A theoretical study of the hydrolysis mechanism of A-234; the suspected novichok agent in the Skripal attack.

A-234, [EtO-P([double bond, length as m-dash]O)(F)-N[double bond, length as m-dash]C(Me)-N(Et)2], is the suspected A-type nerve agent used in the Skripal attack on the 4th of March 2018. Studies related to the structure and reactivity of this compound are limited. We, therefore, aimed at understanding the underlying hydrolysis mechanism of A-234 within the DFT framework. The attack of the water molecule can occur at the phosphinate and acetoamidine reactive centres. Our theoretical findings indicate that the hydrolysis at the acetoamidine centre is thermodynamically favoured compared to the hydrolysis at the phosphinate centre. The hydrolysis at the acetoamidine moiety may proceed via two pathways, depending on the nitrogen atom participating in the hydrolysis. The main pathway consists of four distinct channels to reach the final product, with the concerted 1,3-proton shift favoured kinetically and thermodynamically in the gas phase and water as solvent. The results are in good agreement with the literature, although some differences in the reaction mechanism were observed.

Correction: A colorimetric probe for the real-time naked eye detection of cyanide and hydroxide ions in tap water: experimental and theoretical studies.

Correction for 'A colorimetric probe for the real-time naked eye detection of cyanide and hydroxide ions in tap water: experimental and theoretical studies' by Veikko Uahengo et al., Analyst, 2019, 144, 6422-6431.

A colorimetric probe for the real-time naked eye detection of cyanide and hydroxide ions in tap water: experimental and theoretical studies.

Herein, a colorimetric sensor (L) based on a naphthyl derivative bearing hydrazone receptors was synthesized via a one-step reaction process, and its recognition properties towards biologically important anions in an acetonitrile-water mixture were investigated by naked-eye observation and UV-Vis and 1H NMR spectroscopy. The molar addition of anions, such as TBAF-, TBAOH-, TBACN- and TBAAcO-, induced a significant red shift in the charge transfer band (Δλ = 73 nm, from 337 nm to 410 nm), in agreement with visible "naked eye" detectable colorimetric activities; in addition, soaked-in-L paper strips were prepared, which could significantly discriminate cyanide (KCN) and hydroxide (NaOH) ions dissolved in tap water via the litmus test method. This study was complemented by density functional theory computations to gain more insight into the interaction between L and anions.

Excited State and Non-linear Optical Properties of NIR Absorbing ß-Thiophene-Fused BF2-Azadipyrromethene Dyes-Computational Investigation.

Density functional theory and time-dependent density functional theory computations were used to understand the electronic and photophysical parameters of NIR ß-thiophene-fused BF2-azadipyrromethene dyes. The computed data are in good agreement with those obtained experimentally and they provide insights into the origin of red shifted optical spectra compared to the parent aza-BODIPY, low Stokes shift, non-linear optical responses and quantitative description of the singlet-triplet energy gap. The resultant decrease in the HOMO - LUMO energy gap is responsible for the red shift. The possible use as non-linear optical materials is supported by large enhancement in the non-linear optical properties. On the basis of vertical triplet energies, their possible potential therapeutic use as a photosensitizer in photodynamic therapy is proposed. The singlet-triplet energetic gaps suggest that the ß-thiophene-fused BF2-azadipyrromethene dyes can act as a sensitizer to produce an efficient generation of singlet oxygen. Their optimal use as an efficient singlet fission materials has been proposed on the basis of excitation energies in the ground, lowest singlet and triplet excited states.

2,4-Ditellurouracil and its 5-fluoro derivative: Theoretical investigations of structural, energetics and ADME parameters.

2,4-Ditellurouracil exhibits keto-enol tautomerism via different pathways resulting in seven tautomers. These pathways were studied in the gas phase using density functional theory method. The functionals used were BLYP, B3LYP and BHLYP and the basis sets were 6-311++G(d,p) for all atoms except that LanL2DZ ECP was used for tellurium atom only. The results indicate that the diketo form is more stable as observed for uracil and its sulfur and selenium analogues. The effect of introducing fluorine at position 5 was also investigated and the energy difference between the diketo and dienol forms is reduced. 2,4-Ditellurouracil and its 5-fluoro analogue are expected to exist exclusively as the diketo form due to the high interconversion energy barrier. We extended the investigation to predict ADME parameters of the most stable diketo and dienol tautomers in view of understanding their biological properties. This research enlightens keto-enol tautomerism of 2,4-ditellurouracil and its 5-fluoro derivative with additional insights to biological functions.

A new synthesis of 9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)guanine (AraF-G).

