Conformation In Solid State Research Articles

Effects of Drying Process on an IgG1 Monoclonal Antibody Using Solid-State Hydrogen Deuterium Exchange with Mass Spectrometric Analysis (ssHDX-MS).

Lyophilization and spray drying are widely used to manufacture solid forms of therapeutic proteins. Lyophilization is used to stabilize proteins vulnerable to degradation in solution, whereas spray drying is mainly used to prepare inhalation powders or as an alternative to freezing for storing bulk drug substance. Both processes impose stresses that may adversely affect protein structure, stability and bioactivity. Here, we compared lyophilization with and without controlled ice nucleation, and spray drying for their effects on the solid-state conformation and matrix interactions of a model IgG1 monoclonal antibody (mAb). Solid-state conformation and matrix interactions of the mAb were probed using solid-state hydrogen-deuterium exchange with mass spectrometric analysis (ssHDX-MS), and solid-state Fourier transform infrared (ssFTIR) and solid-state fluorescence spectroscopies. mAb conformation and/or matrix interactions were most perturbed in mannitol-containing samples and the distribution of states was more heterogeneous in sucrose and trehalose samples that were spray dried. The findings demonstrate the sensitivity of ssHDX-MS to changes weakly indicated by spectroscopic methods, and support the broader use of ssHDX-MS to probe formulation and process effects on proteins in solid samples.

1,5-Disubstituted 1,2,3-Triazole-Containing Peptidotriazolamers: Design Principles for a Class of Versatile Peptidomimetics.

Peptidotriazolamers are hybrid foldamers combining features of peptides and triazolamers-repetitive peptidomimetic structures with triazoles replacing peptide bonds. We report on the synthesis of a new class of peptidomimetics, containing 1,5-disubstituted 1,2,3-triazoles in an alternating fashion with amide bonds and the analysis of their conformation in solid state and solution. Homo- or heterochiral peptidotriazolamers were obtained from enantiomerically pure propargylamines with stereogenic centers in the propargylic position and α-azido esters by ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) under microwave conditions in high yields. With such building blocks the peptidotriazolamers are readily available by solution phase synthesis. While the conformation of the homochiral peptidotriazolamer Boc-Ala[5Tz]Phe-Val[5Tz]Ala-Leu[5Tz]Val-OBzl resembles that of a β VIa1 turn, the heterochiral peptidotriazolamer Boc-d-Ala[5Tz]Phe-d-Val[5Tz]Ala-d-Leu[5Tz]Val-OBzl adopts a polyproline-like repetitive structure.

Synthesis, stereochemistry, crystal structure, docking study and biological evaluation of some new N-benzylpiperidin-4-ones

Two new N-benzylpiperidin-4-ones 3 and 4 have been synthesized and characterized using IR, 1D and 2D NMR spectral studies. The NMR data of N-benzylpiperidin-4-ones 3 and 4 reveal that the compounds prefer to exist in chair conformation with equatorial orientation of the bulky substituents and the single crystal X-ray structure of compound 4 also reveals a similar conformation in solid state. Furthermore, the antimicrobial studies carried out for the compounds 1–4 indicate moderate activities with the selected strains. The antioxidant potency of 3 is superior whereas 4 exhibits moderate activity when compared to that of standard drug. The results of molecular docking studies with the AmpC β-lactamase enzyme indicate that compound 3 shows better docking score and binding energy than the co-crystal ligand.

Use of Crystal Structure Informatics for Defining the Conformational Space Needed for Predicting Crystal Structures of Pharmaceutical Molecules.

Determining the range of conformations that a flexible pharmaceutical-like molecule could plausibly adopt in a crystal structure is a key to successful crystal structure prediction (CSP) studies. We aim to use conformational information from the crystal structures in the Cambridge Structural Database (CSD) to facilitate this task. The conformations produced by the CSD Conformer Generator are reduced in number by considering the underlying rotamer distributions, an analysis of changes in molecular shape, and a minimal number of molecular ab initio calculations. This method is tested for five pharmaceutical-like molecules where an extensive CSP study has already been performed. The CSD informatics-derived set of crystal structure searches generates almost all the low-energy crystal structures previously found, including all experimental structures. The workflow effectively combines information on individual torsion angles and then eliminates the combinations that are too high in energy to be found in the solid state, reducing the resources needed to cover the solid-state conformational space of a molecule. This provides insights into how the low-energy solid-state and isolated-molecule conformations are related to the properties of the individual flexible torsion angles.

