Chiral recognition of d- and l-amino acids is achieved and mixtures of enantiomers quantified in
the gas phase, using the kinetics of competitive unimolecular fragmentations of trimeric Cu(II)-bound complexes.
Singly charged copper(II)−amino acid cluster ions [CuII(A)(ref*)2−H]+ (A = amino acid; ref* = chiral reference
ligand, selected from among the natural α-amino acids) undergo competitive collision-induced dissociation
(CID) in a quadrupole ion trap to form the dimeric complexes [CuII(A)(ref*)−H]+ and [CuII(ref*)2−H]+. The
abundance ratio of these fragment ions depends strongly on the stereochemistry of the ligands in the precursor
[CuII(A)(ref*)2−H]+ complex ion and specifically on the chirality of the analyte amino acid. The chiral
selectivity, the ratio of the two fragment ion abundances for the complex containing one enantiomer of analyte
expressed relative to that for the fragments of the corresponding complex containing the other enantiomer,
ranges from 0.47 to 11. An energy quantity, Δ(ΔCuIIBDE), is predicted and shown to serve as a thermochemical
indicator of chiral discrimination; its value is calculated from the fragment ion abundance ratios using the
kinetic method of estimating thermochemical quantities from the kinetics of cluster ion dissociation. Large
chiral distinctions are observed with all of the natural chiral α-amino acids, except cysteine and arginine, by
appropriate choice of the reference ligand. The Δ(ΔCuIIBDE) values range from −2.2 to 6.9 kJ/mol. Amino
acids with aromatic substituents display the largest chiral distinction, which is consistent with ligand exchange
chromatographic results for analogous systems. The structures of the fragment Cu(II) complexes are discussed
in the light of the CID behavior of related compounds. The interactions within these ions that might contribute
to chiral recognition are rationalized to account for the observed chiral effects. The sensitive nature of the
methodology and the linear relationship between the logarithm of the fragment ion abundance ratio and the
optical purity, which is intrinsic to the kinetic method, allows mixtures to be analyzed for small enantiomeric
excess (ee) by simply recording ratios of fragment ion abundances in a mass spectrum.
Chiral recognition of d- and l-amino acids is achieved in the gas phase on the basis of the kinetics of competitive fragmentations of trimeric Cu(II)-bound complexes. The singly charged copper(II)-amino acid trimeric cluster ions [A(2)BCu(II) - H](+) dissociate to form [A(2)Cu(II) - H](+) and [ABCu(II) - H](+) upon collision-induced dissociation (CID) in a quadrupole ion trap. The abundance ratios of these fragments depend strongly on the stereochemistry of the ligands in the [A(2)BCu(II) - H](+) complex ion. The kinetic method was used to calculate relative Cu ion affinities (ΔCu(II)') for homo- and heterochiral copper(II)-bound dimeric cluster ions as the indicator of chiral discrimination. Six amino acids of four different types showed chiral distinctions which ranged from 0 to 6.5 kJ/mol in terms of values of ΔCu(II)' with abundance ratios, referenced to the other enantiomer, ranging from 1 to 9.2. Amino acids with aromatic substituents displayed the largest chiral distinction, which correlates well with reported chromatographic results. The methodology presented here provides a sensitive means to study enantiomers by mass spectrometry, and initial results show that it is applicable to measurement of enantiomeric excess.
Some α-amino acids, especially arginine, form protonated clusters when examined by electrospray ionization in an ion trap mass spectrometer. Singly-, doubly-, triply-and quadruply-protonated arginine clusters [(Arg) n + H] + , [(Arg) m + 2H] +2 , [(Arg) l + 3H] +3 and [(Arg) k + 4H] +4 , were further studied by collision-induced dissociation (CID). The singly-protonated cluster n = 4 displayed enhanced stability and CID of larger clusters (n > 4) showed fragmentation leading to the preferential formation of n = 4 product ions. The n = 4 stable cluster is proposed to bear a formal resemblance to the simple salt cluster [(NaCl) 4 + Na] + , a 3 × 3 × 1 micro-crystallite. This leads to the suggestion that [(Arg) 4 + H] + is planar, with bonding primarily due to the electrostatic interactions between four zwitterionic arginine molecules. In the doubly-charged ion series, clusters of m = 12-15 have enhanced stability relative to those of immediately smaller size. Drawing on the analogous salt structures, the dication, [(Arg) 12 + 2H] +2 might have a structure consisting of three layers of tetramers, two of which are protonated. This structure is analogous to that of the magic number doubly-charged ionic cluster [(NaCl) 12 + 2Na] +2 which is a 3 × 3 × 3 micro-crystallite with an internal anion defect.
Multiply charged serine metaclusters (composed of two or more homochiral octameric units) are generated by electrospray ionization, and their unique fused structures (hydrogen-bonded through the sticky ends of the drum-shaped octameric units) have been elucidated using tandem mass spectrometry experiments and molecular mechanics calculations.
A double-blind, placebo-controlled, multiple oral dose escalation study was conducted to investigate the pharmacokinetics, safety, and tolerability of entecavir in healthy subjects. Eight subjects were assigned to each of the 3 dose panels (0.1 mg, 0.5 mg, and 1 mg or matched placebo once daily for 14 days). Blood and urine samples were collected for pharmacokinetic analyses. Entecavir was rapidly absorbed, with peak plasma concentration occurring within 1 hour of dosing. Steady-state plasma concentrations of entecavir were achieved by 10 days following the initial dose. At steady state, the mean area under the plasma concentration-time curve over 1 dosing interval, increased approximately proportional to dose. Entecavir had a mean terminal half-life ranging from 128 to 149 hours and an effective half-life of approximately 24 hours. Elimination was predominantly through renal excretion, with mean urinary recovery ranging from 62% to 73%. Entecavir was safe and well tolerated when administered at doses ranging from 0.1 mg to 1 mg/d for 14 days.
In this work, the root cause of the non-linear behavior of the standard curve when using a SIL-IS was investigated and identified. Based on the findings, an improved multiple SRM channels approach was proposed and successfully applied to obtain a linear dynamic range of five orders of magnitude for one test compound. This approach may work particularly well for LC/MS/MS bioanalytical assay of dried blood spot (DBS) samples, for which a direct dilution is cumbersome.
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