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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.

Ornithosis was suggested by a routine analysis of tissue specimens from Texas turkey flocks submitted to the Texas AM University Poultry Disease Laboratory at Gonzales on April 30, 1974, and of subsequent specimens from four additional flocks. Subsequently, illness in humans at turkey processing plants in Texas, Nebraska, and Missouri, implicating turkeys from Texas, was confirmed as ornithosis in July 1974; and, associated with this outbreak, ornithosis was suspected as the cause of the death of one human. Action was taken by state and federal poultry disease control and inspection officials, public health agencies, and the turkey industry in Texas.