Substituent Effects on the Crystal Structures of Salts Prepared from (R)-2-Methoxy-2-(1-naphthyl)propanoic Acid and (R)-1-Arylethylamines

The crystal structures of salts 6–9 prepared from (R)-2-methoxy-2-(1-naphthyl)propanoic acid [(R)-MαNP acid, (R)-1] and (R)-1-arylethylamines [salt 6, (R)-1-(4-methoxyphenyl)ethylamine∙(R)-1; salt 7, (R)-1-(4-fluorophenyl)ethylamine∙(R)-1; salt 8, (R)-1-(4-chlorophenyl)ethylamine∙(R)-1; and salt 9, (R)-1-(3-chlorophenyl)ethylamine∙(R)-1] were elucidated by X-ray crystallography. The solid-state associations and conformations of the MαNP salts were defined using the concepts of supramolecular- and planar chirality, respectively, and the crystal structures of salts 6–9 were interpreted as a three-step hierarchical assembly. The para-substituents of the (R)-1-arylethylammonium cations were found on sheet structures consisting of 21 columns. Thus, salts possessing smaller para-substituents, that is, salt 7 (p-F) and salt 9 (p-H), and larger para-substituents, that is, salt 6 (p-OMe) and salt 8 (p-Cl), crystallized in the space groups P21 and C2, respectively. Additionally, weak intermolecular interactions, that is, aromatic C–H···π, C–H···F, and C–H···O interactions, were examined in crystalline salts 6–9.

Impact of Cα‐Chirality on Supramolecular Self‐Assembly in Cyclo‐2:1‐[α/aza]‐Hexamers (d/l‐Phe‐azaPhe‐Ala)2

The design of new cyclic pseudopeptides of the sequence 2:1‐[α/aza]‐hexamers, which contain aza‐amino acid motifs, has gained much prominence to be involved in several potential applications. X‐ray, FTIR, and NMR spectroscopy studies showed the ability of this series to adopt β‐turn conformation in solid state, whereas in solution an equilibrium between the monomeric states (stabilized by β‐turns through intramolecular hydrogen bonds), and supramolecular construction (stabilized by intermolecular hydrogen bonds and π‐π stacking) predominates. Furthermore, both homo‐ and heterochiral 2:1‐[α/aza]‐cyclohexamers 3 and 4, respectively, can self‐assemble into organized 3D structures with increases in concentration that favor the supramolecular construction in which the macrocyles are stacking over each other and stabilized by several non‐covalent intermolecular interactions.

New isoxazole(3,5)substituted thiosemicarbazone: Synthesis, crystal structure and spectroscopic studies of the binding mode to protein and calf thymus DNA

Six new 3,5-isoxazole thiosemicarbazone derivatives (ITCs) (HL1 – HL6) were synthesized and characterized using microanalysis, spectroscopic methods and for HL2, HL3, HL5 and HL6a by a single crystal X-ray diffraction. The combined analyses, utilizing NMR and X-ray techniques, showed that the compounds presented an E conformation both in solution and solid state. The intermolecular N3H3N···S1 hydrogen bonds, between the thiosemicarbazone groups, resulted in rings for all crystals. For HL2 and HL5, one medium strength (N4H4N···S1) and one weak (C8H8···N1) intermolecular hydrogen bond was also observed. HL3 presented a π(ar)- π(ar) stacking interaction and HL6a was stabilized by three hydrogen bonds involving DMSO oxygen. The interconnections in the crystal structures were analyzed using Hirshfeld surfaces. The interaction studies, using fluorescence and absorbance spectroscopy, showed that the ITCs interacted with DNA and human serum albumin (HSA).

Solid state conformations of α,β-unsaturated hydroxamates derived from the ‘chiral Weinreb amide’ auxiliary (S)-N-1-(1′-naphthyl)ethyl-O-tert-butylhydroxylamine

α,β-Unsaturated hydroxamates derived from the ‘chiral Weinreb amide’ auxiliary (S)-N-1-(1′-naphthyl)ethyl-O-tert-butylhydroxylamine consistently adopt a defined conformation and undergo highly diastereoselective conjugate addition reactions with lithium amide reagents. The configuration of the N-1-(1′-naphthyl)ethyl group dictates the position of the O-tert-butyl group and also the configuration adopted by the pyramidal nitrogen atom via a ‘chiral relay’ effect. Conjugate addition of lithium amide reagents to these substrates proceeds on the face opposite to both the O-tert-butyl group and nitrogen lone-pair with high levels of diastereoselectivity.

