Isolation and Identification of 3,4-Seco-Solanidine-3,4-dioic acid (SSDA) as a Urinary Biomarker of Cytochrome P450 2D6 (CYP2D6) Activity.

Cytochrome P450 2D6 (CYP2D6), is responsible for the metabolism and elimination of approximately 25% of clinically used drugs, including antidepressants and antipsychotics, and its activity varies considerably on a population basis primary due to genetic variation. CYP2D6 phenotype can be assessed in vivo following administration of an exogenous probe compound, such as dextromethorphan or debrisoquine, but use of a biomarker that does not require administration of an exogenous compound (i.e., drug) has considerable appeal for assessing CYP2D6 activity in vulnerable populations, such as children. The goal of this study was to isolate, purify and identify an "endogenous" urinary biomarker (M1; m/z 444.3102) of CYP2D6 activity reported previously. Several chromatographic separation techniques (reverse phase HPLC, cation exchange and analytical reverse phase UPLC) were used to isolate and purify 96 µg of M1 from 40 L of urine. Subsequently, 1D and 2D NMR, and functional group modification reactions were used to elucidate its structure. Analysis of mass spectrometry and NMR data revealed M1 to have similar spectroscopic features to the nitrogen-containing steroidal alkaloid, solanidine. 2D NMR characterization by HMBC, COSY, TOCSY, and HSQC-TOCSY proved to be invaluable in the structural elucidation of M1; derivatization of M1 revealed the presence of two carboxylic acid moieties. M1 was determined to be a steroidal alkaloid with a solanidine backbone that had undergone C-C bond scission to yield 3,4-seco-solanidine-3,4-dioic acid (SSDA). SSDA may have value as a dietary biomarker of CYP2D6 activity in populations where potato consumption is common. Significance Statement Endogenous biomarkers of processes involved in drug disposition and response may allow improved individualization of drug treatment, especially in vulnerable populations, such as children. Given that several CYP2D6 substrates are commonly used in pediatrics and the ubiquitous nature of potato consumption in western diets, SSDA has considerable appeal as non-invasive biomarker of CYP2D6 activity to guide treatment with CYP2D6 substrates in children and adults.

Structure and properties of [(4,6-tBu2C6H2O)2Se]2An(THF)2, An = U, Np, and their reaction with p-benzoquinone.

The synthesis and characterization of U(iv) and Np(iv) selenium bis(phenolate) complexes are reported. The reaction of two equivalents of the U(iv) complex with p-benzoquinone results in the formation of a U(v)-U(v) species with a bridging reduced quinone. This represents a rare example of high-valent uranium chemistry as well as a rare example of a neptunium aryloxide complex.

Coordination Chemistry and QTAIM Analysis of Homoleptic Dithiocarbamate Complexes, M(S2CNiPr2)4 (M = Ti, Zr, Hf, Th, U, Np).

In a systematic approach to comparing the molecular structure and bonding in homoleptic transition-metal and actinide complexes, a series of dithiocarbamates, M(S2CNiPr2)4 (M = Ti, Zr, Hf, Th, U, Np), have been synthesized. These complexes have been characterized through spectroscopic and X-ray crystallographic analysis, and their bonding has been examined using density functional theory calculations. Computational results indicate that the covalent character associated with the M-S bonds shows the trend of Hf < Zr < Th < Ti < U ≈ Np.

Formation of Methane versus Benzene in the Reactions of (C5 Me5 )2 Th(CH3 )2 with [CH3 PPh3 ]X (X=Cl, Br, I) Yielding Thorium-Carbene or Thorium-Ylide Complexes.

The reaction of (C5 Me5 )2 Th(CH3 )2 with the phosphonium salts [CH3 PPh3 ]X (X=Cl, Br, I) was investigated. When X=Br and I, two equivalents of methane are liberated to afford (C5 Me5 )2 Th[CHPPh3 ]X, rare terminal phosphorano-stabilized carbenes with thorium. These complexes feature the shortest thorium-carbon bonds (≈2.30 Å) reported to date, and electronic structure calculations show some degree of multiple bonding. However, when X=Cl, only one equivalent of methane is lost with concomitant formation of benzene from an unstable phosphorus(V) intermediate, yielding (C5 Me5 )2 Th[κ2 -(C,C')-(CH2 )(CH2 )PPh2 ]Cl. Density functional theory (DFT) investigations of the reaction energy profiles for [CH3 PPh3 ]X, X=Cl and I showed that in the case of iodide, thermodynamics prevents the production of benzene and favors formation of the carbene.

