Identification and design of a novel series of MGAT2 inhibitors

[Acyl CoA]monoacylglycerol acyltransferase 2 (MGAT2) is of interest as a target for therapeutic treatment of diabetes, obesity and other diseases which together constitute the metabolic syndrome. In this Letter we report our discovery and optimisation of a novel series of MGAT2 inhibitors. The development of the SAR of the series and a detailed discussion around some key parameters monitored and addressed during the lead generation phase will be given. The in vivo results from an oral lipid tolerance test (OLTT) using the MGAT2 inhibitor (S)-10, shows a significant reduction (68% inhibition relative to na?ve, p <0.01) in plasma triacylglycerol (TAG) concentration.     

Nucleolar organiser region (NOR) location in karyotypes of Australian ground frogs (family Myobatrachidae)

Nucleolar organiser regions (NORs) were examined in over 90% of the species of Australian ground frogs (familiy Myobatrachidae), including representatives from all twenty currently recognised genera and the three subfamilies. Throughout the family, location of the NOR within the karyotype showed considerable variation yet karyotype morphology showed uniformity. The precise mechanism(s) whereby variation in NOR location evolved while karyotype morphology was unchanged remains uncertain. Comparison of the two major subfamilies showed that the Limnodynastinae had a greater diversity of NOR location than the Myobatrachinae. The limnodynastine genus,Heleioporus, was the only one to show multiple NOR sites in several species. NOR location was particularly stable within most polytypic genera. Differences in NOR location within the remaining polytypic genera (Heleioporus, Limnodynastes, Neobatrachus, Philoria andRanidella) pointed to taxonomic discriminations that were generally consistent with recent proposals based on other criteria.     

An assay for inhibitors of nucleoside transport based upon the use of 5-[125I]iodo-2'-deoxyuridine as permeant

5-[125I]Iodo-2'-deoxyuridine (IdUrd) has been shown to serve as a permeant for the nucleoside transport system of human erythrocytes and to be matabolically inert in these cells. Linear initial velocities were obtained at 20 degrees C for 125IdUrd transport, yielding a Km of 73 +/- 18 microM (n = 6). Low-affinity inhibitors of 125IdUrd transport, such as adenosine (Ki = 32 +/- 2 microM, n = 2), could be characterized by Michaelis-Menten kinetics. However, high-affinity inhibitors, such as 6-[(4-nitrobenzyl)thio]-9-beta-D-ribofuranosylpurine, caused nonlinear initial velocities when added to the cells simultaneously with 125IdUrd. Conditions were defined (viz., 20-min pretreatment of cells with test compound followed by 5.0-min incubation with 1.0 microM 125IdUrd, all at 20 degrees C) whereby high-affinity inhibitors of IdUrd transport can be identified and evaluated according to their 50% inhibitory concentrations. The use of 125IdUrd as permeant greatly expedites the testing of compounds as inhibitors of nucleoside transport by allowing the cell pellets generated in these assays to be monitored directly in a gamma spectrometer, thereby circumventing the solubilization and decolorization of cell pellets required by assays that use 3H- or 14C-labeled nucleoside permeants.     

Quaternary structure of the hydroxylamine oxidoreductase from Nitrosomonas europaea

The hydroxylamine oxidoreductase from Nitrosomonas europaea was prepared to apparent electrophoretic homogeneity. Electron microscopy of negatively stained preparations of the sample revealed an overall diameter of about 8.8 nm of the enzyme particle. The native structure was determined as a tetrahedron-like assembly of identical subunits exhibiting four protein masses.Abbreviations ESI Electron spectroscopic imaging - HAO Hydroxylamine oxidoreductase     

Polyploidy in the Australian leptodactylid frog genus Neobatrachus

Karyotypic analysis of six species of the Australian leptodactylid frog genus Neobatrachus showed that N. pictus, N. centralis, N. pelobatoides and N. wilsmorei are diploid (2n=24) while N. sudelli and N. sutor are tetraploid (4n=48). Polyploidy has not been reported previously among Australian anurans. Idiograms of the six species indicate that they are similar to the other Australian leptodactylids so far discribed. DNA values of the tetraploids are approximately double the values for diploids. Tetraploid nuclear and cell sizes are greater compared with diploids but total body size shows no increase. At diakinesis in primary spermatocytes of tetraploids, mainly tetravalents together with a few bivalents are present. Silver staining of metaphase spreads clearly demonstrates the location of NORs at the secondary constrictions and their frequent association in the tetraploid N. sutor. Nucleolar number in interphase nuclei provides a reliable guide for distinguishing tetraploid from diploid frogs in the absence of chromosome analysis and can be determined for both living and preserved specimens. The possible origins and relationships of the tetraploid species are discussed.     

Enantiomeric selectivity of carbovir transport.

Carbovir (9-[4 alpha-(hydroxymethyl)cyclopent-2-ene-1 alpha-yl]guanine) (CBV) is a carbocyclic analogue of 2',3'-dideoxyguanosine that exhibits potent and selective in vitro activity against human immunodeficiency virus. Antiviral activity is associated with only the (-)-enantiomer. The transport characteristics of both (-)-CBV and (+)-CBV were investigated in human erythrocytes at 37 degrees C using a papaverine-stop assay. The influx of both enantiomers appeared saturable and was inhibited greater than 90% by a combination of adenine (a low Km permeant of the nucleobase carrier) and dilazep (a potent inhibitor of nucleoside transport). The influx of (-)-CBV and (+)-CBV proceeded primarily via the nucleobase carrier with Vmax (picomoles/second/5 microliters of cells)/Km (millimolar) values of 17/0.12 and 140/1.9, respectively. To a lesser extent, the influx of (-)-CBV and (+)-CBV also occurred via the nucleoside transporter. Although both compounds exhibited a similar low affinity for this latter carrier (Km approximately 2 mM), the Vmax for (-)-CBV influx was approximately 4-fold higher than the Vmax for (+)-CBV influx. We conclude that both CBV enantiomers enter human erythrocytes by two transporters that are enantiomerically selective.     

Long-term platinum retention after treatment with cisplatin and oxaliplatin

Background  

The aim of this study was to evaluate long-term platinum retention in patients treated with cisplatin and oxaliplatin.