The over-expression of the Mcl-1 protein in cancerous cells results in the sequestering of Bak, a key component in the regulation of normal cell apoptosis. Our investigation of the ability of marine-derived small molecule natural products to inhibit this protein-protein interaction led to the isolation of several bioactive oxy-polyhalogenated diphenyl ethers. A semi-pure extract, previously obtained from Dysidea (Lamellodysidea) herbacea and preserved in our repository, along with an untouched Dysidea granulosa marine sponge afforded 13 distinct oxy-polyhalogenated diphenyl ethers. Among these isolates were four new compounds, 5, 6, 10, and 12. The structure elucidation of these molecules was complicated by the plethora of structural variants that exist in the literature. During dereplication, we established a systematic method for analyzing this class of compounds. The strategy is governed by trends in the 1H and 13C NMR shifts of the aromatic rings and the success of the strategy was checked by X-ray crystal structure analysis.

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Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common form of dementia, affecting more than 5.4 million people in the USA. Although the cause of AD is not well understood, the cholinergic, amyloid and tau hypotheses were proposed to explain its development. Drug discovery for AD based on the cholinergic and amyloid theories have not been effective. In this article we summarize tau-based natural products as AD therapeutics from a variety of biological sources, including the anti-amyloid agent curcumin, isolated from turmeric, the microtubule stabilizer paclitaxel, from the Pacific Yew Taxus brevifolia, and the Streptomyces-derived Hsp90 inhibitor, geldanamycin. The overlooked approach of clearing tau aggregation will most likely be the next objective for AD drug discovery.

The focus of this study was on the bastadin class of bromotyrosine derivatives, commonly isolated from Ianthella marine sponges, and is the first report on the secondary metabolites from Ianthella cf. reticulata. Two new bastadins were isolated, (E,Z)-bastadin 19 (1b), a diastereoisomer of the known (E,E)-bastadin 19 (1a), and dioxepine bastadin 3 (2), an unusual dibenzo-1,3-dioxepine. A bastadin NMR database was created and assisted in the structure determination of 1b, 2 and the rapid dereplication of ten other known compounds including bastadins 2–9 (3-10), 13 (11) and 19 (1a). The geometry of the 2-(hydroxyimino)-N-alkylamide chains, a chemical feature present in all bastadins, was further probed and new insights regarding the natural oxime configuration are discussed. Bastadins possessing (E,Z), (Z,E) or (E,E)-dioxime configurations could be artifacts of isolation or storage in solution. Therefore, this point was explored by photochemical and thermal isomerization studies, as well as molecular mechanics calculations. Bastadins 13 (11) and 19 (1a) exhibited moderate inhibition against Trypanosoma brucei and bastadin 4 (5) was cytotoxic to HCT-116 colon cancer cells.