4-Amidophenol Quinone Methide Precursors: Effective and Broad-Scope Nonoxime Reactivators of Organophosphorus-Inhibited Cholinesterases and Resurrectors of Organophosphorus-Aged Acetylcholinesterase.

Acetylcholinesterase (AChE) inhibition by organophosphorus (OP) compounds poses a serious health risk to humans. While many therapeutics have been tested for treatment after OP exposure, there is still a need for efficient reactivation against all kinds of OP compounds, and current oxime therapeutics have poor blood-brain barrier penetration into the central nervous system, while offering no recovery in activity from the OP-aged forms of AChE. Herein, we report a novel library of 4-amidophenol quinone methide precursors (QMP) that provide effective reactivation against multiple OP-inhibited forms of AChE in addition to resurrecting the aged form of AChE after exposure to a pesticide or some phosphoramidates. Furthermore, these QMP compounds also reactivate OP-inhibited butyrylcholinesterase (BChE) which is an in vivo, endogenous scavenger of OP compounds. The in vitro efficacies of these QMP compounds were tested for reactivation and resurrection of soluble forms of human AChE and BChE and for reactivation of cholinesterases within human blood as well as blood and brain samples from a humanized mouse model. We identify compound 10c as a lead candidate due to its broad-scope efficacy against multiple OP compounds as well as both cholinesterases. With methylphosphonates, compound 10c (250 µM, 1 h) shows >60% recovered activity from OEt-inhibited AChE in human blood as well as mouse blood and brain, thus highlighting its potential for future in vivo analysis. For 10c, the effective concentration (EC50) is less than 25 µM for reactivation of three different methylphosphonate-inhibited forms of AChE, with a maximum reactivation yield above 80%. Similarly, for OP-inhibited BChE, 10c has EC50 values that are less than 150 µM for two different methylphosphonate compounds. Furthermore, an in vitro kinetic analysis show that 10c has a 2.2- and 92.1-fold superior reactivation efficiency against OEt-inhibited and OiBu-inhibited AChE, respectively, when compared to an oxime control. In addition to 10c being a potent reactivator of AChE and BChE, we also show that 10c is capable of resurrecting (ethyl paraoxon)-aged AChE, which is another current limitation of oximes.

Elevated concentrations of crude glycerin in diets for beef cattle: feedlot performance, carcass traits, and ruminal metabolism1.

Three experiments were conducted to evaluate the inclusion of crude glycerin (CG) in diets for beef cattle. In Exp. 1, 4 ruminally cannulated steers were fed diets with 0 or 15% CG (DM basis), to evaluate DM disappearance, VFA profiles, and gas production. There was a tendency for an interaction (P = 0.06) between diet fed to donor animals and substrate fed to in vitro system, and digestion was increased when CG was added to cultures with ruminal fluid from CG-fed animals. Total VFA were unaffected by diets or by substrate incubated. The CG increased production of propionate, butyrate, and valerate (P < 0.01) while the gas production was unaffected (P = 0.16). In Exp. 2, 24 crossbred heifers (334.4 ± 0.9 kg BW) were fed the same diets as Exp. 1, for 35 d. Fecal grab samples were collected 3 times daily on day 7, 21, and 35, to evaluate total tract digestibilities of DM, OM, and NDF. The CG improved digestibility of diet OM (P = 0.04), and DM followed a similar trend (P = 0.06), while the NDF digestibility was unaffected (P = 0.29). In Exp. 3, crossbred heifers (n = 374; 375.8 ± 36.1 kg BW) were used to evaluate feedlot performance and carcass traits when fed diets with 0, 7.5, or 15% CG, with or without added 0.3% salt. Heifers were assigned to 25 pens and were harvested on day 125. Removing salt from CG-based diets did not impact performance (P = 0.50). The CG did not influence average daily gain (P = 0.27), but decreased DM intake (P = 0.003), USDA Yield Grade (P = 0.01), and improved feed efficiency (P = 0.03), while tended to decrease USDA prime carcasses (P = 0.10). Carcass weight (P = 0.24), Longissimus muscle area (P = 0.63), and kidney, pelvic, heart fat (P = 0.59) were unaffected by CG. Twelfth-rib fat was less for heifers fed 15% CG without salt compared with the other treatments (P = 0.005), while marbling was less for heifers fed CG diets compared with the control-fed animals (linear, P = 0.004; quadratic, P = 0.02). In conclusion, GC can replace dry-rolled corn in diets for beef heifers when fed at 15% of diet DM, improving OM digestion, increasing ruminal propionate and butyrate without affecting greenhouse gas emissions. Feeding up to 15% CG improves feed efficiency but depresses marbling and tends to decrease Quality Grade. Removing supplemental salt from CG-diets has no impact on performance or carcass traits.

