Development of Cordycepin Formulations for Preclinical and Clinical Studies.

There is extensive literature on in vivo studies with cordycepin, but these studies were generally conducted without validation of the various formulations, especially in terms of the solubility of cordycepin in the dosing vehicles used. Cordycepin is a promising drug candidate in multiple therapeutic areas, and there is a growing interest in studies aimed at assessing the pharmacological activity of this compound in relevant animal disease models. It is likely that many reported in vivo studies used formulations in which cordycepin was incompletely soluble. This can potentially confound the interpretation of pharmacokinetics and efficacy results. Furthermore, the presence of particles in intravenously administered suspension can cause adverse effects and should be avoided. Here, we present the results from our development of simple and readily applicable formulations of cordycepin based on quantitative solubility assessment. Homogeneous solutions of cordycepin were prepared in phosphate-buffered saline (PBS) at different pH levels, suitable as formulations for both intravenously and oral administration. For the purpose of high-dose oral administration, we also developed propylene glycol (PPG)-based vehicles in which cordycepin is completely soluble. The stability of the newly developed formulations was also assessed, as well as the feasibility of their sterilisation by filtration. Additionally, an HPLC-UV method for the determination of cordycepin in the formulations, which may also be useful for other purposes, was developed and validated. Our study could provide useful information for improvement of future preclinical and clinical studies involving cordycepin.

Evaluation of the ability to metabolize 1, 2-propanediol by heterofermentative bacteria of the genus Lactobacillus

Background: New directions of research on lactic acid bacteria include investigation of metabolic pathways for the synthesis and/or metabolism of 1,2-propanediol, commonly used in the food and chemical industry, medicine, pharmacy and cosmetology as well as agriculture. The objective of this study was to compare the capacity of strains representing three diverse heterofermentative species belonging to the genus Lactobacillus to synthesize and/or transform 1,2-PD as well as to suggest new directions of research aimed at commercial use of this metabolite. Results: The novel strain of Lactobacillus buchneri A KKP 2047p, characterized as exhibiting an unusual trait for that species in the form of capacity to metabolize 1,2-PD, grew poorly in a medium containing 1,2-PD as a sole carbon source. The supplementation with glucose facilitated rapid growth of bacteria and use of 1,2-PD for the synthesis of propionic acid. A similar observation was noted for Lactobacillus reuteri. On the other hand, Lactobacillus diolivorans effectively metabolized 1,2-PD which was the sole carbon source in the medium, and the addition of glucose inhibited the synthesis of propionic acid. The experiments also investigated the effect of cobalamin as a diol dehydratase coenzyme involved in the propionic acid synthesis from 1,2-PD whose addition promoted the yield of the reaction in the case of all tested strains. Conclusions: All tested isolates showed the ability to effectively metabolize 1,2-PD (in the presence of cobalamin) and its conversion to propionic acid, which reveals that investigated bacteria meet the essential requirements of microorganisms with a potential application.

Hydrogenolysis of Glycerol to 1,2-Propanediol Over Clay Based Catalysts.

1,2-propanediol (1,2-PDO) is one of the promising product among the valuable products derived from glycerol and it can be obtained by the catalytic hydrogenolysis of glycerol. Copper-supported clay-based catalysts were prepared with different pore sizes using various ratios of kaolin, Mg, and Al by coprecipitation and applied in the selective hydrogenolysis of glycerol to 1,2-PDO. In recent research, variations of pore volume and pore size could affect the diffusion of reagents within the catalyst due to the collision between reagents or pore wall and reagents. It changes selectivities of each product in hydrogenolysis of glycerol reaction. The physico-chemical properties of the catalysts were analyzed by XRD, N2 physisorption, TPR, CO2-TPD, SEM, and a mercury porosimeter. The Cu/TALCITE 4 catalyst showed 98% 1,2-PDO selectivity with 65% glycerol conversion under the optimized condition of 190 degrees C, 25 bar, and 20 wt% glycerol aqueous solution. It was found that the basic strength and meso-macro pore structure of the catalysts play an important role in glycerol conversion and 1,2-PDO selectivity.

Gas phase production and loss of isoprene epoxydiols.