Interesting and very promising antisense properties of 2'-deoxy-2'-fluoroarabinonucleic acids ((a) Wilds, C.J.; Damha, M.J. 2'-Deoxy-2'-fluoroarabinonucleosides and oligonucleotides (2'F-ANA): synthesis and physicochemical studies. Nucl. Acids Res. 2000, 28, 3625-3635; (b) Viazovkina, E.; Mangos, M.; Elzagheid, M.I.; Damha, M.J. Current Protocols in Nucleic Acid Chemistry 2002, 4.15.1-4.15.21) (2'F-ANA) has encouraged our research group to optimize the synthetic procedures for 2'-deoxy-2'-fluoro-beta-D-arabinonucleosides (araF-N). The synthesis of araF-U, araF-T, araF-A and araF-C is straightforward, (Tann, C.H.; Brodfuehrer, P.R.; Brundidge, S.P.; Sapino, C., Jr. Howell H.G. Fluorocarbohydrates in synthesis. An efficient synthesis of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouracil (beta-FIAU) and 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)thymine (beta-FMAU). J. Org. Chem. 1985, 50, 3644-3647; Howell, H.G.; Brodfuehrer, P.R.; Brundidge, S.P.; Benigni, D.A.; Sapino, C., Jr. Antiviral nucleosides. A stereospecific, total synthesis of 2'-fluoro-2'-deoxy-beta-D-arabinofuranosyl nucleosides. J. Org. Chem. 1988, 53, 85-88; Maruyama, T.; Takamatsu, S.; Kozai, S.; Satoh, Y.; Izana, K. Synthesis of 9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine bearing a selectively removable protecting group. Chem. Pharm. Bull. 1999, 47, 966-970) however, the synthesis of the guanine analogue is more complicated and affords poor to moderate yields of araF-G (4) ((a) Elzagheid, M.I.; Viazovkina, E.; Masad, M.J. Synthesis of protected 2'-deoxy-2'-fluoro-beta-D-arabinonucleosides. Synthesis of 2'-fluoroarabino nucleoside phosphoramidites and their use in the synthesis of 2'F-ANA. Current Protocols in Nucleic Acid Chemistry 2002, 1.7.1-1.7.19; (b) Tennila, T.; Azhayeva, E.; Vepsalainen, J.; Laatikainen, R.; Azhayev, A.; Mikhailopulo, I. Oligonucleotides containing 9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-adenine and -guanine: synthesis, hybridization and antisense properties. Nucleosides, Nucleotides and Nucl. Acids 2000, 19, 1861-1884). Here we describe an efficient synthesis of araF-G (4) that involves coupling of 2-deoxy-2-fluoro-3,5-di-O-benzoyl-alpha-D-arabinofuranosyl bromide (1) with 2-chlorohypoxanthine (2) to afford 2-chloro-beta-araF-I (3) in 52% yield. Nucleoside (3) was transformed into araF-G (4) by treatment with methanolic ammonia (150 degrees C, 6 h) in 67% yield.

Synthesis of 2',3'-dideoxy-2'-fluoro-3'-thioarabinothymidine and its 3'-phosphoramidite derivative.

An efficient method for the synthesis of 5'-O-monomethoxytrityl-2',3'-dideoxy-2'-fluoro-3'-thioarabinothymidine [(5'MMT)araF-T(3'SH), (5)] and its 3'-phosphoramidite derivative (6) suitable for automated incorporation into oligonucleotides, is demonstrated. A key step in the synthesis involves reaction of 5'-O-MMT-2,3'-O-anhydrothymidine (4) (Eleuteri, A.; Reese, C.B.; Song, Q. J. Chem. Soc. Perkin Trans. 1 1996, 2237 pp.) with sodium thioacetate to give (5'-MMT)araF-T(3'SAc) (5) (Elzagheid, M.I.; Mattila, K.; Oivanen, M.; Jones, B.C.N.M.; Cosstick, Lönnberg, H. Eur. J. Org. Chem. 2000, 1987-1991). This nucleoside was then converted to its corresponding phosphoramidite derivative, 6, as described previously ((a) Sun, S.; Yoshida, A.; Piccirilli, J.A. RNA, 1997, 3, 1352-1363; (b) Matulic-Adamic, J.; Beigelman, L. Helvetica Chemica Acta 1999, 82, 2141-2150: (c) Fettes, K.J.; O'Neil, I.; Roberts, S.M.; Cosstick, R. Nucleosides, Nucleotides and Nucl. Acids 2001, 20, 1351-1354).

Efficient RNase H-directed cleavage of RNA promoted by antisense DNA or 2'F-ANA constructs containing acyclic nucleotide inserts.

The ability of modified antisense oligonucleotides (AONs) containing acyclic interresidue units to support RNase H-promoted cleavage of complementary RNA is described. Manipulation of the backbone and sugar geometries in these conformationally labile monomers shows great benefits in the enzymatic recognition of the nucleic acid hybrids, while highlighting the importance of local strand conformation on the hydrolytic efficiency of the enzyme more conclusively. Our results demonstrate that the duplexes support remarkably high levels of enzymatic degradation when treated with human RNase HII, making them efficient mimics of the native substrates. Furthermore, interesting linker-dependent modulation of enzymatic activity is observed during in vitro assays, suggesting a potential role for this AON class in an RNase H-dependent pathway of controlling RNA expression. Additionally, the butyl-modified 2'F-ANA AONs described in this work constitute the first examples of a nucleic acid species capable of eliciting high RNase H activity while possessing a highly flexible molecular architecture at predetermined sites along the AON.

Synthesis of protected 2'-deoxy-2'-fluoro-beta-D-arabinonucleosides.

This unit describes in detail the preparation of protected 2'-deoxy-2'-fluoroarabinonucleosides. These building blocks are required for the synthesis of 2'-deoxy-2'-fluoroarabinonucleic acid (2'F-ANA), an oligonucleotide analog exhibiting very promising antisense properties. The preparation of phosphoramidites from these building blocks and the synthesis of 2'F-ANA are described elsewhere in the manual.

Solid-phase synthesis of 2'-deoxy-2'-fluoro- beta-D-oligoarabinonucleotides (2'F-ANA) and their phosphorothioate derivatives.

This unit describes the chemical synthesis of 2'-deoxy-2'-fluoro-b-D-oligoarabinonucleotides (2'F-ANA), both with phosphodiester and phosphorothioate linkages. The protocols described herein include araF phosphoramidite preparation, assembly on DNA synthesizers, and final deprotection and purification of oligonucleotides.