Unciaphenol, an Oxygenated Analogue of the Bergman Cyclization Product of Uncialamycin Exhibits Anti-HIV Activity

Unciaphenol (<b>2</b>), an oxygenated analogue of the Bergman cyclization product of the enediyne uncialamycin (<b>1</b>), has been isolated along with <b>1</b> from cultures of the actinomycete Streptomyces uncialis. It is proposed that the C-22 OH substituent in <b>2</b> might arise from the attack of a nucleophilic oxygen species on the <i>p</i>-benzyne diradical intermediate <b>IA</b> in the Bergman cyclization of <b>1</b>. <b>2</b> shows in vitro anti-HIV activity against viral strains that are resistant to clinically utilized anti-retroviral therapies

Herbicidin Congeners, Undecose Nucleosides from an Organic Extract of <i>Streptomyces</i> sp. L‑9-10

Four new undecose nucleosides (herbicidin congeners), three known herbicidins, and 9-(β-d-arabinofuranosyl)­hypoxanthine (Ara-H) were isolated from the organic extract of a fermentation culture of <i>Streptomyces</i> sp. L-9-10 using proton NMR-guided fractionation. Their structures were elucidated on the basis of comprehensive 1D and 2D NMR and mass spectrometry analyses. These structures included 2′-<i>O</i>-demethylherbicidin F (<b>1</b>), 9′-deoxy-8′,8′-dihydroxyherbicidin B (<b>2</b>), 9′-deoxy-8′-oxoherbicidin B (<b>2a</b>), and the 8′-epimer of herbicidin B (<b>3</b>). This is the first detailed assignment of proton and carbon chemical shifts for herbicidins A, B, and F. The isolated compounds were evaluated for cancer chemopreventive potential based on inhibition of tumor necrosis factor alpha (TNF-α)-induced nuclear factor-kappa B (NF-κB) activity

Affinity Crystallography: A New Approach to Extracting High-Affinity Enzyme Inhibitors from Natural Extracts

Natural products are an important source of novel drug scaffolds. The highly variable and unpredictable timelines associated with isolating novel compounds and elucidating their structures have led to the demise of exploring natural product extract libraries in drug discovery programs. Here we introduce affinity crystallography as a new methodology that significantly shortens the time of the hit to active structure cycle in bioactive natural product discovery research. This affinity crystallography approach is illustrated by using semipure fractions of an actinomycetes culture extract to isolate and identify a cathepsin K inhibitor and to compare the outcome with the traditional assay-guided purification/structural analysis approach. The traditional approach resulted in the identification of the known inhibitor antipain (<b>1</b>) and its new but lower potency dehydration product <b>2</b>, while the affinity crystallography approach led to the identification of a new high-affinity inhibitor named lichostatinal (<b>3</b>). The structure and potency of lichostatinal (<b>3</b>) was verified by total synthesis and kinetic characterization. To the best of our knowledge, this is the first example of isolating and characterizing a potent enzyme inhibitor from a partially purified crude natural product extract using a protein crystallographic approach