Solid-phase synthesis of 7-substituted 3H-imidazo[2,1-i]purines

A method for solid-supported synthesis of N,N-disubstituted (3H-imidazo[2,1-i]purin-7-yl)methyl amines has been developed. The key features of this library synthesis are: (i) immobilization of commercially available N6-benzoyl-5'-O-(4,4'-dimethoxytrityl)-2'-deoxyadenosine 3'-(2-cyanoethyl N,N-diisopropylphosphoramidite) by phosphitylation to a hydroxyl-functionalized support, (ii) quantitative conversion of the deprotected adenine base to 3H-imidazo[2,1-i]purine-7-carbaldehyde with bromomalonaldehyde in DMF in the presence of formic acid and 2,6-lutidine, (iii) reductive amination of the formyl group followed by N-alkylation or N-acylation, and (iv) release from the support by acidolytic cleavage of the N-glycosidic bond. Steps (ii) and (iii) have been optimized in some detail by using (adenin-9-yl)acetic acid anchored to a Phe-Wang resin as a model compound.     

Synthesis and hydrolysis behaviour of poly(ester anhydrides) from polylactone precursors containing alkenyl moieties

Hydroxyl-group functional polylactones were prepared and converted to acid- terminated polyesters in a reaction with a series of alkenylsuccinic anhydrides containing 8, 12, or 18 carbons in their alkenyl chains. These polyester precursors were then linked into higher molecular weight poly(ester anhydrides) containing alkenyl moieties in their polyester blocks. The hydrolysis behaviour of the poly(ester anhydrides) was found to depend on the thermal properties of the polyester precursors. For poly(ester anhydrides) prepared from low molecular weight prepolymers with thermal transitions below 37 degrees C, the presence of hydrophobic alkenyl chains in the polyester precursors slowed the rate of weight loss. Poly(ester anhydrides) prepared from higher molecular weight prepolymers showed the opposite weight-loss behaviour; i.e., the crystallinity and thermal transitions of the alkenyl chain-containing poly(ester anhydrides) were low, and the weight loss was faster than for poly(ester anhydrides) without the alkenyl chains. The differences in length of the alkenyl chain, as such, had little effect on the hydrolysis behaviour and thermal properties of the poly(ester anhydrides).     

Zn2+ Complexes of 3,5‐Bis[(1,5,9‐triazacyclododecan‐3‐yloxy)methyl]phenyl Conjugates of Oligonucleotides as Artificial RNases: The Effect of Oligonucleotide Conjugation on Uridine Selectivity of the Cleaving Agent

2‐(3,5‐Bis{[1,5,9‐tris(trifluoroacetyl)‐1,5,9‐triazacyclododecan‐3‐yloxy]methyl}phenoxy)ethanol was synthesized and converted to a O‐(2‐cyanoethyl)‐N,N‐diisopropylphosphoramidite building block, 12 . 2′‐O‐Methyl oligoribonucleotides incorporating a 2‐[(2S,4S,5R)‐4‐hydroxy‐5‐(hydroxymethyl)tetrahydrofuran‐2‐yl)ethyl 4‐oxopentanoate or a 2‐{2‐[2‐({[(2R,4S,5R)‐4‐hydroxy‐5‐(hydroxymethyl)tetrahydrofuran‐2‐yl]acetyl}amino)ethoxy]ethoxy}ethyl 4‐oxopentanoate non‐nucleosidic unit close to the 3′‐terminus were assembled on a solid support, the 4‐oxopentanoyl protecting groups were removed by treatment with hydrazinium acetate on‐support, and 12 was coupled to the exposed OH function. The deprotected conjugates were purified by HPLC, and their ability to cleave a complementary RNA containing either uridine or some other nucleoside at the potential cleaving site was compared. Somewhat unexpectedly, conjugation to an oligonucleotide did not enhance the catalytic activity of the Zn²⁺? bis(azacrown) complex and virtually abolished its selectivity towards the uridine sites.     

The Acid-Catalyzed Hydrolysis of Anomeric Alkyl Fructofuranosides

Abstract

The rate constants for the hydrolysis of some al-kyl α- and β-d-fructofuranosides in aqueous perchloric acid have been determined at various temperatures. The effects of varying the aglycon structure on the hydrolysis rate suggest, together with the markedly positive entropies of activation, that the substrate, protonated on the glycosidic oxygen atom, undergoes a rate-limiting unimolecular heterolysis to form a glycosyl oxocar-benium ion. The rate variations in mixtures of aqueous perchloric acid and dimethyl sulfoxide are interpreted as lending further support for the proposed mechanism.     

Effect of Droplet Size and Atomization on Spray Formation: A Priori Study Using Large-Eddy Simulation

The paper is mainly focused to the vast number of researchers who work within direct injection (DI) engine fuel spray simulations. The most common simulation framework today within the community is the Reynolds Averaged Navier Stokes (RANS) approach together with the Lagrangian Particle Tracking (LPT) method. In fact, this study is one of the first studies where high resolution LES/LPT diesel spray modeling is considered. The potential of LES to deepen the present day multidimensional LPT fuel spray simulations is discussed. Spray evolution is studied far from an injector by modeling a spray as a particle laden jet (PLJ). The effect of d on mixing in non-atomizing and atomizing sprays is thoroughly investigated at jet inlet Reynolds number Re?=?10⁴ and Mach number Ma?=?0.3. Based on and justified by rather recent and also quite old ideas, novel and compact views on droplet breakup in turbulent flows are pointed out from the literature. We use LES/LPT to illustrate that even in a low Weber number flow (We?<?13) the droplet breakup modeling may need considerable attention in contrast to what is typically assumed in the present-day breakup models. LES and LPT techniques are first applied to essentially confirm certain expected droplet size effects on spray shape in non-atomizing monodisperse sprays. In the simulations LES e.g. produces an expected turbulent dispersion pattern that depends on droplet diameter (d) without a droplet dispersion model in contrast to RANS. A new compact droplet breakup model is formulated and tested for droplets that break with a natural resonance time rate according to the Poisson process. As a result of the study: 1) the analysis gives a rigorous and enriching proof of currently existing views on droplet size effects on mixing, and 2) the presented a priori analysis points out the importance of modeling the resonance breakup even at a low We.     

