Solid dispersions of active pharmaceutical ingredients are of increasing interest due to their versatile use. In the present study polyvinylpyrrolidone (PVP), poly[N-(2-hydroxypropyl)-metacrylamide] (pHPMA), poly(2-ethyl-2-oxazoline) (PEOx), and polyethylene glycol (PEG), each in three Mw, were used to demonstrate structural diversity of solid dispersions. Acetylsalicylic acid (ASA) was used as a model drug. Four distinct types of the solid dispersions of ASA were created using a freeze-drying method: (i) crystalline solid dispersions containing nanocrystalline ASA in a crystalline PEG matrix; (ii) amorphous glass suspensions with large ASA crystallites embedded in amorphous pHPMA; (iii) solid solutions with molecularly dispersed ASA in rigid amorphous PVP; and (iv) nanoheterogeneous solid solutions/suspensions containing nanosized ASA clusters dispersed in a semiflexible matrix of PEOx. The obtained structural data confirmed that the type of solid dispersion can be primarily controlled by the chemical constitutions of the applied polymers, while the molecular weight of the polymers had no detectable impact. The molecular structure of the prepared dispersions was characterized using solid-state NMR, wide-angle X-ray scattering (WAXS), and differential scanning calorimetry (DSC). By applying various (1)H-(13)C and (1)H-(1)H correlation experiments combined with T1((1)H) and T1ρ((1)H) relaxation data, the extent of the molecular mixing was determined over a wide range of distances, from intimate intermolecular contacts (0.1-0.5 nm) up to the phase-separated nanodomains reaching ca. 500 nm. Hydrogen-bond interactions between ASA and polymers were probed by the analysis of (13)C and (15)N CP/MAS NMR spectra combined with the measurements of (1)H-(15)N dipolar profiles. Overall potentialities and limitations of individual experimental techniques were thoroughly evaluated.
The present work aims to the development of innovative new derivatives of chitosan that can be used for medical applications. This innovation is based on the synthesis and characterization of chitosan-g-aminoanthracene derivatives. Thus, N-(anthracen-9-yl)-4,6-dichloro-[1,3,5]-triazin-2-amine (AT) reacted with chitosan by the following steps: at first, cyanuric chloride reacted with 9-aminoanthracene to obtain N-(anthracen-9-yl)-4,6-dichloro-[1,3,5]-triazin-2-amine (AT), then the AT reacted with chitosan to obtain (CH-g-AT). The final product of CH-g-AT was separated, purified and re-crystallized by dioxane. The structure of the prepared chitosan derivatives was confirmed by FTIR-ATR, solid-NMR, TGA, X-RD, and DSC. The new chitosan derivatives showed fluorescence spectra in liquid and in solid state as well. CH-g-AT showed also high antibacterial activity against gram -ve species (Escherichia coli).
- MeSH
- antibakteriální látky chemická syntéza chemie farmakologie MeSH
- chitosan chemická syntéza chemie farmakologie MeSH
- Escherichia coli účinky léků MeSH
- fluorescenční barviva chemická syntéza chemie farmakologie MeSH
- stabilita léku MeSH
- techniky syntetické chemie MeSH
- teplota MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The small bacterial laccase from the actinobacterium Streptomyces coelicolor which lacks the second of the three domains of the laccases structurally characterized to date was crystallized. This multi-copper phenol oxidase crystallizes in a primitive tetragonal lattice, with unit-cell parameters a = b = 179.8, c = 175.3 A. The crystals belong to either space group P4(1)2(1)2 or P4(3)2(1)2. The self-rotation function shows the presence of a noncrystallographic threefold axis in the structure. Phases will be determined from the anomalous signal of the natively present copper ions.
Two new X-ray structures of an HIV-1 protease mutant (A71V, V82T, I84V) in complex with inhibitors SE and SQ, pseudotetrapeptide inhibitors with an acyclic S-hydroxyethylamine isostere, were determined. Comparison of eight structures exploring the binding of four similar inhibitors--SE, SQ (S-hydroxyethylamine isostere), OE (ethyleneamine), and QF34 (hydroxyethylene)--to wild-type and A71V/V82T/I84V HIV-1 protease elucidates the principles of altered interaction with changing conditions. The A71V mutation, which is distant from the active site, causes changes in the structure of the enzyme detectable by the means of X-ray structure analysis, and a route of propagation of the effect toward the active site is proposed.
- MeSH
- ethanolamin chemie MeSH
- financování organizované MeSH
- HIV-proteasa genetika chemie MeSH
- inhibitory HIV-proteasy chemie MeSH
- krystalografie rentgenová MeSH
- ligandy MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- mutace MeSH
- oligopeptidy chemie MeSH
- vazebná místa MeSH
- vodíková vazba MeSH
- vztahy mezi strukturou a aktivitou MeSH
Peptidomimetic inhibitors of human immunodeficiency virus-1 protease are successful lead substances for the development of virostatic drugs against HIV as the causative agent of acquired immunodeficiency syndrome (AIDS). The hydroxyethylamine isostere of the proteolytic cleavage intermediate provides a suitable replacement for the peptide bond. A series of acyclic pseudopeptide inhibitors with the hydroxyethylamine isostere varying in chiral carbon configuration and P'2 residue type were structurally analysed by single-crystal X-ray crystallography. The compounds inhibit HIV protease with subnanomolar inhibition constants and block viral replication in tissue cultures. Here, the structure of such a complex with the R configuration of the isosteric group (PDB code 1zsf) is presented together with newly available synchrotron data for a complex with the S stereoisomer of the inhibitor (PDB code 1zsr). Comparison of the structure and binding with other complexes of HIV-1 protease and similar inhibitors contributes to the understanding of how these molecules bind to the wild-type form of this enzyme. The hydroxy group of the R stereoisomer interacts with one of the catalytic aspartic acids by a short hydrogen bond with rather extreme geometry. The change of configuration of the chiral carbon bearing the hydroxyl from S to R does not influence the inhibition efficiency in this case.
- MeSH
- ethanolaminy chemie MeSH
- financování organizované MeSH
- HIV-1 enzymologie MeSH
- HIV-proteasa chemie metabolismus MeSH
- inhibitory HIV-proteasy chemie MeSH
- krystalografie rentgenová MeSH
- molekulární modely MeSH
- oligopeptidy chemie MeSH
- stereoizomerie MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- vodíková vazba MeSH
The interaction between negatively charged lipid vesicles and positively charged DNA/polylysine complexes was studied. The interaction does not lead to release of DNA from the initial complexes. The particles formed are easy to prepare, they have slight negative charge, small dimensions and show good stability in physiological NaCl solution. Such properties might indicate that stabilization of the particles by lipid coating might be a potent strategy, alternative to PEGylation of DNA/polycation complexes.Interaction of DNA/polycation complex particles with lipid vesicles.
