Four novel bisulfide bromotyrosine derivatives, psammaplins E (9), F (10), G (11), and H (12), and two new bromotyrosine derivatives, psammaplins I (13) and J (14), were isolated from the sponge Pseudoceratina purpurea, along with known psammaplins A (4), B (6), C (7), and D (8) and bisaprasin (5). The structures of psammaplins E (9) and F (10), which each contain an oxalyl group rarely found in marine organisms, were determined by spectroscopic analysis. Compounds 4, 5, and 10 are potent histone deacetylase inhibitors and also show mild cytotoxicity. Furthermore, compounds 4, 5, and 11 are potent DNA methyltransferase inhibitors. The biogenetic pathway previously proposed for the psammaplins class is also revisited.
A series of N-hydroxy-3-phenyl-2-propenamides were prepared as novel inhibitors of human histone deacetylase (HDAC). These compounds were potent enzyme inhibitors, having IC(50)s < 400 nM in a partially purified enzyme assay. However, potency in cell growth inhibition assays ranged over 2 orders of magnitude in two human carcinoma cell lines. Selected compounds having cellular IC(50) < 750 nM were tested for maximum tolerated dose (MTD) and for efficacy in the HCT116 human colon tumor xenograft assay. Four compounds having an MTD > or = 100 mg/kg were selected for dose-response studies in the HCT116 xenograft model. One compound, 9 (NVP-LAQ824), had significant dose-related activity in the HCT116 colon and A549 lung tumor models, high MTD, and low gross toxicity. On the basis, in part, of these properties, 9 has entered human clinical trials in 2002.
Tanikolide seco acid 2 and tanikolide dimer 3, the latter a novel and selective SIRT2 inhibitor, were isolated from the Madagascar marine cyanobacterium Lyngbya majuscula. The structure of 2, isolated as the pure R enantiomer, was elucidated by an X-ray experiment in conjunction with NMR and optical rotation data, whereas the depside molecular structure of 3 was initially thought to be a meso compound as established by NMR, MS and chiral HPLC analyses. Subsequent total synthesis of the three tanikolide dimer stereoisomers 4, 5, and ent-5, followed by chiral GC-MS comparisons with the natural product, showed it to be exclusively the R,R-isomer 5. Tanikolide dimer 3 (=5) inhibited SIRT2 with an IC50 = 176 nM in one assay format, and 2.4 µM in another. Stereochemical determination of symmetrical dimers such as compound 3 pose intriguing and subtle questions in structure elucidation, and as shown in the current work, are perhaps best answered in conjunction with total synthesis.
This paper outlines the results of a collaborative program begun in 1990 under the NIH National Cooperative Drug Discovery Group (NCDDG) program. It involves the unified research of a multi-institutional group from both academic and corporate laboratories. Our working hypothesis is that targets identified through basic molecular and cell biology studies are relevant for the treatment of human cancers. Thus, a broad range of primary biochemical assays have guided the examination of extracts obtained from marine organisms (both collected and cultured) and purified marine natural products. The goal is to discover small molecules effective against these biological targets. An ever-changing panel of assays focus on a number of cancer relevant targets associated with the cell cycle, signal transduction, angiogenesis or apoptosis. A massive library of materials has been assembled for evaluation in the screens and it consists of more than 900 compounds and 16,000 extracts. We believe that these samples have enormous potential for chemodiveristy and progress to date supports this contention. The first part of the paper focuses on highlights from the period 1995-1999. The two most important developments were that the bengamide and the psammaplin families provided important insights leading to the development of two compounds, LAF-389 and NVP-LAQ824. These were both advanced to Phase I anticancer clinical trials. A sampling of recent discoveries, including current leads in development is also discussed. Attention then turns to new technologies and strategies aimed at shortening the time interval from an initial lead candidate discovery to assessment of its future therapeutic potential.
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