Uranium and thorium hydride complexes as multielectron reductants: a combined neutron diffraction and quantum chemical study.

The unusual uranium reaction system in which uranium(4+) and uranium(3+) hydrides interconvert by formal bimetallic reductive elimination and oxidative addition reactions, [(C(5)Me(5))(2)UH(2)](2) (1) ⇌ [(C(5)Me(5))(2)UH](2) (2) + H(2), was studied by employing multiconfigurational quantum chemical and density functional theory methods. 1 can act as a formal four-electron reductant, releasing H(2) gas as the byproduct of four H(2)/H(-) redox couples. The calculated structures for both reactants and products are in good agreement with the X-ray diffraction data on 2 and 1 and the neutron diffraction data on 1 obtained under H(2) pressure as part of this study. The interconversion of the uranium(4+) and uranium(3+) hydride species was calculated to be near thermoneutral (~-2 kcal/mol). Comparison with the unknown thorium analogue, [(C(5)Me(5))(2)ThH](2), shows that the thorium(4+) to thorium(3+) hydride interconversion reaction is endothermic by 26 kcal/mol.

DFT and CASPT2 analysis of polymetallic uranium nitride and oxide complexes: how theory can help when X-ray analysis is inadequate.

Recent studies of organouranium chemistry have provided unusual pairs of similar polymetallic molecules containing (N)(3-) and (O)(2-) ligands, namely [(C(5)Me(5))U(mu-I)(2)](3)(mu(3)-N), 1, and [(C(5)Me(5))U(mu-I)(2)](3)(mu(3)-O), 2, and chair and boat conformations of [(C(5)Me(5))(2)U(mu-N)U(mu-N(3))(C(5)Me(5))(2)](4), 3. These compounds were analyzed by density functional theory and multiconfigurational quantum chemical studies to differentiate nitride versus oxide in molecules for which the crystallographic data were not definitive and to provide insight into the electronic structure and unique chemical bonding of these polymetallic compounds. Calculations were also performed on [(C(5)Me(5))(2)UN(3)(mu-N(3))](3), 4, and [(C(6)F(5))(3)BNU(N[Me]Ph)(3)], 5, for comparison with 1 and 3. On the basis of these results, the complex, [(C(5)Me(5))U(mu(3)-E)](8), 6, for which only low-quality X-ray crystallographic data are available, was analyzed to predict if E is nitride or oxide.

Multi-electron reduction from alkyl/hydride ligand combinations in U4+ complexes.

The U4+ mixed alkyl hydride complex (C5Me5)U[mu-C5Me3(CH2)2](mu-H)2U(C5Me5)2, 1, which contains a cyclopentadienyl ligand with two metalated methylene substituents, can effect four, six, and eight-electron reductions in which the combination of the two H1- ligands and the [C5Me3(CH2)2]3- moiety delivers four electrons and forms (C5Me5)1-. The reaction is formally equivalent to an alkyl hydride reductive elimination, a transformation common with transition metals not previously observed with f element compounds. This type of alkyl hydride reduction reactivity is also observed with a combination of U4+ alkyl and hydride complexes, (C5Me5)2UMe2/[(C5Me5)2UH2]2, which reduces benzene to make [(C5Me5)2U]2(C6H6), a U3+ complex formally containing a (C6H6)2- ligand.

