Identification of unstable metabolites of Lonafarnib using liquid chromatography-quadrupole time-of-flight mass spectrometry, stable isotope incorporation and ion source temperature alteration

Structural characterization of unstable metabolites and other drug-derived entities poses a serious challenge to the analytical chemist using instrumentation such as LC-MS and LC-MS/MS, and may lead to inaccurate identification of metabolite structures. The task of structural elucidation becomes even more difficult when an analyte is unstable in the ion source of the mass spectrometer. However, a judicious selection of the experimental conditions and the advanced features of new generation mass spectrometers can often overcome these difficulties. We describe here the identification of three drug-derived peaks (A, B and C) that were detected from a Schering-Plough developmental compound (Lonafarnib) following incubation with cDNA-expressed human CYP3A4. Definitive characterization was achieved using (1) accurate mass measurement, (2) stable isotope incorporation, (3) reduced ion source temperature, (4) alkali ion attachment and (5) MS/MS fragmentation studies. The protonated ions of compounds A and B fragmented almost completely in the source, yielding ions of the same mass-to-charge ratio (m/z) as that of protonated C (CH+). Fortunately, the presence of Na+ and K+ adducts of A and B provided information crucial to distinguishing AH+ and BH+ from their fragment ions. Metabolite A was shown to be an unstable hydroxylated metabolite of Lonafarnib. The metabolite C was shown to be a dehydrogenated metabolite of Lonafarnib (Lonafarnib-2H), unstable in the presence of protic solvents. Finally, B was artifactually formed most likely from C by the solvolytic addition of methanol during sample preparation. MS/MS fragmentation experiments assisted in identifying the site of metabolism in A and chemical modification in B. A and C readily interconvert through hydration/dehydration, and B and C through addition/elimination of methanol present in the sample-processing solvents. Finally, NMR experiments were performed to confirm the structures of A and C.     

Effects of molecular weight and small amounts of d-lactide units on hydrolytic degradation of poly(l-lactic acid)s

Films of poly(l-lactic acid) (PLLA) with different number-average molecular weights (M_n) and d-lactide unit contents (X_d) were made amorphous and the effects of molecular weight and small amounts of d-lactide units on the hydrolytic degradation behavior in phosphate-buffered solution at 37 °C of PLLA were investigated. The degraded films were investigated using gravimetry, gel permeation chromatography, polarimetry, differential scanning calorimetry, X-ray diffractometry, and tensile testing. To exclude the effects of crystallinity on the hydrolytic degradation, the films were made amorphous by melt-quenching. The incorporation of small amounts of d-lactide units drastically enhanced the hydrolytic degradation of PLLA. In the period of 0-32 weeks, the hydrolytic degradation rate constant (k) of PLLA films increased with increasing X_d, while the k values did not depend on M_n. This means that the effects of X_d on the hydrolytic degradation rate of the films are higher than those of M_n. In contrast, in the period of 32-60 weeks neither X_d nor M_n was a crucial parameter to determine k values, probably because in addition to these parameters the differences in the amount of catalytic oligomers accumulated in films and crystallinity affect the hydrolytic degradation behavior of the films. The initially amorphous PLLA films remained amorphous even after the hydrolytic degradation for 60 weeks.     

Oxo-, hydroxo-, and peroxo-bridged Fe(III) phosphonate cages

A series of five Fe(III) phosphonate clusters with four different topologies is reported. The choice of coligand carboxylate plays an important role in directing the structure of the molecule. [Fe9(O)4(O2CCMe3)13(C10P)3] (1) and [Fe9(O)2(OH)(CO2Ph)10(C10P)6(H2O)2](CH3CN)7 (2; camphyl phosphonic acid, C10H17PO3H2 = C10PH2) represent two unprecedented nonanuclear Fe(III) cages having Fe9O4 and Fe9(O)2(OH) core structures, respectively. Whereas [Fe6O2(O)2(O2CCMe3)8(C10P)2 (H2O)2](CH3CN)4 (3) is a peroxo-bridged hexameric compound with an Fe6(O)2(O2) core. [Fe4(O)(O2CCMe3)4(C10P)3(Py)4](CH3CN)3 (4) and [Fe4(O)(O2CPh)4(C10P)3(Py)4](Py)3(CH3CN)2 (5; Py = pyridine) represents two tetranuclear clusters with the same Fe4O core structure.     

KO(t)Bu mediated synthesis of phenanthridinones and dibenzoazepinones

Synthesis of substituted phenanthridinones and dibenzoazepinones has been realized from 2-halo-benzamides in the presence of potassium tert-butoxide and a catalytic amount of 1,10-phenanthroline or AIBN. This new carbon-carbon bond forming reaction gives direct access to various biaryl lactams containing six- and seven-membered rings chemoselectively. Carbon-carbon coupling seems to proceed by the generation of a radical in the amide ring which leads to C-H arylation of aniline.     

