<i>RMRP</i> depletion is embryonic lethal.

<p><i>RMRP</i> depletion is embryonic lethal.</p

Targeting of murine <i>RMRP</i>.

<p>A. Murine targeting vector (MTV) B. Southern blot of ES cells following selection for alleles with integrated MTV (the southern probe is shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0026270#pone-0026270-g001" target="_blank">figure 1a</a>) C. PCR analysis of RC (<i>RMRP</i> conditional) pups D. PCR analysis of pups derived from the interbreeding of RC mice and mice expressing CMV-Cre.</p

<i>RMRP</i> depletion leads to reduced levels of <i>RMRP</i> transcript.

<p>Total RNA was produced from E13.5 MEFs and <i>RMRP</i> level was measured by A. qRT-PCR B. Northern blot using either a sense or antisense <i>RMRP</i> probe. Error bars represent SD of three replicas.</p

Genes near <i>RMRP</i> are not essential for cellular viability.

<p>MEFs from E13.5 mice of either A. WT or B. <i>RMRP</i>+/− were transfected with siRNAs targeting <i>Ccdc107</i> or <i>E130</i>. Three days later RNA was extracted from the cells and qRT-PCR was preformed using primers for <i>RMRP</i>, <i>Ccdc107</i> or <i>E130</i>. C. The same cells as in A and B were plated (5000 cells/well) in a 96 well plate and 7 days post transfection cell number was assessed by Cell titer glow. Error bars represent SD of three replicas.</p

<i>RMRP</i> depletion is lethal in early stage embryos.

<p><i>RMRP</i> depletion is lethal in early stage embryos.</p

Discovery of Cytochrome P450 4F11 Activated Inhibitors of Stearoyl Coenzyme A Desaturase

Stearoyl-CoA desaturase (SCD) catalyzes the first step in the conversion of saturated fatty acids to unsaturated fatty acids. Unsaturated fatty acids are required for membrane integrity and for cell proliferation. For these reasons, inhibitors of SCD represent potential treatments for cancer. However, systemically active SCD inhibitors result in skin toxicity, which presents an obstacle to their development. We recently described a series of oxalic acid diamides that are converted into active SCD inhibitors within a subset of cancers by CYP4F11-mediated metabolism. Herein, we describe the optimization of the oxalic acid diamides and related <i>N</i>-acyl ureas and an analysis of the structure–activity relationships related to metabolic activation and SCD inhibition

Discovery of Cytochrome P450 4F11 Activated Inhibitors of Stearoyl Coenzyme A Desaturase

Stearoyl-CoA desaturase (SCD) catalyzes the first step in the conversion of saturated fatty acids to unsaturated fatty acids. Unsaturated fatty acids are required for membrane integrity and for cell proliferation. For these reasons, inhibitors of SCD represent potential treatments for cancer. However, systemically active SCD inhibitors result in skin toxicity, which presents an obstacle to their development. We recently described a series of oxalic acid diamides that are converted into active SCD inhibitors within a subset of cancers by CYP4F11-mediated metabolism. Herein, we describe the optimization of the oxalic acid diamides and related <i>N</i>-acyl ureas and an analysis of the structure–activity relationships related to metabolic activation and SCD inhibition

Synthesis and Biological Evaluation of Kibdelone C and Its Simplified Derivatives

Poylcyclic tetrahydroxanthones comprise a large class of cytototoxic natural products. No mechanism of action has been described for any member of the family. We report the synthesis of kibdelone C and several simplified analogs. Both enantiomers of kibdeleone C show low nanomolar cytotoxicity toward multiple human cancer cell lines. Moreover, several simplified derivatives with improved chemical stability display higher activity than the natural product itself. In vitro studies rule out interaction with DNA or inhibition of topoisomerase, both of which are common modes of action for polycyclic aromatic compounds. However, celluar studies reveal that kibdelone C and its simplified derivatives disrupt the actin cytoseketon without directly binding actin or affecting its polymerization in vitro