A feasibility study on obtaining d-orbital populations from aspherical-atom refinements on three spin crossover compounds

Although compounds undergoing thermally induced spin crossover have been widely studied, their experimental d-orbital populations from single-crystal X-ray diffraction have rarely been reported. Three pairs of structures of iron/manganese coordination compounds were re-evaluated. Least-squares refinements relied on aspherical scattering factors obtained from molecular quantum-mechanical DFT single-point computations of the respective solid-state conformation, initiated by accurate starting structures from preliminary invariom refinements of the ligand environment. Further evaluation concerned d-orbital populations of metal ions from (a) single-point computations projected onto the Hansen-Coppens multipole model and from (b) experimental refinements of the metal atoms only. The latter were successful for good-quality data, independent of temperature, and provided only one spin state was exclusively present in the crystal. Crystals that underwent light-induced excited spin state trapping were not showing the expected d-orbital populations.

C11 /C9 Helical Folding in αβ Hybrid Peptides Containing 1-Amino-cyclohexane acetic acid (β3, 3 -Ac6 c).

The present study describes the solid-state conformation of αβ hybrid peptides, Boc-Leu-β3, 3 -Ac6 c-OH, P1; Boc-Leu-β3, 3 -Ac6 c-Leu-β3, 3 -Ac6 c-OMe, P2; and Boc-Leu-β3, 3 -Ac6 c-Leu-β3, 3 -Ac6 c-Leu-OMe, P3. The dipeptide P1 adopts extended conformations, whereas tetrapeptide P2 and pentapeptide P3 favor a helical conformation stabilized by mixed types of C11 /C9 intramolecular hydrogen bonds. In peptide P3, the amino group of β3, 3 -Ac6 c(2) and β3, 3 -Ac6 c(4) residues occupies axial orientation, whereas in P2 it occupies axial and equatorial orientations for residues β3, 3 -Ac6 c(2) and β3, 3 -Ac6 c(4), respectively. The self-assembly of P3 forms channels filled with solvent molecules that present interesting patterns.

A Case of Folding Pattern in Flexible Tripodal of N‐Substituted Bisethylenamine Bridged Pyridazinone Dimers

AbstractPresent manuscript reports three tripodal molecules for their special structural and conformational properties. Interestingly, X‐ray structure revealed that all these molecules adopt folded conformation in solid state. Further, these molecules are flexible due to linker, may exist in various conformations, the studies have been carried out with different conformers through theoretical calculation in gaseous state.

Unprecedented folding in linker based flexible tripodal molecule and their conformational analysis

Here, we first time report the flexible tripodal molecules, contained propylene as a linker, thiocyanuric acid as central core and, p-nitro phenol 1 and pyridazinone 2 as terminal for conformational studies. The conformational studies of these tripodal molecules have been carried by X-ray crystallography, 2D-NOESY spectra and computational studies. Both the molecules have shown folded conformations in solid and solution state however solid state conformation is not stable in gaseous state.

Bacteriochlorins with a Twist: Discovery of a Unique Mechanism to Red-Shift the Optical Spectra of Bacteriochlorins.

Owing to their intense near infrared absorption and emission properties, to the ability to photogenerate singlet oxygen, or to act as photoacoustic imaging agents within the optical window of tissue, bacteriochlorins (2,3,12,13-tetrahydroporphyrins) promise to be of utility in many biomedical and technical applications. The ability to fine-tune the electronic properties of synthetic bacteriochlorins is important for these purposes. In this vein, we report the synthesis, structure determination, optical properties, and theoretical analysis of the electronic structure of a family of expanded bacteriochlorin analogues. The stepwise expansion of both pyrroline moieties in near-planar meso-tetraarylbacteriochlorins to morpholine moieties yields ruffled mono- and bismorpholinobacteriochlorins with broadened and up to 90 nm bathochromically shifted bacteriochlorin-like optical spectra. Intramolecular ring-closure reactions of the morpholine moiety with the flanking meso-aryl groups leads to a sharpened, blue-shifted wavelength λmax band, bucking the general red-shifting trend expected for such linkages. A conformational origin of the optical modulations was previously proposed, but discrepancies between the solid state conformations and the corresponding solution state optical spectra defy simple structure-optical property correlations. Using density functional theory and excited state methods, we derive the molecular origins of the spectral modulations. About half of the modulation is due to ruffling of the bacteriochlorin chromophore. Surprisingly, the other half originates in the localized twisting of the Cβ-Cα-Cα-Cβ dihedral angle within the morpholine moieties. Our calculations suggest a predictable and large spectral shift (2.0 nm/deg twist) for morpholine deformations within these fairly flexible moieties. This morpholine moiety deformation can take place largely independently from the overall macrocycle conformation. The morpholinobacteriochlorins are thus excellent models for localized bacteriochlorin chromophore deformations that are suggested to also be responsible for the optical modulation of naturally occurring bacteriochlorophylls. We propose the use of morpholinobacteriochlorins as mechanochromic dyes in engineering and materials science applications.

