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The mammalian mel‐18/bmi‐1 gene products share an amino acid sequence and a secondary structure, including a RING‐finger motif, with the Drosophila Polycomb group (PcG) gene products Psc and Su(z)2, implying that they represent a gene family with related functions. As Drosophila PcG gene products are thought to function as transcriptional repressors by modifying chromatin structure, Mel‐18/Bmi‐1 might be expected to have similar activities. Here we have analyzed the function of mel‐18 and found that Mel‐18 acts as a transcriptional repressor via its target DNA sequence, 5′‐GACTNGACT‐3′. Interestingly, this binding sequence is found within regulatory or non‐coding regions of various genes, including the c‐myc, bcl‐2 and Hox genes, suggesting diverse functions of mel‐18 as the mammalian homolog of the PcG gene. We also demonstrate that mel‐18 has tumor suppressor activity, in contrast to bmi‐1, which has been defined as a proto‐oncogene.

The first examples of catalytic enantioselective ring-opening/cross-metathesis (EROCM) reactions that involve enol ethers are reported. Specifically, we demonstrate that catalytic EROCM of several oxa- and azabicycles, cyclobutenes and a cyclopropene with an alkyl- or aryl-substituted enol ether proceed readily in the presence of a stereogenic-at-Mo monopyrrolide-monoaryloxide. In some instances, as little as 0.15 mol % of the catalytically active alkylidene is sufficient to promote complete conversion within 10 minutes. The desired products are formed in up to 90% yield and >99:1 enantiomeric ratio (er) with the disubstituted enol ether generated in >90% Z selectivity. The enol ether of the enantiomerically enriched products can be easily differentiated from the terminal alkene through a number of functionalization procedures that lead to the formation of useful intermediates for chemical synthesis (e.g., efficient acid hydrolysis to afford the enantiomerically enriched carboxaldehyde). In certain cases, enantioselectivity is strongly dependent on enol ether concentration: larger equivalents of the cross partner leads to the formation of products of high enantiomeric purity (versus near racemic products with one equivalent). The length of reaction time can be critical to product enantiomeric purity; high enantioselectivity in reactions that proceed to >98% conversion in as brief a reaction time as 30 seconds can be nearly entirely eroded within 30 minutes. Mechanistic rationale that accounts for the above characteristics of the catalytic process is provided.

[reaction: see text] The reaction of dimedone with 1-(2-alkenoyl)-4-bromo-3,5-dimethylpyrazoles in THF, catalyzed by catalytic amounts of both DBFOX/Ph-nickel(II) perchlorate trihydrate and 2,2,6,6-tetramethylpiperidine, in the presence of acetic anhydride in THF produces the corresponding enol lactones in high enantioselectivities through enantioselective Michael additions followed by cyclization with removal of the pyrazole auxiliary. Other related nucleophile precursors can be successfully applied in the enantioselective enol lactone synthesis under the double catalytic conditions.

Allelic loss of chromosome region 3p21.3 occurs early and frequently in non-small-cell lung cancer, and numerous tumor suppressor genes at this locus may be targets of inactivation. Using an incident case series study of non-small-cell lung cancer, we sought to determine the prevalence of loss of heterozygosity (LOH) in the 3p21.3 region and to examine the associations between this alteration and patient outcome, exposure to tobacco smoke, occupational asbestos exposure, and additional molecular alterations in these tumors. We examined LOH at 7 microsatellite markers in the chromosome 3p21.3 region, and LOH was present in at least one of the loci examined in 60% (156 of 258) of the tumors, with the prevalence of LOH at individual loci ranging from 15 to 56%. Occupational asbestos exposure and TP53 mutation were significantly associated with more extensive 3p21 LOH. In squamous cell carcinomas, measures of cumulative smoking dose were significantly lower in patients with LOH at 3p21, particularly in TP53 mutant tumors. Examining patient outcome, we found that in squamous cell carcinomas, having any LOH in this region was associated with a better overall survival (log-rank test, P < 0.04). Together, these results indicate that allelic loss at 3p21 can affect patient outcome, and that this loss may initially be related to carcinogen exposure, but that extension of this loss is related to TP53 mutation status and occupational asbestos exposure.

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In this paper we report on the asymmetric 1,3-dipolar cycloaddition reactions of nitrile oxides mediated by pybox/ytterbium triflates, -/magnesium bromide, and -/magnesium perchlorate. It was confirmed that the reactions proceed smoothly to give isoxazoline derivatives in high enantiomeric excesses with Mg 2+ or Yb 3+ complexes and acrylamide dipolarophiles bearing an oxazolidinone or imidazolidinone coordination auxiliary as well as a pybox ligand. In reactions with a dipolarophile bearing 4,4-dimethyloxazolidinone as the coordination auxiliary, an enantiomeric excess (59 % ee) of the corresponding cycloaddition product was achieved by using a slow addition technique to generate nitrile oxides in