4-Aza Cyclopentenone Prostaglandin Analogues: Synthesis and NF-κB Inhibitory Activities.

Abstract

Inspired by the cyclopentenone family of prostaglandins, a series of 4-aza, cross-conjugated cyclopentenones is described. Synthesised from N-protected (4R)-aza-cyclopentenone 5, the exocyclic alkene was installed using a modified Baylis-Hillman type aldol reaction, whereby carbon-carbon bond formation is accompanied by dehydration. In this manner octanal and octenal, for example, can be introduced to mimic the ω-group present in the natural prostaglandins. Similarly, a focused range of alternative substituents were introduced using different aldehydes and ketones. The presence of the tert-butyloxycarbonyl (Boc) group on the 4-amino-cyclopentenone substituent enabled subsequent derivatisation and various electrophiles were successfully incorporated. The ability of the family of 4-amino functionalised cross-conjugated cyclopentenones to block activation of nuclear factor-kappa B (NF-κB) was studied and compared with the natural prostanoid, Δ^12,14-15-deoxy-PGJ₂ (2). 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-κB than their cyclopentenone precursors and generally demonstrated diminished cytotoxicity. For example, cross-conjugated dieneone 12 inhibited the activation of NF-κB with an IC₅₀ value of 6.2 μM, whereas its endocyclic N-Boc (27) and N-acetyl (28) cysteine adducts blocked NF-κB activity with values of 1.0 and 8.0 μM respectively.