Isoprene epoxydiols (IEPOX) form in high yields from the OH-initiated oxidation of isoprene under low-NO conditions. These compounds contribute significantly to secondary organic aerosol formation. Their gas-phase chemistry has, however, remained largely unexplored. In this study, we characterize the formation of IEPOX isomers from the oxidation of isoprene by OH. We find that cis-ß- and trans-ß-IEPOX are the dominant isomers produced, and that they are created in an approximate ratio of 1:2 from the low-NO oxidation of isoprene. Three isomers of IEPOX, including cis-ß- and trans-ß, were synthesized and oxidized by OH in environmental chambers under high- and low-NO conditions. We find that IEPOX reacts with OH at 299 K with rate coefficients of (0.84 ± 0.07) × 10(-11), (1.52 ± 0.07) × 10(-11), and (0.98 ± 0.05) × 10(-11) cm(3) molecule(-1) s(-1) for the δ1, cis-ß, and trans-ß isomers. Finally, yields of the first-generation products of IEPOX + OH oxidation were measured, and a new mechanism of IEPOX oxidation is proposed here to account for the observed products. The substantial yield of glyoxal and methylglyoxal from IEPOX oxidation may help explain elevated levels of those compounds observed in low-NO environments with high isoprene emissions.

Propane-1,2-diols from dilactides, oligolactides, or poly-L-lactic acid (PLLA): from plastic waste to chiral bulk chemicals.

The preparation of racemic or enantioenriched propane-1,2-diol from dilactides, oligolactides, or poly-L-lactic acid (PLLA) is described. The transformation is carried out as tandem reactions in MeOH, covering hydrolysis and subsequent hydrogenation by using copper chromite as a catalyst. The starting material present undesired side products of the PLLA synthesis or PLLA waste.

Sustained delivery of paclitaxel using thermogelling poly(PEG/PPG/PCL urethane)s for enhanced toxicity against cancer cells.

A multiblock poly(ether ester urethane)s comprising poly(ε-caprolactone), poly(ethylene glycol), and poly(propylene glycol) segments was synthesized. The aqueous copolymer solution exhibited thermogelling behavior at a critical gelation concentration of 3 wt %. The chemical structure and molecular characteristic of the copolymers were studied by gel permeation chromatography, NMR, and fourier transform infrared spectroscopy (FTIR). Rheological characterizations on the thermogel were carried out. Drug release studies using paclitaxel showed that sustained drug release of more than 2 weeks can be achieved with this system. The paclitaxel-loaded gels showed efficiency in the control of the growth of HeLa cells when compared with the paclitaxel dissolved in solution or paclitaxel encapsulated in Pluronics F127. The results demonstrated that the copolymers could be potentially used in chemotherapeutic applications.

Glycerol hydrogenolysis promoted by supported palladium catalysts.

Catalytic hydrogenolysis, with high conversion and selectivity, promoted by supported palladium substrates in isopropanol and dioxane at a low H(2) pressure (0.5 MPa), is reported for the first time. The catalysts, characterized by using BET isotherms, transmission electron microscopy (TEM), temperature-programmed reduction (TPR), powder X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS), were obtained by coprecipitation and impregnation techniques. The coprecipitation method allows catalysts with a metal-metal or a metal-support interaction to be obtained, which enhances the catalytic performance for both the conversion of glycerol and the selectivity to 1,2-propanediol. Analogous reactions carried out with catalysts prepared by using impregnation are less efficient. A study of the solvent and temperature effect is also presented. The obtained results allow the hydrogenolysis mechanism to be inferred; this involves both the direct replacement of the carbon-bonded OH group by an incoming hydrogen or the formation of hydroxyacetone as an intermediate, which subsequently undergoes a hydrogenation process to give 1,2-propanediol. Finally, catalytic tests on a large-scale reaction at a higher H(2) pressure and recycling of the samples were carried out with the better performing catalysts (Pd/CoO and Pd/Fe(2)O(3) prepared by using coprecipitation) to verify possible industrial achievements.

Synthesis, characterizations and biocompatibility of alternating block polyurethanes based on P3/4HB and PPG-PEG-PPG.

