Chemogenomic Investigation of AP-1 Transcriptional Regulation of LTC4 Synthase Expression

Asthma has reached epidemic proportions with approximately 200 million individuals affected worldwide. The disease is characterized by an oxidant / antioxidant imbalance in the lungs leading to activation of redox-sensitive transcription factors e.g. activator protein 1 (AP-1) and nuclear factor kappa B (NF-kappa B). We have previously described PNRI-299, a small molecule beta-strand mimetic template compound, as an inhibitor of the multifunctional AP endonuclease / redox factor 1 (Ref-1) [1]. PNRI-299 has demonstrable effects on the reduction of AP-1 driven transcription and beneficial pharmacological effects in a mouse asthma model. We now report the synthesis of this molecule and the effects of PNRI-299 on the expression of Leukotriene C4 (LTC4) synthase, a crucial enzyme for the formation of the cysteinyl leukotrienes.