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Synthesised from N\u2010protected (4<jats:italic>R<\/jats:italic>)\u2010aza\u2010cyclopentenone <jats:bold>5<\/jats:bold>, the exocyclic alkene was installed using a modified Baylis\u2010Hillman type aldol reaction, whereby carbon\u2010carbon bond formation is accompanied by dehydration. In this manner octanal and octenal, for example, can be introduced to mimic the \u03c9\u2010group present in the natural prostaglandins. Similarly, a focused range of alternative substituents were introduced using different aldehydes and ketones. The presence of the <jats:italic>tert\u2010<\/jats:italic>butyloxycarbonyl (Boc) group on the 4\u2010amino\u2010cyclopentenone substituent enabled subsequent derivatisation and various electrophiles were successfully incorporated. The ability of the family of 4\u2010amino functionalised cross\u2010conjugated cyclopentenones to block activation of nuclear factor\u2010kappa B (NF\u2010\u03baB) was studied and compared with the natural prostanoid, \u0394<jats:sup>12,14<\/jats:sup>\u201015\u2010deoxy\u2010PGJ<jats:sub>2<\/jats:sub> (<jats:bold>2<\/jats:bold>). Thereafter, the synthesis of a series of thiol adducts from these compounds were prepared and similarly evaluated biologically. The adducts showed comparable and, on occasion, more potent inhibition of NF\u2010\u03baB than their cyclopentenone precursors and generally demonstrated diminished cytotoxicity. For example, cross\u2010conjugated dieneone <jats:bold>12<\/jats:bold> inhibited the activation of NF\u2010\u03baB with an IC<jats:sub>50<\/jats:sub> value of 6.2\u2005\u03bcM, whereas its endocyclic <jats:italic>N<\/jats:italic>\u2010Boc (<jats:bold>27<\/jats:bold>) and <jats:italic>N<\/jats:italic>\u2010acetyl (<jats:bold>28<\/jats:bold>) cysteine adducts blocked NF\u2010\u03baB activity with values of 1.0 and 8.0\u2005\u03bcM respectively.<\/jats:p>","DOI":"10.1002\/cmdc.202400823","type":"journal-article","created":{"date-parts":[[2024,12,8]],"date-time":"2024-12-08T22:29:56Z","timestamp":1733696996000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["4\u2010Aza Cyclopentenone Prostaglandin Analogues: Synthesis and NF\u2010\u03baB Inhibitory 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