Influence of heterochirality on the structure, dynamics, biological properties of cyclic(PFPF) tetrapeptides obtained by solvent-free ball mill mechanosynthesis.

Cyclic tetrapeptides c(Pro-Phe-Pro-Phe) obtained by the mechanosynthetic method using a ball mill were isolated in a pure stereochemical form as a homochiral system (all L-amino acids, sample A) and as a heterochiral system with D configuration at one of the stereogenic centers of Phe (sample B). The structure and stereochemistry of both samples were determined by X-ray diffraction studies of single crystals. In DMSO and acetonitrile, sample A exists as an equimolar mixture of two conformers, while only one is monitored for sample B. The conformational space and energetic preferences for possible conformers were calculated using DFT methods. The distinctly different conformational flexibility of the two samples was experimentally proven by Variable Temperature (VT) and 2D EXSY NMR measurements. Both samples were docked to histone deacetylase HDAC8. Cytotoxic studies proved that none of the tested cyclic peptide is toxic.

Solvent-Free Mechanosynthesis of Oligopeptides by Coupling Peptide Segments of Different Lengths - Elucidating the Role of Cesium Carbonate in Ball Mill Processes.

We report an idea for the synthesis of oligopeptides using a solvent-free ball milling approach. Our concept is inspired by block play, in which it is possible to construct different objects using segments (blocks) of different sizes and lengths. We prove that by having a library of short peptides and employing the ball mill mechanosynthesis (BMMS) method, peptides can be easily coupled to form different oligopeptides with the desired functional and biological properties. Optimizing the BMMS process we found that the best yields we obtained when TBTU and cesium carbonate were used as reagents. The role of Cs2CO3 in the coupling mechanism was followed on each stage of synthesis by 1H, 13C and 133Cs NMR employing Magic Angle Spinning (MAS) techniques. It was found that cesium carbonate acts not only as a base but is also responsible for the activation of substrates and intermediates. The unique information about the BMMS mechanism is based on the analysis of 2D NMR data. The power of BMMS is proved by the example of different peptide combinations, 2+2, 3+2, 4+2, 5+2 and 4+4. The tetra-, penta-, hexa-, hepta- and octapeptides obtained under this project were fully characterized by MS and NMR techniques.

Synthesis and Characterization of Functionalized Polylactides Containing Acetal Units.

New functionalized lactide copolymers containing acetal units were prepared for the first time in a controlled manner that enabled the regulation of the number of reactive groups introduced into the polyester chain. The presence of functional groups in the copolymer backbone provided chemical modification sites, and the nature of the acetal unit affected the material degradability. First, paraformaldehyde was reacted with selected diols containing reactive pendant groups (3-allyloxypropane-1,2-diol and 3-chloropropane-1,2-diol), which was catalyzed by p-toluenesulfonic acid, to synthesize new cyclic acetals with different functionalities (allyl- or chloro-). In addition, using butane-1,4-diol, a nonfunctionalized seven-membered cyclic acetal (dioxepane) was obtained for comparative studies. In the next step, the prepared cyclic acetals were used for cationic copolymerization with lactide in the presence of glycol as an initiator and triflic acid as a catalyst. Different temperatures (-15, 2, and 30 °C) and copolymerization times (24, 48, 72, and 192 h) were investigated to produce copolyesters with variable contents of acetal units in the range of 5-27%. The copolymers' structure and molar masses were carefully investigated using 1H, 13C NMR, 2D NMR, and size-exclusion chromatography. Moreover, the ability of functionalized copolymers to perform post modifications was also proven by the reaction with sodium azide and propanethiol. Finally, we speculate that structurally diverse groups can be attached to the copolyester chain, fine-tuning the on-demand properties, which could rapidly expand the library of polylactide-based materials.

Cationic Phenosafranin Photosensitizers Based on Polyhedral Oligomeric Silsesquioxanes for Inactivation of Gram-Positive and Gram-Negative Bacteria.

The high photodynamic effect of the Newman strain of the S. aureus and of clinical strains of S. aureus MRSA 12673 and E. coli 12519 are observed for new cationic light-activated phenosafranin polyhedral oligomeric silsesquioxane (POSS) conjugates in vitro. Killing of bacteria was achieved at low concentrations of silsesquioxanes (0.38 µM) after light irradiation (λem. max = 522 nm, 10.6 mW/cm2) for 5 min. Water-soluble POSS-photosensitizers are synthesized by chemically coupling a phenosafranin dye (PSF) (3,7-diamino-5-phenylphenazine chloride) to an inorganic silsesquioxane cage activated by attachment of succinic anhydride rings. The chemical structure of conjugates is confirmed by 1H, 13C NMR, HRMS, IR, fluorescence spectroscopy and UV-VIS analyzes. The APDI and daunorubicin (DAU) synergy is investigated for POSSPSFDAU conjugates. Confocal microscopy experiments indicate a site of intracellular accumulation of the POSSPSF, whereas iBuPOSSPSF and POSSPSFDAU accumulate in the cell wall or cell membrane. Results from the TEM study show ruptured S. aureus cells with leaking cytosolic mass and distorted cells of E. coli. Bacterial cells are eradicated by ROS produced upon irradiation of the covalent conjugates that can kill the bacteria by destruction of cellular membranes, intracellular proteins and DNA through the oxidative damage of bacteria.

