer scale. Typically, bacterial S-layer glycans are O-glycosidically linked to serine, threonine, or tyrosine residues, and they rely on a much wider variety of constituents, glycosidic linkage types, and structures than their eukaryotic counterparts. As the S-layer glycome of several bacteria is unravelling, a picture of how S-layer glycoproteins are biosynthesized is evolving. X-ray crystallography experiments allowed first insights into the catalysis mechanism of selected enzymes. In the future, it will be exciting to fully exploit the S-layer glycome for glycoengineering purposes and to link it to the bacterial interactome.

The Reaction of Some N-(Nitrophenyl)azoles With Alkali: Preparation of the Corresponding Azoxybenzenes. X-Ray Structure of 2,2′-Bis(1″,2″,4″-triazol-1″-yl)azoxybenzene

1993 ◽  
Vol 46 (4) ◽  
pp. 417 ◽  
Author(s):  
MF Mackay ◽  
GJ Trantino ◽  
JFK Wilshire
Keyword(s):  
Solid State ◽  
Benzene Ring ◽  
Dihedral Angle ◽  
Experimental Error ◽  
Potassium Hydroxide ◽  
Potassium Hydroxide Solution ◽  
Triazole Ring ◽  
X Ray ◽  
X Ray Crystallography ◽  
Weak Electron

The reactions of some representative N-( nitrophenyl )azoles with boiling aqueous ethanolic potassium hydroxide solution gave the corresponding bis ( azolyl ) azoxybenzenes . It is deduced that, in these reactions, the N-attached azolyl groups concerned are acting as weak electron-withdrawing groups. The structure of 2,2′-bis(1″,2″,4″-triazol-1″-yl) azoxybenzene was determined in the solid state by X-ray crystallography. The monoclinic crystals belong to the space group P21/c with a 8.815(1), b 7.863(1), c 11.836(1) Ǻ, β 109.96(1)° and Z 2. The structure was refined to an R index of 0.041 for 1172 observed terms. The midpoint of the exocyclic N=N bond lies on an inversion centre so that the azoxy oxygen is statistically distributed between two sites. The benzene ring atoms are coplanar to within experimental error, as are the triazole ring atoms, and the dihedral angle between the perpendiculars to the two rings is 35.3(3)°.

scholarly journals Crystal structure of 5-[(benzoyloxy)methyl]-5,6-dihydroxy-4-oxocyclohex-2-en-1-yl benzoate

2020 ◽  
Vol 76 (7) ◽  
pp. 1096-1100
Author(s):  
Theerachart Leepasert ◽  
Patchreenart Saparpakorn ◽  
Kittipong Chainok ◽  
Tanwawan Duangthongyou
Keyword(s):  
Crystal Structure ◽  
Hydrogen Bonds ◽  
Single Crystal ◽  
Natural Product ◽  
Dihedral Angle ◽  
Absolute Configuration ◽  
Hydroxyl Groups ◽  
X Ray Diffraction ◽  
X Ray ◽  
Ring Form

The crystal structure of the natural product zeylenone, C21H18O7, was confirmed by single-crystal X-ray diffraction. The crystal structure has three chiral centers at positions C1, C5 and C6 of the cyclohexanone ring, but the absolute configuration could not be determined reliably. The methyl benzoate and benzoyloxy substituents at positions C1 and C5 of the cyclohexenone ring are on the same side of the ring with the dihedral angle between their mean planes being 16.25 (10)°. These rings are almost perpendicular to the cyclohexenone ring. The benzoate groups and two hydroxyl groups on the cyclohexenone ring form strong hydrogen bonds to consolidate the crystal structure. In addition, weak C—H...O hydrogen bonds also contribute to the packing of the structure.

Regiospecificity in the Hydroborationof 6-Hydroxyandrost-4-enes.

1997 ◽  
Vol 50 (4) ◽  
pp. 249 ◽  
Author(s):  
James R. Hanson ◽  
Peter B. Hitchcock ◽  
Mansur D. Liman
Keyword(s):  
Hydroxy Group ◽  
Tertiary Alcohol ◽  
X Ray ◽  
X Ray Crystallography ◽  
The Face

The hydroboration of 6α- and 6β-hydroxyandrost-4-en-17-one is shown to take place predominantly on the face of the alkenetrans to the allylic hydroxy group. The regiochemistry of the reaction is also modified with the formation of some 5β,6α,17β-trihydroxy-5β-androstane from 6α-hydroxyandrost-4-en-17-one. The structure of this tertiary alcohol was established by X-ray crystallography.

scholarly journals Ensemble-based enzyme design can recapitulate the effects of laboratory directed evolution in silico

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Aron Broom ◽  
Rojo V. Rakotoharisoa ◽  
Michael C. Thompson ◽  
Niayesh Zarifi ◽  
Erin Nguyen ◽  
...  
Keyword(s):  
Directed Evolution ◽  
Protein Design ◽  
Active Site ◽  
Room Temperature ◽  
De Novo ◽  
Conformational Ensemble ◽  
Enzyme Design ◽  
X Ray ◽  
Conformational Ensembles ◽  
X Ray Crystallography

Abstract The creation of artificial enzymes is a key objective of computational protein design. Although de novo enzymes have been successfully designed, these exhibit low catalytic efficiencies, requiring directed evolution to improve activity. Here, we use room-temperature X-ray crystallography to study changes in the conformational ensemble during evolution of the designed Kemp eliminase HG3 (kcat/KM 146 M−1s−1). We observe that catalytic residues are increasingly rigidified, the active site becomes better pre-organized, and its entrance is widened. Based on these observations, we engineer HG4, an efficient biocatalyst (kcat/KM 103,000 M−1s−1) containing key first and second-shell mutations found during evolution. HG4 structures reveal that its active site is pre-organized and rigidified for efficient catalysis. Our results show how directed evolution circumvents challenges inherent to enzyme design by shifting conformational ensembles to favor catalytically-productive sub-states, and suggest improvements to the design methodology that incorporate ensemble modeling of crystallographic data.

