Inhibitors of \u3cem\u3eN\u3csup\u3eα\u3c/sup\u3e\u3c/em\u3e-acetyl-l-ornithine Deacetylase: Synthesis, Characterization and Analysis of their Inhibitory Potency

A series of N α-acyl (alkyl)- and N α-alkoxycarbonyl-derivatives of l- and d-ornithine were prepared, characterized, and analyzed for their potency toward the bacterial enzyme N α-acetyl-l-ornithine deacetylase (ArgE). ArgE catalyzes the conversion of N α-acetyl-l-ornithine to l-ornithine in the fifth step of the biosynthetic pathway for arginine, a necessary step for bacterial growth. Most of the compounds tested provided IC50 values in the μM range toward ArgE, indicating that they are moderately strong inhibitors. N α-chloroacetyl-l-ornithine (1g) was the best inhibitor tested toward ArgE providing an IC50 value of 85 μM while N α-trifluoroacetyl-l-ornithine (1f), N α-ethoxycarbonyl-l-ornithine (2b), and N α-acetyl-d-ornithine (1a) weakly inhibited ArgE activity providing IC50 values between 200 and 410 μM. Weak inhibitory potency toward Bacillus subtilis-168 for N α-acetyl-d-ornithine (1a) and N α-fluoro- (1f), N α-chloro- (1g), N α-dichloro- (1h), and N α-trichloroacetyl-ornithine (1i) was also observed. These data correlate well with the IC50 values determined for ArgE, suggesting that these compounds might be capable of getting across the cell membrane and that ArgE is likely the bacterial enzymatic target

Rational steering of insulin binding specificity by intra-chain chemical crosslinking

Insulin is a key hormone of human metabolism with major therapeutic importance for both types of diabetes. New insulin analogues with more physiological profiles and better glycemic control are needed, especially analogues that preferentially bind to the metabolic B-isoform of insulin receptor (IR-B). Here, we aimed to stabilize and modulate the receptor-compatible conformation of insulin by covalent intra-chain crosslinking within its B22-B30 segment, using the Cu I -catalyzed Huisgen 1,3-dipolar cycloaddition reaction of azides and alkynes. This approach resulted in 14 new, systematically crosslinked insulin analogues whose structures and functions were extensively characterized and correlated. One of the analogues, containing a B26-B29 triazole bridge, was highly active in binding to both IR isoforms, with a significant preference for IR-B. Our results demonstrate the potential of chemistry-driven modulation of insulin function, also shedding new light on the functional importance of hormones B-chain C-terminus for its IR-B specificity

Synthesis of N-Succinyl-L,L-Diaminopimelic Acid Mimetics Via Selective Protection

The search for potential inhibitors that target so far unexplored bacterial enzyme mono-N-succinyl-L,Ldiaminopimelic acid desuccinylase (DapE) has stimulated a development of methodology for quick and efficient preparation of mono-N-acylated 2,6-diaminopimelic acid (DAP) derivatives bearing the different carboxyl groups or lipophilic moieties on their amino group

The electric field in northern England and southern Scotland: implications for geomagnetically induced currents.

Magnetotelluric (MT) data, in the form of MT tensors, are used to estimate directly the size and spatial distribution of the electric field in northern England and southern Scotland with the aim of predicting the flow of geomagnetically induced currents in power networks in the region. MT and Geomagnetic Deep Sounding data from a number of different field campaigns, at a period of 750 s, are employed. The MT data are cast in the form of telluric vectors which allow a joint hypothetical event analysis of both Geomagnetic Deep Sounding and MT data. This analysis reveals qualitatively the pervasive effects of electric field distortion in the region. Two approaches are taken to understand how the spatial structure of the regional electromagnetic field is affected by local distortions, and what the origin of these distortions might be. The dimensionality, and form of electric field distortion, of the MT tensors is investigated using the Weaver et al. and Bahr classification schemes, and by examining the misfit of a galvanic distortion model as a function of rotation angle. At sites where the galvanic distortion model is found to be appropriate the regional MT tensors are recovered using tensor decomposition techniques. It is found that recovering the regional MT response reconciles the geometry of induced currents implied by the MT data with that of the Magnetic Variation anomalies. Lilley's (1993) central imped ances are used to calculate rotationally invariant effective telluric responses. In the Southern Uplands the magnitude of the effective telluric response is approximately 0.25-0.5 mV/km.nT, but as the Southern Uplands Fault is approached it rises steadily to 3 mV/km.nT. In the Midland Valley, the effective telluric response is approximately 0.5 mV/km.nT which rises steadily to 2.5 mV/km.nT as the Southern Uplands and Highland Boundary Faults are approached to the south-east and north-west respectively. Therefore, the increase in the magnitude of the effective telluric response correlates with the approach of a major tectonic boundary such as the Southern Uplands Fault. These results show that the induced electric field strength varies considerably throughout the central Scotland region. In addition, the Hypothetical Event Analysis indicates that due to lateral changes in conductivity structure the direction of the electric field deviates significantly from the regional direction implied by the polarisation azimuth of the primary geomagnetic induction. Therefore, any attempts to model the flow of geomagnetically induced currents in the region need to account for the spatial variation of both the magnitude and azimuth of the electric field