Mesoporous Silica Particles as Drug Delivery Systems-The State of the Art in Loading Methods and the Recent Progress in Analytical Techniques for Monitoring These Processes.

Conventional administration of drugs is limited by poor water solubility, low permeability, and mediocre targeting. Safe and effective delivery of drugs and therapeutic agents remains a challenge, especially for complex therapies, such as cancer treatment, pain management, heart failure medication, among several others. Thus, delivery systems designed to improve the pharmacokinetics of loaded molecules, and allowing controlled release and target specific delivery, have received considerable attention in recent years. The last two decades have seen a growing interest among scientists and the pharmaceutical industry in mesoporous silica nanoparticles (MSNs) as drug delivery systems (DDS). This interest is due to the unique physicochemical properties, including high loading capacity, excellent biocompatibility, and easy functionalization. In this review, we discuss the current state of the art related to the preparation of drug-loaded MSNs and their analysis, focusing on the newest advancements, and highlighting the advantages and disadvantages of different methods. Finally, we provide a concise outlook for the remaining challenges in the field.

Porous SiC and SiC/Cf Ceramic Microspheres Derived from Polyhydromethylsiloxane by Carbothermal Reduction.

A simple and inexpensive method for the preparation of porous SiC microspheres is presented. Polysiloxane microspheres derived from polyhydromethylsiloxane (PHMS) cross-linked with divinylbenzene (DVB) were ceramized under conditions leading to the removal of oxygen from the material. The content of free carbon (Cf) in highly crystalline silicon carbide (SiC) particles can be controlled by using various proportions of DVB in the synthesis of the pre-ceramic material. The chemical structure of the ceramic microspheres was studied by elemental analysis for carbon and oxygen, 29Si MAS NMR, 13C MAS NMR, SEM/EDS, XRD and Raman spectroscopies, and their morphology by SEM, nitrogen adsorption and mercury intrusion porosimetries. The gaseous products of the thermal reduction processes formed during ceramization created a porous structure of the microspheres. In the SiC/Cf microspheres, meso/micro pores were formed, while in carbon-free SiC, microspheres macroporosity dominated.

Reasons for enhanced activity of doxorubicin on co-delivery with octa(3-aminopropyl)silsesquioxane.

This paper presents results of spectroscopic (NMR, FTIR, fluorescence), Q-TOF mass spectrometry and Z-potential analyses of interactions between octa(3-aminopropyl)silsesquioxane hydrochloride (POSS-NH2·HCl) and anticancer drug - doxorubicin hydrochloride. These studies aimed at explanation of the enhanced activity of doxorubicin on co-delivery with POSS-NH2. The results point to the formation of active complexes via ionic interactions between the ammonium chloride groups of silsesquioxane and the drug, and not, as suggested earlier, via NH⋯N hydrogen bonding. It has also been shown that the main driving force for the formation of the complexes can be strengthened by π-π stacking and hydrogen bonds. The experimental results are supported by quantum mechanical calculations. This work has proven that co-delivery with POSS offers a potentially advantageous and simple approach for improved efficacy in chemotherapy, avoiding often complicated synthesis of conjugates, involving covalent bonding between drug, nanocarrier and targeting agents.

Synthesis, Biological Activity and Preliminary in Silico ADMET Screening of Polyamine Conjugates with Bicyclic Systems.

Polyamine conjugates with bicyclic terminal groups including quinazoline, naphthalene, quinoline, coumarine and indole have been obtained and their cytotoxic activity against PC-3, DU-145 and MCF-7 cell lines was evaluated in vitro. Their antiproliferative potential differed markedly and depended on both their chemical structure and the type of cancer cell line. Noncovalent DNA-binding properties of the most active compounds have been examined using ds-DNA thermal melting studies and topo I activity assay. The promising biological activity, DNA intercalative binding mode and favorable drug-like properties of bis(naphthalene-2-carboxamides) make them a good lead for further development of potential anticancer drugs.

Synthesis of (1R,2R)- and (1S,2R)-1,2-epoxy-3-hydroxypropylphosphonates as analogues of fosfomycin.

Cyclohexylammonium (1R,2R)-1,2-epoxy-3-hydroxypropylphosphonate was conveniently synthesized from dibenzyl (1S,2R)-2,3-O-cyclohexylidene-1,2,3-trihydroxypropylphosphonate by a reaction sequence including mesylation, hydrolysis of acetal, intramolecular Williamson reaction, and hydrogenation in the presence of cyclohexylamine. For dibenzyl (1S,2R)-2,3-O-cyclohexylidene-1,2,3-trihydroxypropylphosphonates the same approach was not successful, since prior the epoxide-ring closure tritylation of HO-C3 in dibenzyl (1R,2R)-2,3-dihydroxy-1-mesyloxypropylphosphonate was necessary and the hydrogenolysis of dibenzyl (1S,2R)-1,2-epoxy-3-trityloxypropylphosphonate yielded a complex reaction mixture.