Search

Previous studies have demonstrated that TP53 mutation is correlated with insufficient therapy response and unfavorable prognosis in acute lymphoblastic leukemia (ALL). Few studies have investigated the impact of TP53 mutation in ALL patients after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We completed a retrospective study of 65 ALL patients with available TP53 status who underwent haplo-HSCT. They were divided into a TP53 mutation group (TP53

Cuprizone is an amide compound that has been wildly used in various animal studies, such as in the investigation of remyelination in mouse model. It is important to control the amount of cuprizone dosed in animals to be consistent as different amounts may lead to different clinical observations. Cuprizone is usually administrated as a minor component (i.e., 0.3%) of a mixture with powdered or pelleted rodent chow. Its low content, combined with the complex nature of chow, represents a significant challenge for the quantification of cuprizone in the mixture. To the best of our knowledge, no method has been reported in the literature so far. In this study, a simple, selective, and sensitive hydrophilic interaction liquid chromatographic method was developed for the quantification of cuprizone in cuprizone pre-clinical formulations. The analytical method comprises a fast ultrasound assisted extraction with acetonitrile/water as a solvent followed by gradient separation using a Waters Xbridge HILIC column with 0.1% TFA in water and acetonitrile as mobile phases and UV detection at 220 nm. The specificity, linearity, accuracy, repeatability, and limit of quantitation (LOQ) of the method were established. The method was determined to be linear in the range of 10–200 μg/mL. Accuracy was assessed by spiking a chow placebo with various amounts of a cuprizone reference standard to achieve target concentration levels and the recoveries were within the acceptance criterion of 90–110% of the target concentrations. Repeatability was demonstrated at the nominal concentration of 100 µg/mL and LOQ level of 2.5 μg/mL. This method has been demonstrated to be suitable for its intended use and has been successfully applied to the quantification of low levels of cuprizone in chow formulations. It was found that the cuprizone content in chow could varied significantly between batches and the potential causes of the variability were investigated.

[R(+) OC Cl(-)] ion pairs were generated in methanol/dichloroethane solutions, with R(+) as the 1-bicyclo[2.2.2]octyl, 1-adamantyl, or 3-homoadamantyl cation. Ion pairs were produced either by the direct fragmentation of alkoxychlorocarbenes (ROCCl), with R = 1-bicyclo[2.2.2]octyl, 1-adamantyl, or 3-homoadamantyl, or by the ring expansion-fragmentation of R'CH(2)OCCl, with R' = 1-norbornyl, 3-noradamantyl, or 1-adamantyl. Correlations of the [ROMe]/[RCl] product ratios as a function of the mole fraction of MeOH in dichloroethane showed that the homoadamantyl chloride ion pairs, produced by either the direct or ring expansion-fragmentations, were identical, solvent- and anion-equilibrated, and precursor independent. Laser flash photolysis experiments gave 20-30 ps as the time required for solvent equilibration and precursor independence. Methanol/chloride selectivities of the (less-stable) 1-adamantyl chloride and 1-bicyclo[2.2.2]octyl chloride ion pairs were not independent of their ROCCl or R'CH(2)OCCl precursors. Computational studies provided transition states for the fragmentations and for the structures of the ion pairs.

Alkoxychlorocarbenes (ROCCl, R = benzyl, cyclohexyl, and 1-octyl) were generated from the corresponding diazirines in acetonitrile, dichloroethane, benzene, cyclohexane, and pentane solutions at 25...

[reaction: see text]The products, kinetics, and activation parameters were determined for the fragmentation-ring expansions of 1-norbornylmethyloxychlorocarbene (11) and 3-noradamantylmethyloxychlorocarbene (17). Products from 11 (in dichloroethane) included 1-chlorobicyclo[2.2.2]octane (9, 56%) and 1-chlorobicyclo[3.2.1]octane (10, 37%); from 17, we obtained 1-chloroadamantane (15, 68%) and protoadamantyl chloride (16, 28%).

Carbon atom reactions with anisole and methoxybenzaldehyde demonstrate the reversible ring expansion of methoxyphenylcarbene (CH(3)O-C(6)H(4)-C-H). Trapping with HBF(4) yields the methoxytropylium ion, analogous to the well-known reactions of phenylcarbene. For instance, in the reaction of carbon atom with p-methoxybenzaldehyde, which proceeds by deoxygenation of the carbonyl group and formation of the corresponding arylcarbene, the products formed are methoxytropylium fluoroborate, p-methoxytoluene and m-methoxytoluene in yields of 69.4, 7.6, and 22.9%, respectively. Gas-phase density functional theory calculations were also carried out. The observed product yields from the uniquely generated p- and m-methoxyphenylcarbenes are in good agreement with the calculations. In the case of o-methoxyphenylcarbene, however, the calculations indicate that formation of dihydrobenzofuran is the most facile rearrangement on the ground-state singlet surface. In contrast, ring expansion is observed to be the major reaction path experimentally. The exothermicity of the deoxygenation step for carbon atom reaction with methoxybenzaldehyde ( approximately 100 kcal/mol) can allow for an excited singlet state to be formed initially. This excited singlet state of the methoxyphenylcarbene will resemble open-shell phenylnitrene, which is known to undergo ring expansion much more readily than phenylcarbene. On the basis of this analogy, we reconcile the difference in reactivity of the arylcarbene predicted by density functional theory calculations with the reactivity observed experimentally.

