Synthesis and evaluation of 5-lipoxygenase translocation inhibitors from acylnitroso hetero-Diels–Alder cycloadducts

Abstract

Acylnitroso cycloadducts have proven to be valuable intermediates in the syntheses of a plethora of biologically active molecules. Recently, organometallic reagents were shown to open bicyclic acylnitroso cycloadducts and, more interestingly, the prospect of highly regioselective openings was raised. This transformation was employed in the synthesis of a compound with excellent inhibitory activity against 5-lipoxygenase ((±)-4a, IC50 51 nM), an important mediator of inflammation intimately involved in a number of disease states including asthma and cancer. Optimization of the copper-mediated organometallic ring opening reaction was accomplished allowing the further exploration of the biological activity. Synthesis of a number of derivatives with varying affinity for metal binding as well as pendant groups in a range of sizes was accomplished. Analogues were tested in a whole cell assay which revealed a subset of the compounds to be inhibitors of enzyme translocation, a mode of action not previously known and, potentially, extremely important for better understanding of the enzyme and inhibitor development. Additionally, the lead compound was tested in vivo in an established colon cancer model and showed very encouraging anti-tumorogenic properties.

Lipoxygenase and Cyclooxygenase Pathways and Colorectal Cancer Prevention

“…These studies support the conclusion that 5-LOX is an important target; they show that blockade of 5-LOX inhibits colon cancer cell proliferation both in vitro and in vivo and they suggest that 5-LOX inhibitors may provide a beneficial chemopreventive therapy in colon cancer [83]. Bolger et al [84] recently developed (±)-4-acylnitroso cycloadducts with excellent inhibitory activity against 5-LOX. One compound was tested in vivo in an established colon cancer APC −Min mouse model and was shown to have antitumorigenic properties.…”

Cyclooxygenases and lipoxygenases in cancer

“…In the past few years, effort has been made in generating and refining 5-LOX inhibitors for the treatment of inflammation, allergies, cardiovascular disease, and cancer [154]. Recently, a new generation of 5-LOX inhibitors has been described and shown to selectively inhibit 5-LOX activity in vitro as well as to decrease the incidence of adenoma in APCmin/+ mice [155]. In addition, novel di-O-prenylated chalcone derivatives have been generated and shown to be potent 5-LOX inhibitors in vivo and to inhibit human breast cancer cell proliferation in vitro [156].…”

Diaryl ether containing N-hydroxycarbamates from nitroso cycloadducts

“…We recently reported synthetic variations of the metal binding groups and found that representative compounds potently inhibit 5-lipoxygenase translocation 5. Herein, report on synthetic elaboration of analogs containing substituents on the distal ring of the diaryl ether.…”

“…The route not only employed regioselective ring opening alkylation chemistry, but also copper-mediated condensation of a phenol and arylboronic acids, as well as a useful one-pot, alumina-mediated transcarbamoylation. Based on our previous studies,5 these compounds are expected to possess significant inhibitory activity against the 5-lipoxygenase enzyme.…”