Block copolymers with exactly controlled structures, that is, alternating block polyurethanes based on poly(3-hydroxybutyrate-co-4-hydroxybutrate) (P3/4HB-diol) and poly (propylene glycol)-poly(ethylene glycol)-poly(propylene glycol) (PPG-PEG-PPG) were synthesized by solution polymerization via specifically selective coupling reaction between terminal hydroxyl P3/4HB segment and isocyanate group end-capped PPG-PEG-PPG segment, using 1,6-hexamethylene diisocyanate (HDI) as end-capped agent. The chemical structure, molecular weight and distribution were systematically characterized by nuclear magnetic resonance spectrum (¹H NMR), Fourier transform infrared spectroscopy (FTIR) and gel permeation chromatography (GPC). The thermal property was investigated by differential scanning calorimetry (DSC) and thermogravimetric analysis. The hydrophilicity was studied by static contact angle of H2O and CH2I2. DSC revealed that the PU3/4HB-alt-PPG-PEG-PPG exhibited a distinct change from amorphous to 30% crystallinity degree, T(g) from -25 to -50 °C, T(m) from 110 to 145 °C. The polyurethanes were more hydrophilic (water contact angle centers around 80 °) than the raw PHA materials. The platelet adhesion assay showed that the obtained polyurethanes had a lower platelet adhesion than the raw materials and the amount of platelet adhesion could be controlled by varying the segmental length of P3/4HB-diol. This could be explained by the inclusion of PPG-PEG-PPG between the P3/4HB segments, improving the hemocompatibility of P3/4HB. The cell culture assay revealed that the obtained polyurethanes were cell inert and unfavorable for the attachment of mouse fibroblast cell line L929 and rabbit blood vessel smooth muscle cells (RaSMCs). This suggests that these polyurethanes would be promising candidates as hemocompatibility and tissue-inert materials.

Acid-, water- and high-temperature-stable ruthenium complexes for the total catalytic deoxygenation of glycerol to propane.

The ruthenium aqua complexes [Ru(H(2)O)(2)(bipy)(2)](OTf)(2), [cis-Ru(6,6'-Cl(2)-bipy)(2)(OH(2))(2)](OTf)(2), [Ru(H(2)O)(2)(phen)(2)](OTf)(2), [Ru(H(2)O)(3)(2,2':6',2''-terpy)](OTf)(2) and [Ru(H(2)O)(3)(Phterpy)](OTf)(2) (bipy = 2,2'-bipyridine; OTf(-) = triflate; phen = phenanthroline; terpy = terpyridine; Phterpy = 4'-phenyl-2,2':6',2''-terpyridine) are water- and acid-stable catalysts for the hydrogenation of aldehydes and ketones in sulfolane solution. In the presence of HOS(O)(2)CF(3) (triflic acid) as a dehydration co-catalyst they directly convert 1,2-hexanediol to n-hexanol and hexane. The terpyridine complexes are stable and active as catalysts at temperatures > or = 250 degrees C and in either aqueous sulfolane solution or pure water convert glycerol into n-propanol and ultimately propane as the final reaction product in up to quantitative yield. For the terpy complexes the active catalyst is postulated to be a carbonyl species [(4'-R-2,2':6',2''-terpy)Ru(CO)(H(2)O)(2)](OTf)(2) (R = H, Ph) formed by the decarbonylation of aldehydes (hexanal for 1,2-hexanediol and 3-hydroxypropanal for glycerol) generated in the reaction mixture through acid-catalyzed dehydration. The structure of the dimeric complex [{(4'-phenyl-2,2':6',2''-terpy)Ru(CO)}(2)(mu-OCH(3))(2)](OTf)(2) has been determined by single crystal X-ray crystallography (Space group P1 (a = 8.2532(17); b = 12.858(3); c = 14.363(3) A; alpha = 64.38(3); beta = 77.26(3); gamma = 87.12(3) degrees, R = 4.36 %).

Catalytic glycerol conversion into 1,2-propanediol in absence of added hydrogen.

Conversion of glycerol into high yields of 1,2-propanediol in absence of added hydrogen is possible with Pt impregnated NaY zeolite characterized by extra-zeolitic metal particles combined with zeolite Brønsted acidity.

[The synthesis of thio- and selenoanalogues of phospholipids on the basis of 2-butyl-2-hydroxymethyl-1,3-propanediol].

New analogues of nonglycerol polyol phospholipids were prepared on the basis of 1,1,1-trimethylolethane. Amidophosphites and cyclophosphites of the isopropylidene derivative of this polyol were intermediates in the syntheses. They were treated with sulfur or selenium. Phosphoacetals were converted into lipids by the direct acylation with higher fatty acid chlorides. The triol bicyclophosphite was also used in the lipid syntheses. It was directly acylated at the oxygen atom, the resulting acylpolyol of chlorophosphite was then converted into phospholipids by alcoholysis and subsequent treatment with sulfur.