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Structure assigned: The revised structure of (+)‐hexacyclinol (1) proposed recently was confirmed following the total synthesis of the natural product. The synthesis was designed around the highly stereoselective Diels–Alder dimerization of an epoxyquinol monomer, followed by intramolecular acid‐catalyzed cyclization.

[reaction: see text] The asymmetric synthesis of the natural product (+)-epoxyquinol A (1) and related epoxyquinoid dimers, employing a cascade oxidation/electrocyclization/Diels-Alder dimerization sequence, is reported. In addition, we show that 1 and related molecules inhibit activation of the transcription factor NF-kappaB.

Rel/nuclear factor-B (NF-B) transcription factors control a variety of cellular processes, such as cell growth and apoptosis, and are continually activated in many human diseases, including chronic inflammatory diseases and cancer. Jesterone dimer (JD) is a synthetic derivative of the natural fungal metabolite jesterone, and JD has previously been shown to be cytotoxic in select tumor cell lines. In this report, we demonstrate that JD is a potent inhibitor of the activation of transcription factor NF-B. Namely, JD inhibits tumor necrosis factor-␣-induced activation of NF-B in mouse 3T3 and human HeLa cells. JD seems to block the induction of the NF-B pathway by inhibiting the inhibitor of B kinase (IKK); that is, treatment of cells with JD blocks phosphorylation of IB␣, inhibits the activity of a constitutively active form of the IKK␤ catalytic subunit, and converts IKK␤ to stable high molecular mass forms. Like JD, a JD-related epoxyquinoid (isotorreyanic acid) inhibits activation of NF-B at 20 M, whereas several other epoxyquinoids that are related to JD, including its parent compound jesterone, do not block activation of NF-B at this concentration. Finally, JD inhibits both proliferation and DNA binding by REL-containing complexes in the human lymphoma SUDHL-4 cell line, and JD activates caspase-3 activity in these cells. In summary, these results suggest that JD induces apoptosis in tumor cells through a mechanism that involves the inhibition of Rel/NF-B activity and demonstrate the usefulness of assessing the bioactivity of synthetic derivatives of natural products.

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