Exploration of structural motifs influencing solid-state conformation and packing of unclosed cryptands sharing the same 19-membered macrocyclic core

The crystal structures of a series of readily available, highly crystalline bisamide unclosed cryptands (UCs), sharing the same 19-membered macrocyclic core were thoroughly studied in order to rationalize their organization in the solid state. Despite structural variations introduced into intraannular substituents, mode of their attachment to the macrocyclic core, and relative acidity of exterior amide protons, UCs adopted only three well-defined geometries in all 10 analyzed crystals. This structural resemblance between conformations of UCs, however, is not translated into similarities in terms of intermolecular interactions and crystal packing. This contradicting intra- and intermolecular solid-state behavior is likely connected with an ability of these macrocyclic compounds to engage in numerous interactions of comparable energy within the crystal lattice.

Structural Determination, DFT Calculation, and Formation Mechanism of Ethyl 2-Cyano-3-alkoxypent-2-enoates Synthesized via Ru-Mediated Coupling Reaction between α,β-Unsaturated Acetals and Cyanoacetate

Abstract Ethyl 2-cyano-3-alkoxypent-2-enoates were synthesized in moderate yields via the coupling reaction between α,β-unsaturated acetals and cyanoacetate, catalyzed by [RuHCl(CO)(PPh3)3]. The E- and Z-isomers were separated and determined by X-ray crystallography for the first time. Structural distortion associated with steric hindrance around the tetrasubstituted alkene moiety was revealed: e.g., the C(carbonyl)–C(α)–C(β) angle expands to about 125°. Density functional theory calculation was performed, and the restricted B3LYP hybrid functional with the 6-31G(d,p) basis set was found to successfully elucidate the solid-state structure and conformation, as well as spectroscopic properties. A plausible formation mechanism was proposed, in which the Ru complex catalyzed the C=C bond migration of the α,β-unsaturated acetal to give the corresponding ketene acetal and assisted the subsequent condensation reaction with cyanoacetate to some extent.

Crystallographic characterization of the α,γ C12 helix in hybrid peptide sequences.

The solid-state conformations of two αγ hybrid peptides Boc-[Aib-γ(4) (R)Ile]4 -OMe 1 and Boc-[Aib-γ(4) (R)Ile]5 -OMe 2 are described. Peptides 1 and 2 adopt C12 -helical conformations in crystals. The structure of octapeptide 1 is stabilized by six intramolecular 4 → 1 hydrogen bonds, forming 12 atom C12 motifs. The structure of peptide 2 reveals the formation of eight successive C12 hydrogen-bonded turns. Average backbone dihedral angles for αγ C12 helices are peptide 1, Aib; φ (°) = -57.2 ± 0.8, ψ (°) = -44.5 ± 4.7; γ(4) (R)Ile; φ (°) = -127.3 ± 7.3, θ1 (°) = 58.5 ± 12.1, θ2 (°) = 67.6 ± 10.1, ψ (°) = -126.2 ± 16.1; peptide 2, Aib; φ (°) = -58.8 ± 5.1, ψ (°) = -40.3 ± 5.5; ψ(4) (R)Ile; φ (°) = -123.9 ± 2.7, θ1 (°) = 53.3 θ 4.9, θ 2 (°) = 61.2 ± 1.6, ψ (°) = -121.8 ± 5.1. The tendency of γ(4) -substituted residues to adopt gauche-gauche conformations about the C(α) -C(β) and C(β) -C(γ) bonds facilitates helical folding. The αγ C12 helix is a backbone expanded analog of α peptide 310 helix. The hydrogen bond parameters for α peptide 310 and α-helices are compared with those for αγ hybrid C12 helix. Copyright © 2016 European Peptide Society and John Wiley & Sons.

Six-membered cyclopalladated N,N′,N″-triarylguanidines, [{κ2(C,N)Pd}2(μ-OAc)(μ-Pz)], [κ2(C,N)Pd(μ-Pz)]2 and a novel [AgNO3⊂{{κ2(C,N)Pd}2(μ-NO3)(μ-Pz)}]: Syntheses, reactivity studies, structural aspects, and solution behavior