Synthesis of meso-phenyl-4,6-dipyrrins, preparation of their Cu(II), Ni(II), and Zn(II) chelates, and structural characterization of bis[meso-phenyl-4,6-dipyrrinato]Ni(II)

1996 ◽  
Vol 74 (11) ◽  
pp. 2182-2193 ◽  
Author(s):  
Christian Brückner ◽  
Veranja Karunaratne ◽  
Steven J. Rettig ◽  
David Dolphin
Keyword(s):  
Dihedral Angle ◽  
Direct Methods ◽  
Metal Chelates ◽  
Central Metal ◽  
Full Matrix ◽  
X Ray ◽  
X Ray Crystallography ◽  
Transition Metal Chelates ◽  
Square Planar

meso-Phenyldipyrromethanes can be oxidized by 2,6-dicyano-3,5-dichloro-para-benzoquinone (DDQ) to the corresponding meso-phenyldipyrrins. As expected, these novel, stable bipyrrolic pigments readily form metal chelates with copper(II), nickel(II), and zinc(II). Their UV–VIS spectra are compared with a series of known alkyl-substituted dipyrrin chelates and, based on the UV–VIS spectral analysis, the dihedral angle between the two ligands in the bis[meso-phenyldipyrrinato]Ni(II) complex was calculated to be 42°. The molecular structure of this complex was determined by X-ray crystallography, essentially confirming the calculation. Crystals of C30H22N4Ni are orthorhombic, a = 17.156(3), b = 35.217(1), c = 7.886(1) Å, Z = 8, space group Fddd. The structure was solved by direct methods and refined by full-matrix least-squares procedures to R = 0.040 and Rw = 0.031 for 1058 reflections with I ≥ 3σ(F2). The central nickel is coordinated in a distorted square-planar fashion by four nitrogens. The pair of the planar dipyrrinato ligands enclose a dihedral angle of 38.5°. This is the lowest angle reported for nickel(II) complexes of this kind. As a result of this, and in sharp contrast to previously described nickel(II) dipyrrin chelates, the central metal is diamagnetic. Key words: meso-phenyldipyrromethanes, meso-phenyldipyrrins, meso-phenyldipyrrinato transition metal chelates, X-ray crystallography.

scholarly journals Cadmium SAD phasing at CuKα wavelength

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 84
Author(s):  
Igor E. Eliseev ◽  
Anna N. Yudenko ◽  
Valeria M. Ukrainskaya ◽  
Oleg B. Chakchir
Keyword(s):  
Experimental Model ◽  
De Novo ◽  
Common Method ◽  
Single Domain Antibody ◽  
Anomalous Diffraction ◽  
Cadmium Ions ◽  
X Ray ◽  
X Ray Crystallography ◽  
Domain Antibody ◽  
Sad Phasing

Single-wavelength anomalous diffraction (SAD) is the most common method for de novo elucidation of macromolecular structures by X-ray crystallography. It requires an anomalous scatterer in a crystal to calculate phases. A recent study by Panneerselvam et al. emphasized the utility of cadmium ions for SAD phasing at the standard synchrotron wavelength of 1 Å. Here we show that cadmium is also useful for phasing of crystals collected in-house with CuKα radiation. Using a crystal of single-domain antibody as an experimental model, we demonstrate how cadmium SAD can be conveniently employed to solve a CuKα dataset. We then discuss the factors which make this method generally applicable.

Structural assignment of a bis-cyclopentenyl-β-cyanohydrin formedviaalkene metathesis from either a triene or a tetraene precursor

2013 ◽  
Vol 69 (11) ◽  
pp. 1207-1211 ◽  
Author(s):  
Keith G. Andrews ◽  
Christopher S. Frampton ◽  
Alan C. Spivey
Keyword(s):  
Density Functional Theory ◽  
Single Crystal ◽  
Natural Product ◽  
Density Functional ◽  
Major Product ◽  
Functional Theory ◽  
X Ray ◽  
X Ray Crystallography ◽  
Structural Assignment ◽  
Nmr Prediction

The identity of the major product of Ru-catalysed alkene metathesis of two polyene substrates has been determined using density functional theory (DFT) NMR prediction, a1H–1H Total Correlated Spectroscopy (TOCSY) NMR experiment and ultimately by single-crystal X-ray crystallography. The substrates were designed as those that would potentially allow expedient access to thetrans-decalin skeleton of the natural product (−)-euonyminol, but the product was found to be a bis-cyclopentenyl-β-cyanohydrin [1-(1-hydroxycyclopent-3-en-1-yl)cyclopent-3-ene-1-carbonitrile, C11H13NO] rather than thetrans-2,3,6,7-dehydrodecalin-β-cyanohydrin.

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