Reductive reactivity of the organolanthanide hydrides, [(C5Me5)2LnH]x, leads to ansa-allyl cyclopentadienyl (eta(5)-C5Me4CH2-C5Me4CH2-eta(3))2- and trianionic cyclooctatetraenyl (C8H7)3- ligands.

The reductive reactivity of lanthanide hydride ligands in the [(C5Me5)2LnH]x complexes (Ln = Sm, La, Y) was examined to see if these hydride ligands would react like the actinide hydrides in [(C5Me5)2AnH2]2 (An = U, Th) and [(C5Me5)2UH]2. Each lanthanide hydride complex reduces PhSSPh to make [(C5Me5)2Ln(mu-SPh)]2 in approximately 90% yield. [(C5Me5)2SmH]2 reduces phenazine and anthracene to make [(C5Me5)2Sm]2(mu-eta(3):eta(3)-C12H8N2) and [(C5Me5)2Sm]2(mu-eta(3):eta(3)-C10H14), respectively, but the analogous [(C5Me5)2LaH]x and [(C5Me5)2YH]2 reactions are more complicated. All three lanthanide hydrides reduce C8H8 to make (C5Me5)Ln(C8H8) and (C5Me5)3Ln, a reaction that constitutes another synthetic route to (C5Me5)3Ln complexes. In the reaction of [(C5Me5)2YH]2 with C8H8, two unusual byproducts are obtained. In benzene, a (C5Me5)Y[(eta(5)-C5Me4CH2-C5Me4CH2-eta(3))] complex forms in which two (C5Me5)(1-) rings are linked to make a new type of ansa-allyl-cyclopentadienyl dianion that binds as a pentahapto-trihapto chelate. In cyclohexane, a (C5Me5)2Y(mu-eta(8):eta(1)-C8H7)Y(C5Me5) complex forms in which a (C8H8)(2-) ring is metalated to form a bridging (C8H7)(3-) trianion.

Analysis of uranium azide and nitride complexes by atmospheric pressure chemical ionization mass spectrometry.

Atmospheric pressure chemical ionization mass spectrometry (APCI-MS) has been used to characterize the air-sensitive paramagnetic organouranium azide and nitride complexes [(C5Me5)2UN3(mu-N3)]3 and [(C5Me5)U(mu-I)2]3N, respectively. The trimetallic complex [(C5Me5)U(mu-I)2]3E had been identified by X-ray crystallography, but the data did not definitively identify E as N3- versus O2- or (OH)-, a common problem in heavy-element nitride complexes involving metals with variable oxidation states. A comparison of the 250 degrees C APCI-MS spectra of products made from NaN3 and Na15NNN showed mixed [M]+ and [M + H]+ envelopes at expected ion intensities for the 14N and 15N isotopomers. A compilation of U-C(C5Me5) and U-I bond distance data for U3+ and U4+ is also reported that shows that the ranges for the two oxidation states have significant overlap.

Synthesis of (O2CEPh)1- ligands (E = S, Se) by CO2 insertion into lanthanide chalcogen bonds and their utility in forming crystallographically characterizable organoaluminum complexes [Me2Al(mu-O2CEPh)]2.