Six-membered cyclopalladated N,N′,N″-triarylguanidines, [{κ2(C,N)Pd}2(μ-OAc)(μ-Pz)] (1–4), [κ2(C,N)Pd(μ-Pz)]2 (5–11), and [AgNO3⊂{{κ2(C,N)Pd}2(μ-NO3)(μ-Pz)}] (12) have been isolated in good yields and characterized by micro-analytical, IR, and NMR (1H, 19F, and 13C) spectroscopic techniques. Molecular structures of ten complexes were determined by SCXRD, which revealed cisoid in–out (1–4), transoid out–out (5, 6, 8 and 11), transoid in–in (7) and cisoid (12) conformations. VT 1H NMR spectra of 1 revealed the presence of cisoid in–in as the major species and an equilibrating mixture of cisoid in–out and cisoid out–out as the minor species in solution and this was verified by DFT calculations. In solution, 4 indicated the presence of a mixture of cisoid, and transoid conformers, [κ3(C,N,O)Pd(OAc)], and [κ2(C,N)Pd(κ2O,O′-OAc)] (VT 1H NMR), and a mixture of three conformers of each cisoid and transoid, and [κ3(C,N,O)Pd(Pz)] (VT 19F NMR). Palladacycles 5 and 10 revealed the presence of a mixture of four and five species, respectively in solution and these species are a mixture of cisoid and transoid conformers as revealed by VT 1H NMR. Factors that dictate the solid state conformations and number and nature of solution species of the new complexes are outlined.

X-ray Molecular Structure of ({[(1E)-3-(1<i>H</i>-Imidazol-1-yl)-1- phenylpropylidene]amino} oxy)(3,4,5-trimethoxyphenyl)- methanone: A Potential Anti-<i>Candida</i> Agent

Purpose: To elucidate the solid-state conformation as well as the imine double bond configuration of a potential anti-Candida agent ({[(1E)-3-(1H-imidazol-1-yl)-1-phenylpropylidene]amino}oxy)(3,4,5trimethoxyphenyl)methanone. Methods: Acetophenone was used as a starting material to prepare the target oximino ester in a fourstep reaction sequence. Nuclear magnetic resonance ( 1 H-NMR and 13 C-NMR) and mass spectrometry were used to confirm the chemical structure of the synthesized compounds. Thereafter, x-ray crystallography was performed on single crystals of the target compound. The solid-state conformation of the target molecule and the (E)-configuration of its imine double bond were determined via the investigation of its single crystal x-ray molecular structure. Results: The titled compound crystallized in the triclinic space group P-1 with a = 11.0719 (7) A, b = 14.6602 (9) A, c = 14.8530 (9) A, α = 67.205 (4)°, β = 80.388 (5)o, γ = 70.100 (5)°, V = 2088.2 (2) A 3 , and Z = 4. Individual molecules were packed in the crystal by three weak non-classical intermolecular hydrogen interactions, including C9A—H9AA•••O3A, C9B—H9BA•••O3B, C18B—H18C•••O2A and C20B—H20B•••O4B. Conclusion: The results of the single crystal x-ray molecular structure of the titled anti-Candida agent unequivocally confirmed its (E)-configuration.

Synthesis and conformational studies of 9-benzyloxy-18-substituted [3.3]metacyclophanes

A series of syn-[3.3]metacyclophanes (MCPs) containing internal substituted benzyloxy group have been synthesized by the modified TosMIC coupling reaction followed by acid treatment and Wolff–Kishner reduction. anti-Mono- and di-benzyloxy[3.3]MCPs are synthesized by O-benzylation of the corresponding hydroxy[3.3]MCPs, which are obtained by demethylation of methoxy[3.3]MCPs with BBr3at room temperature. An interesting and intriguing result was obtained when syn-6,15-di-tert-butyl-9-methoxy-18-methyl[3.3]MCP-2,11-dione was treated with TMSI to afford the formation of a dihydrobenzofuran ring by a nucleophilic intramolecular cyclization reaction. The1H NMR and X-ray analysis of 6a confirms that it adopts a syn (chair–chair) conformation in both solution and solid state.

Crystal structure of tramadol hydrochloride, C16H26NO2Cl

The crystal structure of tramadol hydrochloride has been solved and refined using synchrotron X-ray powder diffraction data, and optimized using density functional techniques. Tramadol hydrochloride crystallizes in space groupCc(#9) witha= 9.680 72(2),b= 19.191 27(4),c= 9.285 94(1) Å,β= 100.5923(1)°,V= 1695.795(5) Å3, andZ= 4. The solid-state conformation of the cation differs from the minimum-energy conformation of the tramadol cation in water, and from the conformation observed in the benzoic acid adduct of tramadol hydrochloride. N–H···Cl and O–H···Cl hydrogen bonds form a zigzag chain with graph setC1,2(8) along thec-axis. C–H···O hydrogen bonds also contribute to the crystal energy. The powder pattern has been submitted to ICDD for inclusion in the Powder Diffraction File™.