An improved LC–MS/MS method for determination of docetaxel and its application to population pharmacokinetic study in Chinese cancer patients

Because of its unpredictable side effects and efficacy, the anticancer drug docetaxel (DTX) requires improved characterisation of its pharmacokinetic profiles through population pharmacokinetic studies. A sensitive and rugged LC–MS/MS method for the detection of DTX in human plasma was developed and optimised using paclitaxel as an internal standard (IS). The plasma samples underwent rapid extraction using hybrid solid-phase extraction-protein precipitation. The analyte and IS were separated with an isocratic system on a Zorbax Eclipse Plus C₁₈ column using water containing 0.05% acetic acid along with 20 μM of sodium acetate and methanol (30/70, v/v) as the mobile phase. Quantification was performed using a triple quadrupole mass spectrometer through multiple reaction monitoring in positive mode, using the m/z 830.3 → 548.8 and m/z 876.3 → 307.7 transitions for DTX and paclitaxel, respectively. The range of the calibration curve was 1–500 ng/mL for DTX, and the linear correlation coefficient was >0.99. The accuracies ranged from −4.6 to 4.2%, and the precision was no higher than 7.0% for the analytes. No significant matrix effect was observed. Both DTX and the IS showed considerable recovery. This method was finally applied to the establishment of a population pharmacokinetic model to optimise the clinical use of DTX.     

Fast and efficient preparation of Baylis-Hillman-derived (E)-allylic azides and related compounds in aqueous medium

A practical access to alkyl- and aryl-substituted (E)-2-(azidomethyl)alkenoates and related azido compounds from the corresponding allylic bromides in aqueous acetone is described. An alternative method to obtain the starting bromides based on heterogeneous catalysis under mild conditions was also investigated.     

Synthesis of poly-substituted nitrobenzene derivatives from Baylis-Hillman adducts via [3+3] annulation protocol

Poly-substituted nitrobenzenes were synthesized from Baylis-Hillman adducts via the [3+3] annulation strategy as the key step. 1,3-Dinitroalkanes served as the 1,3-dinucleophilic component and the Baylis-Hillman acetates as a 1,3-dielectrophilic part.     

Regioselective construction of polysubstituted benzene ring from Baylis-Hillman adduct via [4+2] annulation strategy

A new and regioselective [4+2] benzannulation protocol toward polysubstituted benzenes was developed. Nitroalkane derivative, which was prepared from Baylis-Hillman adduct, served as the four-carbon unit and Michael acceptor as a two-carbon unit.     

1-Benzopyran-4(4H)-ones as novel activated alkenes in the Baylis-Hillman reaction: a simple and facile synthesis of indolizine-fused-chromones

1-Benzopyran-4(4H)-one derivatives have been successfully employed as novel activated alkenes in the Baylis-Hillman coupling with heteroaromatic-aldehydes, nitrobenzaldehydes and isatin-derivatives and the corresponding adducts, derived from pyridine-2-carboxaldehyde, have been transformed into a novel indolizine-fused-chromone framework.     

Tributyltin hydride-mediated straightforward synthesis of a new isoxazolo-benzazulene ring system

Tributyltin hydride-mediated straightforward synthesis of a new isoxazolo-benzazulene system from the derivatives afforded by the Baylis-Hillman reaction of 3-(2-bromophenyl)-4-isoxazolecarbaldehydes is described.     

1H and 13C NMR characterization of hemiamidal isoniazid-NAD(H) adducts as possible inhibitors of InhA reductase of Mycobacterium tuberculosis

Isoniazid (INH) is easily oxidized with manganese(III) pyrophosphate, a chemical model of the KatG protein involved in activation of INH inside the bacteria Mycobacterium tuberculosis. Performed in the presence of NAD(+), this oxidation generates a family of isomeric INH-NAD(H) adducts, which have been shown to be effective inhibitors of InhA, an enzyme essential in mycolic acid biosynthesis. In this work, we fully characterized by (1)H and (13)C NMR spectroscopy four main species of INH-NAD(H) adducts that coexist in solution. Two of them are open diastereoisomers consisting of the covalent attachment of the isonicotinoyl radical at position four of the nicotinamide coenzyme. The other two result from a cyclization involving the amide group from the nicotinamide and the carbonyl group from the isonicotinoyl radical to give diastereoisomeric hemiamidals. Although an INH-NAD(H) adduct with a 4S configuration has been characterized within the active site of InhA from Xray crystallography and this bound adduct interpreted as an open form (Rozwarski et al., Science 1998, 279, 98-102), it is legitimate to raise the question about the effective active form(s), open or cyclic, of INH-NAD(H) adduct(s). Is there a single active form or are several forms able to inhibit the InhA activity with different levels of inhibitory potency?     

Trifluoroacetic acid: a more effective and efficient reagent for the synthesis of 3-arylmethylene-3,4-dihydro-1H-quinolin-2-ones and 3-arylmethyl-2-amino-quinolines from Baylis-Hillman derivatives via Claisen rearrangement

Trifluoroacetic acid has been discovered to be a highly effective and efficient reagent for the tandem Claisen rearrangement and cyclization reaction to yield 3-arylmethylene-3,4-dihydro-1H-quinolin-2-ones from compounds obtained from the S_N2 reaction between anilines and acetyl derivatives of Baylis-Hillman adducts of acrylates in the presence of DABCO. In contrast, similar compounds obtained from the acetyl derivatives of Baylis-Hillman adduct of acrylonitrile on treatment with trifluoroacetic acid directly furnish 3-arylmethyl-2-amino-quinoline via tandem Claisen rearrangement, cyclization and isomerization.     

胺催化下的Baylis-Hillman反应

Baylis-Hillman (B-H)反应是在催化剂作用下由活泼烯烃和亲电试剂发生的偶合反应, 其产物是一个具有多官能团的化合物. 胺类催化剂是反应中应用最广泛的一类催化剂. 综述了各种胺催化下的Baylis-Hillman反应的研究进展.     

Styrene oxide DNA adducts: quantitative determination using <Superscript>31</Superscript>P monitoring

The reaction of styrene oxide, a potential carcinogen in humans, with DNA constituents has been used to develop an improved method for quantification of DNA adducts. To enable monitoring of DNA adducts caused by xenobiotics at physiological relevant levels, a robust, reliable and powerful method based on monitoring of phosphorus in nucleotides is described. An efficient enzymatic digestion step and a sample-preconcentration procedure are essential, and enable separation of alkylated nucleotides from the large excess of native nucleotides. The adducts are detected by means of the phosphorus signal measured at mass m/z=31 with an inductively-coupled-plasma mass spectrometer. Bis(4-nitrophenyl)phosphate (BNPP) serves as internal standard for quantification of the adducts. The absolute limit of detection, 45 fmol, corresponds to detection of three modified nucleotides among 10⁷ native nucleotides (the calculation is based on use of 50 g calf thymus DNA). An adduct formation ratio at the DNA of 3.6 adducts per 1000 nucleotides was measured, which is 75% lower than for reaction with monomeric 2-deoxy-nucleotides. In addition, a substantial amount of phosphate adducts were detected, but in DNA the rate of phosphate formation was lower than with monomeric nucleotides. Most probably these adducts escaped unnoticed when ³¹P-post-labelling was employed.