Routing by ranking: A link analysis method for the constrained dial-a-ride problem

The dial-a-ride problem involves the dispatching of a fleet of vehicles in order to transport a set of customers from specific pick-up nodes to specific drop-off nodes. Using a modified version of hyperlink-induced topic search (HITS), we characterize hubs as nodes with many out-links to other hubs and calculate a hub score for each pick-up and drop-off node. Ranking the nodes by hub score gives guidance to a backtracking algorithm for efficiently finding feasible solutions to the dial-a-ride problem.     

Aerosol characterization and lung deposition of synthesized TiO2 nanoparticles for murine inhalation studies

This study presents a novel exposure protocol for synthesized nanoparticles (NPs). NPs were synthesized in gas phase by thermal decomposition of metal alkoxide vapors in a laminar flow reactor. The exposure protocol was used to estimate the deposition fraction of titanium dioxide (TiO₂) NPs to mice lung. The experiments were conducted at aerosol mass concentrations of 0.8, 7.2, 10.0, and 28.5 mg m^?3. The means of aerosol geometric mobility diameter and aerodynamic diameter were 80 and 124 nm, and the geometric standard deviations were 1.8 and 1.7, respectively. The effective density of the particles was approximately from 1.5 to 1.7 g cm^?3. Particle concentration varied from 4 × 10⁵ cm^?3 at mass concentrations of 0.8 mg m^?3 to 12 × 10⁶ cm^?3 at 28.5 mg m^?3. Particle phase structures were 74% of anatase and 26% of brookite with respective crystallite sized of 41 and 6 nm. The brookite crystallites were approximately 100 times the size of the anatase crystallites. The TiO₂ particles were porous and highly agglomerated, with a mean primary particle size of 21 nm. The specific surface area of TiO₂ powder was 61 m² g^?1. We defined mice respiratory minute volume (RMV) value during exposure to TiO₂ aerosol. Both TiO₂ particulate matter and gaseous by-products affected respiratory parameters. The RMV values were used to quantify the deposition fraction of TiO₂ matter by using two different methods. According to individual samples, the deposition fraction was 8% on an average, and when defined from aerosol mass concentration series, it was 7%. These results show that the exposure protocol can be used to study toxicological effects of synthesized NPs.     

Modeling uncertain passenger arrivals in the elevator dispatching problem with destination control

An Elevator Group Control System (EGCS) assigns an elevator of a group to each passenger transportation request by solving a snapshot optimization problem, the Elevator Dispatching Problem (EDP). In the destination control, passengers register their destination floors in the elevator lobbies, after which the EGCS completes the assignment at once and is not allowed to change it later. Therefore, the EDP is formulated as a stochastic optimal control problem, where uncertain future passenger arrivals are modeled by a Poisson and a geometric Poisson process. The EDP is considered as a certainty equivalent controller in which the uncertain quantities are replaced by their expected values, and as a robust controller in which they take multiple values according to risk scenarios. Numerical experiments show that the expectations do not accurately predict EDP variables. The modeling with the geometric Poisson process results in better forecasting accuracy than with the Poisson process and many scenarios that closely match the realizations of the variables. Hence, the scenarios can be used as a basis for a robust EDP which simultaneously minimizes a passenger service quality criterion and its variation due to uncertain demand.     

Solid-phase synthesis of oligonucleotide glycoconjugates bearing three different glycosyl groups: orthogonally protected bis(hydroxymethyl)-N,N'-bis(3-hydroxypropyl)malondiamide phosphoramidite as key building block

Diethyl O,O'-(methoxymethylene)bis(hydroxymethyl)malonate (3) was observed to undergo a stepwise aminolysis when treated with 3-aminopropanol. This allowed convenient preparation of bis(hydroxymethyl)-N,N'-bis(3-hydroxypropyl)malondiamide bearing orthogonal levulinyl (Lev) and tert-butyldiphenylsilyl (TBDPS) protections at the two N-hydroxypropyl groups (8). One of the hydroxylmethyl functions was then protected with a 4,4'-dimethoxytrityl (DMTr) group, and the other one was phosphitylated to obtain a methyl N,N-diisopropylphosphoramidite (1). This building block was used for the synthesis of oligonucleotide glycoconjugates (25 and 26) carrying three different sugar units. After conventional phosphoramidite chain assembly of the sequence containing 1, the 5'-terminal DMTr group was removed and an appropriate glycosyl 6-O-phosphoramidite was coupled. The remaining protections of the branching unit were removed in the order of Lev and TBDPS, and the exposed hydroxyl functions were reacted one after another with the desired glycosyl 6-O-phosphoramidites. Global deprotection and cleavage of the conjugate from the support were achieved by conventional ammonolysis.     

Compelling evidence for a stepwise mechanism of the alkaline cyclisation of uridine 3'-phosphate esters

A Bronsted graph with a convex break at pK(a)(Lg)= 12.58 provides compelling evidence for an intermediate in the alkaline cyclisation of uridine 3'-phosphate esters. The transient pentacoordinated oxyphosphorane dianion intermediate collapses to reactant and cyclic uridine 2',3'-monophosphate faster than it can pseudo-rotate and isomerise to the 2'-isomer.