Synthesis of 2'-O-[2-[(N,N-dimethylamino)oxy]ethyl] modified nucleosides and oligonucleotides.

A versatile synthetic route has been developed for the synthesis of 2'-O-[2-[(N,N-dimethylamino)oxy]ethyl] (abbreviated as 2'-O-DMAOE) modified purine and pyrimidine nucleosides and their corresponding nucleoside phosphoramidites and solid supports. To synthesize 2'-O-DMAOE purine nucleosides, the key intermediate B (Scheme 1) was obtained from the 2'-O-allyl purine nucleosides (13a and 15) via oxidative cleavage of the carbon-carbon bond to the corresponding aldehydes followed by reduction. To synthesize pyrimidine nucleosides, opening the 2,2'-anhydro-5-methyluridine 5 with the borate ester of ethylene glycol gave the key intermediate B. The 2'-O-(2-hydroxyethyl) nucleosides were converted, in excellent yield, by a regioselective Mitsunobu reaction, to the corresponding 2'-O-[2-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)oxy]ethyl] nucleosides (18, 19, and 20). These compounds were subsequently deprotected and converted into the 2'-O-[2-[(methyleneamino)oxy]ethyl] derivatives (22, 23, and 24). Reduction and a second reductive amination with formaldehyde yielded the corresponding 2'-O-[2-[(N,N-dimethylamino)oxy]ethyl] nucleosides (25, 26, and 27). These nucleosides were converted to their 3'-O-phosphoramidites and controlled-pore glass solid supports in excellent overall yield. Using these monomers, modified oligonucleotides containing pyrimidine and purine bases were synthesized with phosphodiester, phosphorothioate, and both linkages (phosphorothioate and phosphodiester) present in the same oligonucleotide as a chimera in high yields. The oligonucleotides were characterized by HPLC, capillary gel electrophoresis, and ESMS. The effect of this modification on the affinity of the oligonucleotides for complementary RNA and on nuclease stability was evaluated. The 2'-O-DMAOE modification enhanced the binding affinity of the oligonucleotides for the complementary RNA (and not for DNA). The modified oligonucleotides that possessed the phosphodiester backbone demonstrated excellent resistance to nuclease with t(1/2) > 24 h.     

Biotransformation of (−)β-pinene by Aspergillus niger ATCC 9642

The main objective of this work was to investigate the biotransformations of (−)α-pinene, (−)β-pinene, and (+) limonene by Aspergillus niger ATCC 9642. The culture conditions involved—concentration of cosolvent (EtOH), substrate applied, and sequential addition of substrates—were investigated. Adaptation of the precultures with small amounts of substrate was also studied. The experiments were performed in conical flasks with liquid cultures. This strain of A. niger was able to convert only (−)β-pinene into α-terpineol. An optimum conversion of (−)β-pinene into α-terpineol of about 4% was obtained when the substrate was applied as a diluted solution in EtOH and sequential addition of substrate was used.     

Topological Space of the Chemical Elements and its Properties

We carried out a mathematical study of 72 chemical elements taking advantage of the chemotopological method. We selected 128 properties to define the elements (physico-chemical, geochemical and chemical properties). Then, we looked for correlated properties and we reduced the number of them to 90. In this way we defined each element as a 90-tuple. Afterwards, we applied principal component analysis and cluster analysis (4 similarity functions and 5 grouping methodologies). Then, we calculated a consensus tree for the 20 dendrograms generated by the CA. Afterwards, we extracted the similarity relationships from the consensus tree and built up a basis for a topology on the set of chemical elements. Finally, we calculated some topological properties (closures, derived sets, boundaries, interiors and exteriors) of several subsets of chemical elements. We found that alkali metals, alkaline earth metals and noble gases appear not related to the rest of the elements. Also, we found that the boundary of non-metals are the semimetals with a stair-shape on the periodic table     

Stereocontrolled diels-alder cycloadditions of sugar-derived dihydropyranones with dienes