Extremely large birefringence and shifting of zero dispersion wavelength of photonic crystal fibers

Three different types of photonic crystal fibers have been investigated which promise very large birefringence. The first type fiber is band gap guiding, the second index guiding, while the third type is index guiding with high refractive index circular and elliptical regions in the innermost ring. The birefringence, group velocity dispersion, modal effective index and mode field area of these fibers have been numerically estimated by employing finite difference time domain method. When elliptical regions are introduced in the first and second rings with the combination of small circular regions, each of these proposed fibers exhibits large birefringence with shifted zero dispersion point. Among these three different types of fibers, the band gap guiding photonic crystal fiber promises the largest birefringence (～5.45×10^?2) reported so far. The value of the birefringence and group velocity dispersion of these fibers can be controlled by controlling the hole pitch. Largest birefringence is achieved with a specific value of hole pitch.     

Can functionalized cucurbituril bind actinyl cations efficiently? A density functional theory based investigation

The feasibility of using cucurbituril host molecule as a probable actinyl cation binders candidate is investigated through density functional theory based calculations. Various possible binding sites of the cucurbit[5]uril host molecule to uranyl are analyzed and based on the binding energy evaluations, μ(5)-binding is predicted to be favored. For this coordination, the structure, vibrational spectra, and binding energies are evaluated for the binding of three actinyls in hexa-valent and penta-valent oxidation states with functionalized cucurbiturils. Functionalizing cucurbituril with methyl and cyclohexyl groups increases the binding affinities of actinyls, whereas fluorination decreases the binding affinities as compared to the native host molecule. Surprisingly hydroxylation of the host molecule does not distinguish the oxidation state of the three actinyls.     

Regulating Charge-Transfer in Conjugated Microporous Polymers for Photocatalytic Hydrogen Evolution

Bandgap engineering in donor–acceptor conjugated microporous polymers (CMPs) is a potential way to increase the solar-energy harvesting towards photochemical water splitting. Here, the design and synthesis of a series of donor–acceptor CMPs [tetraphenylethylene (TPE) and 9-fluorenone (F) as the donor and the acceptor, respectively], F_0.1CMP , F_0.5CMP , and F_2.0CMP , are reported. These CMPs exhibited tunable bandgaps and photocatalytic hydrogen evolution from water. The donor–acceptor CMPs exhibited also intramolecular charge-transfer (ICT) absorption in the visible region (λ_max=480 nm) and their bandgap was finely tuned from 2.8 to 2.1 eV by increasing the 9-fluorenone content. Interestingly, they also showed emissions in the 540–580 nm range assisted by the energy transfer from the other TPE segments (not involved in charge-transfer interactions), as evidenced from fluorescence lifetime decay analysis. By increasing the 9-fluorenone content the emission color of the polymer was also tuned from green to red. Photocatalytic activities of the donor–acceptor CMPs ( F_0.1CMP , F_0.5CMP , and F_2.0CMP ) are greatly enhanced compared to the 9-fluorenone free polymer ( F_0.0CMP ), which is essentially due to improved visible-light absorption and low bandgap of donor–acceptor CMPs. Among all the polymers F_0.5CMP with an optimum bandgap (2.3 eV) showed the highest H₂ evolution under visible-light irradiation. Moreover, all polymers showed excellent dispersibility in organic solvents and easy coated on the solid substrates.     

Strong Equatorial Crystal Field Enhances the Axial Anisotropy and Energy Barrier for Spin Reversal Process in Yb2 Single Molecule Magnets

The importance of equatorial crystal fields on magnetic anisotropy of ytterbium single molecule magnets (SMMs) is observed for the first time. Herein, we report three similar dinuclear ytterbium complexes with the formula [Yb₂(3-OMe-L)₂(DMF)₂(NO₃)₂]⋅DMF ( 1 ), [Yb₂(3-H-L)₂(DMF)₂(NO₃)₂]⋅DMF⋅H₂O ( 2 ), and [Yb₂(3-NO₃-L)₂(DMF)₂(NO₃)₂] ( 3 ), [where 3-X-H₂L=N′-(2-hydroxy-3-X-benzylidene)picolinohydrazide, X=OMe ( 1 ), H ( 2 ) NO₂ ( 3 )]. Detailed magnetic measurements reveal the presence of weak antiferromagnetic interactions between the Yb centers and a field-induced slow relaxation of magnetization in all complexes. A higher energy barrier for spin reversal was observed for complex 1 (U_eff=50 K) and it decreases in the order of 2 (47 K) to 3 (40 K). Notably, complex 1 shows a remarkable energy barrier within the frequency range of 1–850 Hz reported for Yb-based SMMs. Further, ab initio calculations show a higher axial anisotropy and lower quantum tunneling of magnetization (QTM) in the ground state for 1 compared to 2 and 3 . It was also observed that the presence of a strong crystal field in the equatorial plane (when the ∡ O1−Yb−O3 bond angle is close to 90°) enhances the axial anisotropy and improves the SMM behavior in the studied complexes. Both the experimental and theoretical analysis of relaxation dynamics discloses that Raman and QTM play major role on slow relaxation process for all complexes. To provide more insight into the exchange interactions, broken-symmetry DFT calculations were performed.