Uranium(iii) and thorium(iv) alkyl complexes as potential starting materials.

The synthesis and characterisation of a rare U(iii) alkyl complex, U[η4-Me2NC(H)C6H5]3, using the dimethylbenzylamine (DMBA) ligand has been accomplished. While attempting to prepare the U(iv) compound, reduction to the U(iii) complex occurred. In the analogous Th(iv) system, C-H bond activation of a methyl group of one dimethylamine was observed yielding Th[η4-Me2NC(H)C6H5]2[η5-(CH2)MeNC(H)C6H5] with a dianionic DMBA ligand. The utility of these complexes as starting materials has been analyzed using a bulky dithiocarboxylate ligand to yield tetravalent actinide species.

Insertion of (t)BuNC into thorium-phosphorus and thorium-arsenic bonds: phosphaazaallene and arsaazaallene moieties in f element chemistry.

The reactivity of thorium-phosphido and thorium-arsenido bonds was probed using tert-butyl isocyanide, (t)BuNC. Reaction of (C5Me5)2Th[E(H)R]2, E = P, As; R = 2,4,6-(i)Pr3C6H2, 2,4,6-Me3C6H2 with (t)BuNC affords the first phosphaazaallene and arsaazaallene moieties with an f-element.

Dithio- and Diselenophosphinate Thorium(IV) and Uranium(IV) Complexes: Molecular and Electronic Structures, Spectroscopy, and Transmetalation Reactivity.

We report a comparison of the molecular and electronic structures of dithio- and diselenophosphinate, (E2PR2)(1-) (E = S, Se; R = (i)Pr, (t)Bu), with thorium(IV) and uranium(IV) complexes. For the thorium dithiophosphinate complexes, reaction of ThCl4(DME)2 with 4 equiv of KS2PR2 (R = (i)Pr, (t)Bu) produced the homoleptic complexes, Th(S2P(i)Pr2)4 (1S-Th-(i)Pr) and Th(S2P(t)Bu2)4 (2S-Th-(t)Bu). The diselenophosphinate complexes were synthesized in a similar manner using KSe2PR2 to produce Th(Se2P(i)Pr2)4 (1Se-Th-(i)Pr) and Th(Se2P(t)Bu2)4 (2Se-Th-(t)Bu). U(S2P(i)Pr2)4, 1S-U-(i)Pr, could be made directly from UCl4 and 4 equiv of KS2P(i)Pr2. With (Se2P(i)Pr2)(1-), using UCl4 and 3 or 4 equiv of KSe2P(i)Pr2 yielded the monochloride product U(Se2P(i)Pr2)3Cl (3Se-U(iPr)-Cl), but using UI4(1,4-dioxane)2 produced the homoleptic U(Se2P(i)Pr2)4 (1Se-U-(i)Pr). Similarly, the reaction of UCl4 with 4 equiv of KS2P(t)Bu2 yielded U(S2P(t)Bu2)4 (2S-U-(t)Bu), whereas the reaction with KSe2P(t)Bu2 resulted in the formation of U(Se2P(t)Bu2)3Cl (4Se-U(tBu)-Cl). Using UI4(1,4-dioxane)2 and 4 equiv of KSe2P(t)Bu2 with UCl4 in acetonitrile yielded U(Se2P(t)Bu2)4 (2Se-U-(t)Bu). Transmetalation reactions were investigated with complex 2Se-U-(t)Bu and various CuX (X = Br, I) salts to yield U(Se2P(t)Bu2)3X (6Se-U(tBu)-Br and 7Se-U(tBu)-I) and 0.25 equiv of [Cu(Se2P(t)Bu2)]4 (8Se-Cu-(t)Bu). Additionally, 2Se-U-(t)Bu underwent transmetalation reactions with Hg2F2 and ZnCl2 to yield U(Se2P(t)Bu2)3F (6) and U(Se2P(t)Bu2)3Cl (4Se-U(tBu)-Cl), respectively. The molecular structures were analyzed using (1)H, (13)C, (31)P, and (77)Se NMR and IR spectroscopy and structurally characterized using X-ray crystallography. Using the QTAIM approach, the electronic structure of all homoleptic complexes was probed, showing slightly more covalent bonding character in actinide-selenium bonds over actinide-sulfur bonds.

