Evidence of avian-mediated long distance dispersal in American tardigrades.

Terrestrial tardigrades, commonly known as "water bears", are part of a phylum of microscopic, aquatic invertebrates famous for cryptobiosis and space travel, but little is known about their modes of dispersal on Earth. Wind is assumed, but not truly demonstrated, to be the major method of global dispersal. Yet, some water bear distribution patterns cannot be explained by patterns of prevailing winds.

Total synthesis of complestatin: development of a Pd(0)-mediated indole annulation for macrocyclization.

Full details of the initial development and continued examination of a powerful intramolecular palladium(0)-mediated indole annulation for macrocyclization closure of the strained 16-membered biaryl ring system found in complestatin (1, chloropeptin II) and the definition of factors impacting its intrinsic atropodiastereoselectivity are described. Its examination and use in an alternative, second-generation total synthesis of complestatin are detailed in which the order of the macrocyclization reactions was reversed from our first-generation total synthesis. In this approach and with the ABCD biaryl ether ring system in place, the key Larock cyclization was conducted with substrate 36 (containing four phenols, five secondary amides, one carbamate, and four labile aryl chlorides) and provided the product 37 (56%) exclusively as a single atropisomer (>20:1, detection limits) possessing the natural (R)-configuration.

X-ray crystallographic analysis of alpha-ketoheterocycle inhibitors bound to a humanized variant of fatty acid amide hydrolase.

Three cocrystal X-ray structures of the alpha-ketoheterocycle inhibitors 3-5 bound to a humanized variant of fatty acid amide hydrolase (FAAH) are disclosed and comparatively discussed alongside those of 1 (OL-135) and its isomer 2. These five X-ray structures systematically probe each of the three active site regions key to substrate or inhibitor binding: (1) the conformationally mobile acyl chain-binding pocket and membrane access channel responsible for fatty acid amide substrate and inhibitor acyl chain binding, (2) the atypical active site catalytic residues and surrounding oxyanion hole that covalently binds the core of the alpha-ketoheterocycle inhibitors captured as deprotonated hemiketals mimicking the tetrahedral intermediate of the enzyme-catalyzed reaction, and (3) the cytosolic port and its uniquely important imbedded ordered water molecules and a newly identified anion binding site. The detailed analysis of their key active site interactions and their implications on the interpretation of the available structure-activity relationships are discussed providing important insights for future design.

Total synthesis of chloropeptin II (complestatin) and chloropeptin I.

The first total synthesis of chloropeptin II (1, complestatin) is disclosed. Key elements of the approach include the use of an intramolecular Larock indole synthesis for the initial macrocyclization, adopting conditions that permit utilization of a 2-bromoaniline, incorporating a terminal alkyne substituent (-SiEt(3)) that sterically dictates the indole cyclization regioselectivity, and benefiting from an aniline protecting group (-Ac) that enhances the atropdiastereoselectivity and diminishes the strained indole reactivity toward subsequent electrophilic reagents. Not only did this key reaction provide the fully functionalized right-hand ring system of 1 in superb conversion (89%) and good atropdiastereoselectivity (4:1 R:S), but it also represents the first reported example of what will prove to be a useful Larock macrocyclization strategy.

Synthesis and evaluation of heteroaromatic 6,7-diaryl-2,3,8,8a-tetrahydroindolizin-5(1H)-ones for cytotoxicity against the HCT-116 colon cancer cell line.

A heteroaromatic 6,7-diaryl-2,3,8,8a-tetrahydroindolizin-5(1H)-one analog library was prepared and tested for cytotoxic properties against the HCT-116 colon cancer cell line, thus providing additional information pertaining to structure-activity relationships for this class of compounds. The most active of the new analogs proved to be the C6 2-thiophene and 3-thiophene analogs with IC(50) values of 0.27 microM and 0.

Enantiospecific synthesis and cytotoxicity of 7-(4-methoxyphenyl)-6-phenyl-2,3,8,8a-tetrahydroindolizin-5(1H)-one enantiomers.

An enantiospecific synthesis was developed to generate both enantiomers of 7-(4-methoxyphenyl)-6-phenyl-2,3,8,8a-tetrahydroindolizin-5(1H)-one. A biological assay utilizing the HCT-116 colon cancer cell line to determine the cytotoxicity of these analogs revealed that only the (R)-enantiomer exhibited appreciable cytotoxicity with an IC(50) value of 0.2 microM.

Optimization of alpha-ketooxazole inhibitors of fatty acid amide hydrolase.

A series of alpha-ketooxazoles containing conformational constraints in the flexible C2 acyl side chain of 2 (OL-135) and representative oxazole C5 substituents were prepared and examined as inhibitors of fatty acid amide hydrolase (FAAH). Exceptionally potent and selective FAAH inhibitors emerged from the series (e.g.

Synthesis, in vitro and in vivo cytotoxicity of 6,7-diaryl-2,3,8,8a-tetrahydroindolizin-5(1H)-ones.

A 6,7-diaryl-2,3,8,8a-tetrahydroindolizin-5(1H)-one library was constructed and tested against the colon cancer cell line HCT-116 as an initial screen for cytotoxic properties. Of this library, the parent compound, in which the southern aromatic ring remains unsubstituted, and the northern aromatic ring carries a 4-methoxy group, exhibited the most potent cytotoxicity with an IC50 value of 0.39 microM and displayed promising activity in vivo in the NCI's mouse hollow fiber assay.

Potent and selective alpha-ketoheterocycle-based inhibitors of the anandamide and oleamide catabolizing enzyme, fatty acid amide hydrolase.

A study of the structure-activity relationships (SAR) of 2f (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed, targeting the 5-position of the oxazole. Examination of a series of substituted benzene derivatives (12-14) revealed that the optimal position for substitution was the meta-position with selected members approaching or exceeding the potency of 2f. Concurrent with these studies, the effect of substitution on the pyridine ring of 2f was also examined.

Differential effects of insulin and dietary amino acids on muscle protein synthesis in adult and old rats.

The potential roles of insulin and dietary amino acids in the regulation of skeletal muscle protein synthesis were examined in adult and old rats. Animals were fed over 1 h with either a 25% or a 0% amino acid/protein meal. In each nutritional condition, postprandial insulin secretion was either maintained or blocked with diazoxide injections.