Cyclopropylmethylchlorocarbene ( 3 ) and dicyclopropylmethylchlorocarbene ( 4 ) give only 1,2-H shift products with k H =2.0×10 7 and 1.3×10 7 s −1 , respectively, at 25°C.

exo- and endo-2-norbornyloxychlorocarbenes (7) were generated photochemically from the corresponding diazirines (6). Both carbenes fragmented to [2-norbornyl cation (carbon monoxide) chloride] ion pairs in MeCN or 1,2-dichloroethane solutions. Products included exo-norbornyl chloride (8), endo-norbornyl chloride (9), norbornene (10), and nortricyclene (11). Fragmentation activation energies were very low (approximately 4 kcal/mol) and, as a result, the (laser flash photolytic) rate constants for fragmentation were essentially identical for exo-7 and endo-7 ( approximately 5 x 10(5) s(-1) in MeCN). Due to chloride return within the ion pairs, product distributions from exo- and endo-7 differed, with more endo-chloride formed from the endo-carbene: the 8/9 product ratio in MeCN was approximately 41 from exo-7, but only 4.6 from endo-7. Norbornene, formed by proton transfer to Cl(-) within the ion pairs, was a major product in both cases (44% from exo-7 and 62% from endo-7). In MeOH/MeCN, up to 28% of exo-2-norbornyl methyl ether formed at the expense of some of the norbornene, but even in 100% MeOH, the norbornyl chloride products of ion pair return still accounted for 46% and 31% of the exo-7 and endo-7 product mixtures (accompanied by 26-32% of norbornene). Electronic structure calculations on the ground states and fragmentation transition states of exo-7 and endo-7 are presented.

Fragmentations of cyclobutoxychlorocarbene (13, kfrag = 7.1 × 105 s−1) and cyclopropylmethoxychlorocarbene (14, kfrag = 7.6 × 105 s−1) in MeCN proceed to tight and distinct [R+ OC Cl−] ion pairs, which collapse to different distributions of cyclopropylcarbinyl, cyclobutyl and allylcarbinyl chlorides. B3LYP/6–31G* calculations support these conclusions, affording computed fragmentation activation energies of 6.4 (13) and 3.0 (14) kcal mol−1. Copyright © 2001 John Wiley & Sons, Ltd.

Reaction of arc generated carbon atoms with tert-butylbenzene, 4, gives 3-methyl-3-phenyl-1-butene, 5, and 1,1-dimethylindane, 6. Labeling studies and isotope effects demonstrate that 5 results from an insertion into a methyl C−H bond followed by 1,2 hydrogen shift while 6 arises from initial ortho C−H insertion followed by intramolecular insertion into a methyl C−H bond. When fluoroboric acid is added to the 77 K matrix of 4 + C, tert-butyltropylium fluoroborate, 18, is formed. Labeling studies indicate that 18 results from initial insertion of C into meta and para C−H bonds of 4 followed by ring expansion to cycloheptatetraenes which are subsequently protonated. The reaction of C with benzene gives similar results, indicating that initial C−H insertion is the preferred mode of attack of atomic carbon on benzene rings.

In contrast to photolysis or thermal decomposition in solution, which is dominated by ionic reactions, flash vacuum pyrolysis of alkylchlorodiazirines in the gas phase generates radicals. The cyclopropylcarbinyl system is re-examined and the 1-norbornylcarbinyl system is studied for the first time.

The ‘phenyl’ carbon migration of 1-indanylchlorocarbene is accelerated by appropriate aromatic methoxyl substitution in accord with a π-mediated rearrangement mechanism.

Reaction of arc generated carbon atoms with tert-butylbenzene, 4, gives 3-methyl-3-phenyl-1-butene, 5, and 1,1-dimethylindane, 6. Labeling studies and isotope effects demonstrate that 5 results from an insertion into a methyl C−H bond followed by 1,2 hydrogen shift while 6 arises from initial ortho C−H insertion followed by intramolecular insertion into a methyl C−H bond. When fluoroboric acid is added to the 77 K matrix of 4 + C, tert-butyltropylium fluoroborate, 18, is formed. Labeling studies indicate that 18 results from initial insertion of C into meta and para C−H bonds of 4 followed by ring expansion to cycloheptatetraenes which are subsequently protonated. The reaction of C with benzene gives similar results, indicating that initial C−H insertion is the preferred mode of attack of atomic carbon on benzene rings.

Absolute rate constants were measured for the 1,2-CH2, 1,2-cyclopropyl, and 1,2-CMe2 rearrangements of spiropentylchlorocarbene (5), [3]triangulylchlorocarbene (6), and tetramethylcyclopropylchlorocarbene (7). The factors responsible for the observed relative migratory aptitudes (cyclopropyl > CH2 > CMe2) were analyzed with the aid of electronic structure calculations.

Fragmentations of cyclopropylmethoxychlorocarbene (6) and cyclobutoxychlorocarbene (10) lead to rearrangments that afford mixtures of cyclopropylmethyl chloride (7), cyclobutyl chloride (8), and 3-butenyl chloride (9). Isotopic substitution studies show that these rearrangments are accompanied by partial exchange of the methylene groups within 6 and 10. Surprisingly, these processes that are typical of carbocations persist in hydrocarbon solvents such as pentane and cyclohexane-d(12). Quantum chemical calculations reveal that the cis-conformers of the incipient oxychlorocarbenes C(4)H(7)OC(..)Cl decay to C(4)H(7)Cl + CO via transient hydrogen bonded C(4)H(7)(delta)(+)...Cl(delta-) complexes which possess significant ion pair character, even in the gas phase or in nonpolar solvents. In contrast to benzyloxychlorocarbene, no free radicals are formed upon generation or photolysis of 6 or 10 in Ar matrixes, although acid chlorides (the recombination products of these radical pairs) are observed. The IR spectra obtained in these experiments show the presence of several conformers of the two C(4)H(7)OC(..)Cl.