Formation of a Bridging Phosphinidene Thorium Complex.

The synthesis and structural determination of the first thorium phosphinidene complex are reported. The reaction of 2 equiv of (C5Me5)2Th(CH3)2 with H2P(2,4,6-(i)Pr3C6H2) at 95 °C produces [(C5Me5)2Th]2(µ2-P[(2,6-CH2CHCH3)2-4-(i)PrC6H2] as well as 4 equiv of methane, 2 equiv from deprotonation of the phosphine and 2 equiv from C-H bond activation of one methyl group of each of the isopropyl groups at the 2- and 6-positions. Transition state calculations indicate that the steps in the mechanism are P-H, C-H, C-H, and then P-H bond activation to form the phosphinidene.

Stabilization of MIV = Ti, Zr, Hf, Ce, and Th using a selenium bis(phenolate) ligand.

We report M(iv) M = Ti, Zr, Hf, Ce, and Th, complexes of a selenium bis(phenolate) ligand, 2,2'-selenobis(4,6-di-tert-butylphenol), (H(2)(Ar)OSeO), 1. Reaction of Ti(NEt(2))(4) with two equivalents of affords Ti((Ar)OSeO)(2), 2. Salt metathesis of ZrCl(4) and HfCl(4) with two equivalents of Na(2)(Ar)OSeO produces Zr((Ar)OSeO)(2)(THF), 3, and Hf((Ar)OSeO)(2)(THF), 4, respectively. Protonolysis of ThCl[N(SiMe(3))(2)](3) with two equivalents of yields Th((Ar)OSeO)(2)(THF)(2), 5. Salt metathesis of Ce(OTf)(3) and two equivalents of Na(2)(Ar)OSeO produces [Na(THF)(3)][Ce((Ar)OSeO)(2)], which was oxidized in situ using 0.5 equivalents of I(2) to yield the diamagnetic Ce(iv) product, Ce((Ar)OSeO)(2)(THF)(2), 6. Addition of 2,2'-bipyridyl to forms Ce((Ar)OSeO)(2)(bipy), 6a. Each diamagnetic complex was characterized using (1)H, (13)C, and (77)Se NMR and IR spectroscopy and the structures of 2-6a were established with X-ray crystallography. Electrochemical measurements using cyclic voltammetry on complexes 2, 5, and 6a re also reported.

Systematic investigation of thorium(IV)- and uranium(IV)-ligand bonding in dithiophosphonate, thioselenophosphinate, and diselenophosphonate complexes.

Homoleptic soft-donor actinide complexes of the general form An[E2PROR']4 were synthesized from salt metathesis between ThCl4(DME)2 or UI4(1,4-dioxane)2 and M[E2PROR'], M = Na, K, to yield 2 (An = Th, E = S, R = 4-MeOC6H4, R' = Me), 3 (An = Th, E = S, R = 4-MeOC6H4, R' = (t)Bu), 4 (An = U, E = S, R = 4-MeOC6H4, R' = Me), 5 (An = Th, E = Se, R = C6H5, R' = Me), and 6 (An = U, E = Se, R = C6H5, R' = Me). In addition thorium and uranium thioselenophosphinate complexes 7 and 8 were produced from the reaction of ThCl4(DME)2 and UI4(1,4-dioxane)2 and Na[SSePPh2], respectively. All compounds were characterized using elemental analysis, (1)H and (31)P NMR, and IR spectroscopy, and the U(IV) compounds were also examined with UV-vis spectroscopy. The (77)Se NMR spectrum of 5 reveals the first reported resonance with a Th-Se bond. The solid-state structures of 2, 5, 7, and 8 were determined by X-ray crystallography. The actinide-ligand bonding was examined using density functional theory calculations in conjunction with quantum theory of atoms-in-molecules analysis and shows slightly increased covalency in actinide-selenium bonds than actinide-sulfur.