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 (−SiEt3) 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. Subsequent introduction of the left-hand ring system enlisting an aromatic nucleophilic substitution reaction for macrocyclization with biaryl ether formation completed the assemblage of the core bicyclic structure of 1. Intrinsic in the design of the approach and by virtue of the single-step acid-catalyzed conversion of chloropeptin II (1) to chloropeptin I (2), the route also provides a total synthesis of 2.
Full text
Available for:
IJS, KILJ, NUK, PNG, UL, UM
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. In this instance, the complexity of the substrate and the reverse macrocyclization order did not diminish the atropodiastereoselectivity; rather, it provided an improvement over the 4:1 selectivity that was observed with the analogous substrate used to provide the isolated DEF ring system in our first-generation approach. Just as significant, the atroposelectivity represents a complete reversal of the diasteroselectivity observed with analogous macrocyclizations conducted using a Suzuki biaryl coupling.
Full text
Available for:
IJS, KILJ, NUK, PNG, UL, UM
We present a sample of 723 optically selected BL Lac candidates from the Sloan Digital Sky Survey Data Release 7 (SDSS DR7) spectroscopic database encompassing 8250 deg2 of sky; our sample ...constitutes one of the largest uniform BL Lac samples yet derived. Each BL Lac candidate has a high-quality SDSS spectrum from which we determine spectroscopic redshifts for ~60% of the objects. Redshift lower limits are estimated for the remaining objects utilizing the lack of host galaxy flux contamination in their optical spectra; we find that objects lacking spectroscopic redshifts are likely at systematically higher redshifts. Approximately 80% of our BL Lac candidates match to a radio source in FIRST/NVSS, and ~40% match to a ROSAT X-ray source. The homogeneous multiwavelength coverage allows subdivision of the sample into 637 radio-loud BL Lac candidates and 86 weak-featured radio-quiet objects. The radio-loud objects broadly support the standard paradigm unifying BL Lac objects with beamed radio galaxies. We propose that the majority of the radio-quiet objects may be lower-redshift (z < 2.2) analogs to high-redshift weak line quasars (i.e., active galactic nucleus with unusually anemic broad emission line regions). These would constitute the largest sample of such objects, being of similar size and complementary in redshift to the samples of high-redshift weak line quasars previously discovered by the SDSS. However, some fraction of the weak-featured radio-quiet objects may instead populate a rare and extreme radio-weak tail of the much larger radio-loud BL Lac population. Serendipitous discoveries of unusual white dwarfs, high-redshift weak line quasars, and broad absorption line quasars with extreme continuum dropoffs blueward of rest-frame 2800 A are also briefly described.
Increasing volumes of data and computational capacity afford unprecedented opportunities to scale up infectious disease (ID) mapping for public health uses. Whilst a large number of IDs show global ...spatial variation, comprehensive knowledge of these geographic patterns is poor. Here we use an objective method to prioritise mapping efforts to begin to address the large deficit in global disease maps currently available.
Automation of ID mapping requires bespoke methodological adjustments tailored to the epidemiological characteristics of different types of diseases. Diseases were therefore grouped into 33 clusters based upon taxonomic divisions and shared epidemiological characteristics. Disability-adjusted life years, derived from the Global Burden of Disease 2013 study, were used as a globally consistent metric of disease burden. A review of global health stakeholders, existing literature and national health priorities was undertaken to assess relative interest in the diseases. The clusters were ranked by combining both metrics, which identified 44 diseases of main concern within 15 principle clusters. Whilst malaria, HIV and tuberculosis were the highest priority due to their considerable burden, the high priority clusters were dominated by neglected tropical diseases and vector-borne parasites.
A quantitative, easily-updated and flexible framework for prioritising diseases is presented here. The study identifies a possible future strategy for those diseases where significant knowledge gaps remain, as well as recognising those where global mapping programs have already made significant progress. For many conditions, potential shared epidemiological information has yet to be exploited.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Three cocrystal X-ray structures of the α-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 α-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.
The northern limits of three mangrove species—Avicennia germinans (Black Mangrove), Rhizophora mangle (Red Mangrove), Laguncularia racemosa (White Mangrove)—on the United States Atlantic coast are ...vouchered and described in comparison to previous boundaries defined in literature and herbarium collections. The location and general status of individual trees were used to delineate northern maxima and show that present ranges extend beyond historic records. The gradient structure of the ecotone within an area of uniform climate is interpreted as ongoing latitudinal movement.
Full text
Available for:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
A series of α-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., 6, K i = 200 and 260 pM for rat and rhFAAH). With simple and small C5 oxazole substituents, each series bearing a biphenylethyl, phenoxyphenethyl, or (phenoxymethyl)phenethyl C2 side chain was found to follow a well-defined linear relationship between −log K i and Hammett σp of a magnitude (ρ = 2.7–3.0) that indicates that the substituent electronic effect dominates, confirming its fundamental importance to the series and further establishing its predictive value. Just as significantly, the nature of the C5 oxazole substituent substantially impacts the selectivity of the inhibitors whereas the effect of the C2 acyl chain was more subtle but still significant even in the small series examined. Combination of these independent features, which display generalized trends across a range of inhibitor series, simultaneously improves FAAH potency and selectivity and can provide exquisitely selective and potent FAAH inhibitors.
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. A series of small, nonaromatic C5-substituents was also explored and revealed that the K i follows a well-defined correlation with the Hammett σp constant (ρ = 3.01, R 2 = 0.91) in which electron-withdrawing substituents enhance potency, leading to inhibitors with K is as low as 400 pM (20n). Proteomic-wide screening of the inhibitors revealed that most are exquisitely selective for FAAH over all other mammalian proteases, reversing the 100-fold preference of 20a (C5 substituent = H) for the enzyme TGH.
A heteroaromatic 6,7-diaryl-2,3,8,8a-tetrahydroindolizin-5(1
H)-one library was prepared and tested for cytotoxic properties against the HCT-116 colon cancer cell line, thus providing 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 an IC
50 values of 0.27
μM and 0.60
μM, respectively.
A heteroaromatic 6,7-diaryl-2,3,8,8a-tetrahydroindolizin-5(1
H)-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
μM and 0.60
μM, respectively.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A 6,7-diaryl-2,3,8,8a-tetrahydroindolizin-5(1H)-one library was constructed and assayed for cytotoxicity toward the HCT-116 colon cancer cell line. Micromolar and sub-micromolar potencies were ...observed. One of the compounds displayed promising activity in the NCI’s mouse hollow fiber assay.
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 0.39μM and displayed promising activity in vivo in the NCI’s mouse hollow fiber assay.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
PDF
