Transfer of electrophilic NH using convenient sources of ammonia: direct synthesis of N–H sulfoximines from sulfoxides

The transfer of nitrogen atoms is extremely valuable in the preparation of medicinal compounds. Here, a new system for NH transfer is developed to prepare sulfoximines, which are emerging as valuable motifs for drug discovery. This is achieved using readily available sources of nitrogen without the requirement for pre-activation or for metal catalysts in an operationally simple protocol. Mixing ammonium salts with diacetoxyiodobenzene in a choice of solvents directly converts sulfoxides to sulfoximines. The protocol is tolerant of many other functional groups and heterocycles that are important in drug compounds. This is the first example of the use of ammonia sources with diacetoxyiodobenzene providing a source of electrophilic nitrogen. Control and mechanistic studies suggest a short-lived electrophilic intermediate, likely to be PhINH or PhIN+

Excited State Pathways Leading to Formation of Adenine Dimers

International audienceThe reaction intermediate in the path leading to UV-induced formation ofadenine dimers A=A and AA* is identified for the first time quantum mechanically, usingPCM/TD-DFT calculations on (dA)2 (dA: 2′deoxyadenosine). In parallel, its fingerprint isdetected in the absorption spectra recorded on the millisecond time-scale for the singlestrand (dA)20 (dA: 2′deoxyadenosine)

Effect of C5-Methylation of Cytosine on the UV-Induced Reactivity of Duplex DNA: Conformational and Electronic Factors

International audienceC5-methylation of cytosines is strongly correlated with UV-induced mutations detected in skin cancers. Mutational hot-spots appearing at TCG sites are due to the formation of pyrimidine cyclobutane dimers (CPDs). The present study, performedfor the model DNA duplex (TCGTA)3·(TACGA)3 and the constitutive single strands, examines the factors underlying the effect of C5-methylation on pyrimidine dimerization at TCG sites. This effect is quantified for the first time by quantum yields ϕ.They were determined following irradiation at 255, 267, and 282 nm and subsequent photoproduct analysis using HPLC coupled to mass spectrometry. C5-methylation leads to an increase of the CPD quantum yield up to 80% with concomitant decrease of that of pyrimidine(6−4) pyrimidone adducts (64PPs) by at least a factor of 3. The obtained ϕ values cannot be explained only by the change of the cytosine absorption spectrum upon C5-methylation. The conformational and electronic factors that may affect the dimerization reaction are discussed in light of results obtained by fluorescence spectroscopy,molecular dynamics simulations, and quantum mechanical calculations. Thus, it appears that the presence of an extra methyl on cytosine affects the sugar puckering, thereby enhancing conformations of the TC step that are prone to CPD formation but less favorable to 64PPs. In addition, C5-methylation diminishes the amplitude of conformational motions in duplexes; in the resulting stiffer structure, ππ* excitations may be transferred from initially populated exciton states to reactive pyrimidines giving rise to CPDs

Anchoring the Potential Energy Surfaces of Homogenous and Heterogenous Dimers of Formaldehyde and Thiofomaldehyde

This work characterizes five stationary points of the formaldehyde dimer, (CH2O)2, two of which are minima, seven newly-identified stationary points of the formaldehyde/thioformaldehyde (mixed) dimer, CH2O/CH2S, four of which are minima, and five newly-identified stationary points of the thioformaldehyde dimer, (CH2S)2 , three of which are minima. Full geometry optimizations and corresponding harmonic vibrational frequencies were performed on CH2O and CH2S as well as each of the dimer configurations (Figures 3-5). The computations were carried out with second order Møller-Plesset perturbation theory (MP2), with the heavy-auc-cc-pVTZ (haTZ) basis set. Additionally, thirteen density functional theory methods were employed: B3LYP, B3LYP-D3, B3LYP-D3(BJ), TPSS, TPSS-D3, TPSS-D3(BJ), APF, APF-D, M06-2X, M06-2X-D3, N12SX, MN12SX, and VSXC, in conjunction with the 6-311+G(2df,2pd) basis set. Six of these functionals are dispersion corrected with either the original D3 damping function (DFT-D3) or the Becke-Johnson damping function [DFT-D3(BJ)]. Binding energies were computed via the supermolecular approach. Single-point energies were also computed for all optimized structures using explicitly correlated MP2-F12 and CCSD(T)-F12 methods with the haTZ basis set. The (CH2O)2 and CH2O/CH2S global minimum are the same at the MP2, MP2-F12, and CCSD(T) levels of theory. However, MP2 methods overbind (CH2S)2 by as much as 1.1 kcal mol-1, effectively altering the energetic ordering of the (CH2S)2 minima relative to the CCSD(T)-F12 energies

Photooxygenation of Non-Aromatic Heterocycles

Photooxygenation of non-aromatic heterocycles and cyclic compounds containing non-usual heteroatoms, namely silicon, germanium and tellurium has been reviewed. All three types of photooxygenation (Types I-III) can take place. Moreover the heteroatom can be frequently involved endorsing electron-transfer reactions which turn out to be the main pathways, even in singlet oxygen oxygenation. A vast collection of novel and unexpected products are often formed, sometimes in a stereocontrolled manner

Synthesis of fluorinated oxygen- and sulfur-containing heteroaromatics

Milk protein concentrate (79% protein) reconstituted at 13.5% (w/v) protein was heated (90 °C, 25 min, pH 7.2) with or without added calcium chloride. After fractionation of the casein and whey protein aggregates by fast protein liquid chromatography, the heat stability (90 °C, up to 1 h) of the fractions (0.25%, w/v, protein) was assessed. The heat-induced aggregates were composed of whey protein and casein, in whey protein:casein ratios ranging from 1:0.5 to 1:9. The heat stability was positively correlated with the casein concentration in the samples. The samples containing the highest proportion of caseins were the most heat-stable, and close to 100% (w/w) of the aggregates were recovered post-heat treatment in the supernatant of such samples (centrifugation for 30 min at 10,000 × g). κ-Casein appeared to act as a chaperone controlling the aggregation of whey proteins, and this effect was stronger in the presence of αS- and β-casein

Inductive queries for a drug designing robot scientist

It is increasingly clear that machine learning algorithms need to be integrated in an iterative scientific discovery loop, in which data is queried repeatedly by means of inductive queries and where the computer provides guidance to the experiments that are being performed. In this chapter, we summarise several key challenges in achieving this integration of machine learning and data mining algorithms in methods for the discovery of Quantitative Structure Activity Relationships (QSARs). We introduce the concept of a robot scientist, in which all steps of the discovery process are automated; we discuss the representation of molecular data such that knowledge discovery tools can analyse it, and we discuss the adaptation of machine learning and data mining algorithms to guide QSAR experiments