2-Acetoxy-3,4-di-O-acetyl-D-arabinal (6), similar to its D-xylo analogue 4, reacted with benzyl alcohol by the tin(IV) chloride-promoted glycosylation to produce optically active (S)-2-benzyloxy-2H-pyran-3(6H)-one (8a). The L-arabinal derivative (5) gave 9a, the dihydropyranone enantiomer of 8a. These results indicated that the configuration of the C-4 stereocenter in the starting glycal defines the configuration of the new chiral center in the resulting dihydropyranone. The influence of other catalysts (BF(3) or iodine) employed for the glycosylation on the optical purity of the dihydropyranone was studied. Enantiomerically pure dihydropyranones 8b and 9c were obtained using chiral alcohols ((R)- and (S)-2-octanol, respectively) as glycosylating agents. Compounds 8a,b and 9a,c proved to be reactive dienophiles in thermal and Lewis acid-promoted Diels-Alder reactions. The addition of 2,3-dimethylbutadiene, cyclopentadiene, and 1,3-cyclohexadiene to the beta-pyranones 8a,b led to the corresponding adducts 10a,b, 12a,b, and 16a,b as major products. Enantiomeric cycloadducts were synthesized from the alpha-pyranones 9a,c. The main products were formed by highly facial-diastereoselective addition of dienes to the pyranone ring, guided by the sterical hindrance of the alkoxy substituent of the C-2 stereocenter. As cycloadditions with cycloalkadienes were also highly endo diastereoselective, these reactions gave access to pure tetrahydrobenzopyranones that carry a multitude of stereogenic centers installed in a predictable way.     

2,6-diaminopurine in TNA: effect on duplex stabilities and on the efficiency of template-controlled ligations

Replacement of adenine by 2,6-diaminopurine-two nucleobases to be considered equivalent from an etiological point of view-strongly enhances the stability of TNA/TNA, TNA/RNA, or TNA/DNA duplexes and efficiently accelerates template-directed ligation of TNA ligands. [reaction: see text]     

Determination of pirimicarb and endosulfan in commercial pesticide formulations by Fourier transform infrared spectrometry

A routine method based on Fourier transform infrared spectrometry was developed for the simultaneous determination of pirimicarb and endosulfan in commercially available pesticide formulations. The method is based on peak area absorbance measurements between 1362 and 1352 cm(-1), corrected with a baseline fixed at 1338 cm(-1), for pirimicarb and peak area absorbance measurements between 919 and 909 cm(-1) with a baseline fixed at 931 cm(-1) for endosulfan; chloroform solutions for analysis were obtained by direct dilution of emulsifiable concentrates or by solvent extraction from solid samples. Various extraction conditions and appropriate band selection were investigated, and interference studies were performed. Under the experimental conditions selected, limits of detection of 13 microg/g for pirimicarb and 150 microg/g for endosulfan were obtained that correspond to 0.13 and 1.6% (w/w), respectively, in commercial samples. Results from analyses of commercial samples by the developed method compared well with those obtained by a liquid chromatography reference method.     

Modular bis(oxazoline) ligands for palladium catalyzed allylic alkylation: unprecedented conformational behaviour of a bis(oxazoline) palladium eta3-1,3-diphenylallyl complex

New families of enantiopure bis(oxazolines) with 4,5-trans (5 a-g) or 4,5-cis (6 c) stereochemistry at the individual rings have been prepared in high yield. Their eta(3)-allyl palladium complexes (8 a-g, 9 c and 10) have been used as catalytic precursors in allylic alkylation reactions with excellent enantioselectivities (up to 96 %) for the trans oxazoline derivatives, while Pd/6 c system was inactive. NMR studies on palladium eta(3)-1,3-diphenylallyl intermediates (11 a, c and e) showed the presence of syn/syn- and syn/anti-allyl isomers in solution; this resembles the first example of eta(3)-eta(1)-eta(3) isomerism in Pd allylic complexes containing bis(oxazolines) derived from malonic acid.     

Singlet oxygen generation versus O–O homolysis in phenyl-substituted anthracene endoperoxides investigated by RASPT2, CASPT2, CC2, and TD-DFT methods

Peptidylarginine deiminase 4 (PAD4), also known as protein arginine deiminase 4, performs a post-translational deimination that converts arginine to citrulline. The dysregulation of PAD4 has been implicated in a number of diseases, including rheumatoid arthritis (RA) and cancer. This makes PAD4 an important therapeutic target. To develop small-molecule inhibitors as potential treatments, it is advantageous if the catalytic mechanism is well understood. The protonation states of the active site residues, which have long been under controversy, have a direct impact on the catalytic mechanism. Two competing mechanisms are under investigation in the current literature. The first is a reverse protonation mechanism that depends on the active site histidine and cysteine existing as an ion pair. The second is a substrate-assisted mechanism that depends on the active site histidine and cysteine being neutral. This study uses the semimicroscopic protein dipoles Langevin dipoles (PDLD/S) linear response approximation method in the MOLARIS software package to calculate the change in solvation energy of moving the residue from water to the protein interior, and then using that information to assess the protonation states of the active site residues of PAD4. Results from these calculations suggest that in the enzyme–substrate complex of PAD4, the cysteine and histidine are protonated and deprotonated, respectively, and are therefore both neutral, analogous to the proposed protonation states of the active site residues in the Michaelis complex in the substrate-assisted mechanism.