Although Michael acceptors display a potent and broad spectrum of bioactivity, they have largely been ignored in drug discovery because of their presumed indiscriminate reactivity. As such, a dearth of information exists relevant to the thiol reactivity of natural products and their analogs possessing this moiety. In the midst of recently approved acrylamide-containing drugs, it is clear that a good understanding of the hetero-Michael addition reaction and the relative reactivities of biological thiols with Michael acceptors under physiological conditions is needed for the design and use of these compounds as biological tools and potential therapeutics. This perspective provides information that will contribute to this understanding, such as kinetics of thiol addition reactions, bioactivities, as well as steric and electronic factors that influence the electrophilicity and reversibility of Michael acceptors. This perspective is focused on α,β-unsaturated carbonyls given their preponderance in bioactive natural products.

α-Methylene−γ-lactones are present in ∼3% of known natural products, and compounds comprising this motif display a range of biological activities. However, this reactive lactone limits informed structure−activity relationships for these bioactive molecules. Herein, we describe chemically tuning the electrophilicity of the α-methylene−γ-lactone by replacement with an α-methylene−γ-lactam. Guaianolide analogues having α-methylene−γ-lactams are synthesized using the allenic Pauson−Khand reaction. Substitution of the lactam nitrogen with electronically different groups affords diverse thiol reactivity. Cellular NF-κB inhibition assays for these lactams were benchmarked against parthenolide and a synthetic α-methylene−γ-lactone showing a positive correlation between thiol reactivity and bioactivity. Cytotoxicity assays show good correlation at the outer limits of thiol reactivity but less so for compounds with intermediate reactivity. A La assay to detect reactive molecules by nuclear magnetic resonance and mass spectrometry peptide sequencing assays with the La antigen protein demonstrate that lactam analogues with muted nonspecific thiol reactivities constitute a better electrophile for rational chemical probe and therapeutic molecule design.

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London's Docklands Light Railway (DLR) has been in service for 20 years and has previously been strengthened when it was upgraded from one-car trains to two-car trains in 1990. It is now to be upgraded again to carry three-car trains to be run at higher frequencies and is required to have a fatigue life of 120 years from the year 2010, namely for the structures to remain serviceable until the year 2130. Some of the welds connecting stiffeners to main beams, which were found to be under strength in fatigue, were strengthened by ultrasonic impact treatment (UIT). A programme of fatigue tests has been carried out to evaluate the extent of the improvement and confirm that it is adequate. The tests were on tensile test pieces having non-load-carrying fillet welded attachments relevant to the (BS5400 class F2) under strength welds. Test pieces were pre-fatigued to simulate 20 years' service and treated by ultrasonic impact. The UIT improved the class F2 fillet welds to a performance between class D and class E. There is a 97?5% probability that performance is improved by a factor of 3 on life and the value of s o (the constant amplitude non-propagating design stress range) is raised from 35 to 50 N/mm 2 . The action of UIT is to halt crack propagation from the weld toe and propagation from the root is slowed as it passes through the treated zone. Furthermore, UIT is effective on existing fatigue cracks having an estimated surface length of up to 8 mm and depth of 1?5 mm. Experiences gained from the experimental programme enabled an improved specification for UIT quality control to be developed. These data were used in support of the design work to upgrade the DLR structures and the UIT was successfully applied to the under-strength welds under live loading.