HuskinDB, a database for skin permeation of xenobiotics.

Skin permeation is an essential biological property of small organic compounds our body is exposed to, such as drugs in topic formulations, cosmetics, and environmental toxins. Despite the limited availability of experimental data, there is a lack of systematic analysis and structure. We present a novel resource on skin permeation data that collects all measurements available in the literature and systematically structures experimental conditions.

Extrapolation of in vitro structural alerts for mutagenicity to the in vivo endpoint.

As part of the hazard and risk assessment of chemicals in man, it is important to assess the ability of a chemical to induce mutations in vivo. Because of the commonalities in the molecular initiating event, mutagenicity in vitro can correlate well to the in vivo endpoint for certain compound classes; however, the difficulty lies in identifying when this correlation holds true. In silico alerts for in vitro mutagenicity may therefore be used as the basis for alerts for mutagenicity in vivo where an expert assessment is carried out to establish the relevance of the correlation.

Gram-Scale Synthesis of the (-)-Sparteine Surrogate and (-)-Sparteine.

An 8-step, gram-scale synthesis of the (-)-sparteine surrogate (22 % yield, with just 3 chromatographic purifications) and a 10-step, gram-scale synthesis of (-)-sparteine (31 % yield) are reported. Both syntheses proceed with complete diastereocontrol and allow access to either antipode. Since the syntheses do not rely on natural product extraction, our work addresses long-term supply issues relating to these widely used chiral ligands.

A quantitative in silico model for predicting skin sensitization using a nearest neighbours approach within expert-derived structure-activity alert spaces.

Dermal contact with chemicals may lead to an inflammatory reaction known as allergic contact dermatitis. Consequently, it is important to assess new and existing chemicals for their skin sensitizing potential and to mitigate exposure accordingly. There is an urgent need to develop quantitative non-animal methods to better predict the potency of potential sensitizers, driven largely by European Union (EU) Regulation 1223/2009, which forbids the use of animal tests for cosmetic ingredients sold in the EU.

Predicting skin sensitisation using a decision tree integrated testing strategy with an in silico model and in chemico/in vitro assays.

There is a pressing need for non-animal methods to predict skin sensitisation potential and a number of in chemico and in vitro assays have been designed with this in mind. However, some compounds can fall outside the applicability domain of these in chemico/in vitro assays and may not be predicted accurately. Rule-based in silico models such as Derek Nexus are expert-derived from animal and/or human data and the mechanism-based alert domain can take a number of factors into account (e.

Using in vitro structural alerts for chromosome damage to predict in vivo activity and direct future testing.

While the in vivo genotoxicity of a compound may not always correlate well with its activity in in vitro test systems, for certain compound classes a good overlap may exist between the two endpoints. The difficulty, however, lies in establishing the cases where this relationship holds true and selecting the most appropriate protocol to highlight any potential in vivo hazard. With this in mind, a project was initiated in which existing structural alerts for in vitro chromosome damage in the expert system Derek Nexus were assessed for their relevance to in vivo activity by assessing their predictivity against an in vivo chromosome damage data set.

Establishing Good Computer Modelling Practice (GCMP) in the Prediction of Chemical Toxicity.

This paper suggests guidelines for good computer modelling practice (GCMP) when predicting chemical toxicity, with similar purposes to those for Good Laboratory Practice (GLP). The purpose of GCMP is not to specify what should be delivered with models or predictions but to set out what must be done to ensure that work can be audited, on site, in a way analogous to the auditing of studies conforming to GLP; it is intended to confirm that work has been done properly, as distinct from providing advice on how to do it. Comments are made on the guidelines and how they might be followed, based on practical experience with the implementation of such a scheme in the development of knowledge-based and quantitative structure activity relationship models.

One-ligand catalytic asymmetric deprotonation of a phosphine borane: synthesis of P-stereogenic bisphosphine ligands.

A new protocol for the catalytic asymmetric deprotonation of a phosphine borane using s-BuLi and substoichiometric quantities of chiral diamines is reported. The method involves three sequential additions of s-BuLi, and use of (-)-sparteine or the (+)-sparteine surrogate facilitates access to P-stereogenic phosphines with opposite configuration. The method is exemplified by the catalytic asymmetric synthesis of each enantiomer of precursors to QuinoxP*, trichickenfootphos, and Mini-PHOS.

Catalytic asymmetric deprotonation of phosphine boranes and sulfides as a route to P-stereogenic compounds.

A comparison between phosphine boranes and sulfides in their catalytic asymmetric deprotonation using organolithiums and sub-stoichiometric amounts of (-)-sparteine has revealed superior catalytic efficiency in the phosphine sulfide deprotonation.

Catalytic asymmetric synthesis of ferrocenes and P-stereogenic bisphosphines.

The catalytic asymmetric synthesis of planar chiral ferrocenes and P-stereogenic phosphines and bisphosphines (important classes of chiral ligands for metal-catalyzed asymmetric processes) is successfully demonstrated using n-BuLi or s-BuLi in combination with substoichiometric quantities (0.1-0.5 equiv) of (-)-sparteine or the (+)-sparteine surrogate.