CO(2) inserts into the Sm-S and Sm-Se bonds of [(C(5)Me(5))(2)Sm(mu-EPh)](2) (E = S, Se) to form the first crystallographically characterized (O(2)CEPh)(1-) complexes, [(C(5)Me(5))(2)Sm(mu-O(2)CEPh)](2). These complexes are structurally analogous to [(C(5)Me(5))(2)Sm(mu-O(2)CR)](2) complexes, but they are less soluble. This feature was utilized in the reaction of Me(2)AlCl with [(C(5)Me(5))(2)Sm(mu-O(2)CEPh)](2), which forms crystallographically characterizable [Me(2)Al(mu-O(2)CEPh)](2) complexes. Such complexes could not be isolated from an analogous carboxylate reaction. [(C(5)Me(5))(2)Sm(mu-O(2)CSePh)](2) decarboxylates in THF to form (C(5)Me(5))(2)Sm(SePh)(THF). The loss of CO(2) rather than COSe with formation of (C(5)Me(5))(2)Sm(OPh)(THF) was established by (13)CO(2) studies and independent synthesis of (C(5)Me(5))(2)Sm(OPh)(THF) from (C(5)Me(5))(2)Sm[N(SiMe(3))(2)] and PhOH.

Genetic differences in lethality of newborn mice treated in utero with coplanar versus non-coplanar hexabromobiphenyl.

Polybrominated biphenyl (PBB) exposure in humans is known to cause immunotoxicity and disorders related to the central nervous system. Coplanar PBBs bind to the aryl hydrocarbon receptor (AHR) in vertebrates. We compared the coplanar PBB, 3,3',4,4',5,5'-hexabromobiphenyl (cHBB), with its stereoisomer, the non-coplanar PBB, 2,2',4,4'6,6'-hexabromobiphenyl (ncHBB), using C57BL/6J (B6) inbred mice (having the high-affinity AHR) and congenic B6.D2-Ahr d mice (having the low-affinity AHR in a >99.8% C57BL/6J genetic background). Pregnant dams were treated i.p. with vehicle alone, cHBB, or ncHBB on gestational day 5 (GD 5). Unexpectedly, neonatal lethality within the first 72 h postpartum was significant in cHBB-treated B6 mice at doses as low as 2.5 mg/kg, whereas no deaths were seen in B6 pups whose mother had received ncHBB 100 mg/kg or in either B6.D2-Ahr d or Ahr(-/-) knockout mice whose mother had received cHBB 100 mg/kg. Histological and gross anatomical analyses of a battery of tissues in the mother or fetus at GD 18, as well as 24 h postpartum, revealed no significant differences, except for decreased thymus and spleen weights in cHBB-treated B6 GD 18 fetuses. Cross-fostering and genetics experiments confirmed the association of neonatal deaths principally with in utero (rather than lactational) exposure to cHBB, and also no paternal effect. For the end points of mouse neonatal lethality and immunotoxicity, cHBB appears to act through the high-affinity AHR receptor. Although dioxin in utero is well known to cause AHR-dependent cleft palate and hydronephrosis, cHBB did not; thus, chronic activation of the AHR appears to be necessary but not sufficient for AHR-mediated teratogenicity.

Synthesis, structure, and ligand-based reduction reactivity of trivalent organosamarium benzene chalcogenolate complexes (C(5)Me(5))(2)Sm(EPh)(THF) and [(C(5)Me(5))(2)Sm(mu-EPh)](2).

To compare the ligand-based reduction chemistry of (EPh)(-) ligands in a metallocene environment to the sterically induced reduction chemistry of the (C(5)Me(5))(-) ligands in (C(5)Me(5))(3)Sm, (C(5)Me(5))(2)Sm(EPh) (E = S, Se, Te) complexes were synthesized and treated with substrates reduced by (C(5)Me(5))(3)Sm: cyclooctatetraene; azobenzene; phenazine. Reactions of PhEEPh with (C(5)Me(5))(2)Sm(THF)(2) and (C(5)Me(5))(2)Sm produced THF-solvated monometallic complexes, (C(5)Me(5))(2)Sm(EPh)(THF), and their unsolvated dimeric analogues, [(C(5)Me(5))(2)Sm(mu-EPh)](2), respectively. Both sets of the paramagnetic benzene chalcogenolate complexes were definitively identified by X-crystallography and form homologous series. Only the (TePh)(-) complexes show reduction reactivity and only upon heating to 65 degrees C.