In silico prediction of the skin sensitisation potential of non-quinonoid Michael acceptors: new reactivity assessments and evidence based precursor selection
Michael acceptors are well recognised as an important chemical class of potential skin sensitisers. However not all chemicals able to undergo Michael addition reactions in conditions utilised in synthetic organic chemistry are demonstrable skin sensitisers and some initially unreactive compounds may be metabolised, hydrolysed or oxidised to sensitising Michael acceptors.
This is reflected in the relatively complex scopes of skin sensitisation alerts in Derek Nexus. The released knowledge base (2015.1.0) has eight principal alerts that cover skin sensitisation potential for non-quinonoid Michael acceptors or their precursors. These have now been critically reviewed, refined and updated using advances in available data and mechanistic understanding. For example, earlier studies [e.g. Franot et al 1994, Chem. Res. Toxicol. 7, 297-306] suggested that beta elimination reactions of beta-halo carbonyl compounds could produce unsaturated Michael substrates in the skin. However, the scarcity of relevant supporting examples and the possibility of direct (e.g. SN2) reactivity of many of these so-called Michael substrate “precursors”, has led to the re-evaluation of the in vivo relevance of this mechanism.
As a result the range of qualifying precursors has been reduced. Appropriate alpha and beta substituents that determine the quantitative reactivity has been further investigated and refined, and three new alerts covering sub-classes of Michael acceptors with distinctive mechanisms added, e.g. for cyclopropenones and cyanoacrylates, enhancing the accuracy of the quantitative EC3 predictions. The revised set of alerts, is better supported and shows improved accuracy and sensitivity of qualitative predictions (94% vs 78% earlier).
Presented by Dr Martin Payne at the 2017 EUROTOX meeting.