Validation of a robust and rapid liquid chromatography tandem mass spectrometric method for the quantitative analysis of navitoclax

The Bcl-2 family small molecule inhibitor navitoclax is being clinically evaluated to treat multiple cancers including lymphoid malignancies and small cell lung cancer. A sensitive and reliable method was developed to quantitate navitoclax in human plasma using liquid chromatography with tandem mass spectrometry with which to perform detailed pharmacokinetic studies. Sample preparation involved protein precipitation using acetonitrile. Separation of navitoclax and the internal standard, navitoclax-d8, was achieved with a Waters Acquity UPLC BEH C₁₈ column using isocratic flow over a 3 min total analytical run time. A SCIEX 4500 triple quadrupole mass spectrometer operated in positive electrospray ionization mode was used for the detection of navitoclax. The assay range was 5–5,000 ng/ml and proved to be accurate (89.5–104.9%) and precise (CV ≤ 11%). Long-term frozen plasma stability for navitoclax at −70°C was at least 43 months. The method was applied for the measurement of total plasma concentration of navitoclax in a patient receiving a 250 mg daily oral dose.     

Synthesis of 1,3,4,14b-tetrahydro-2H,10H-pyrazino[1,2-α]- pyrrolo[2,1-c][1,4]benzodiazepines

1,3,4,14b-Tetrahydro-2H,10H-pyrazino[1,2-α]pyrrolo[2,1-c] [1,4]benzodiazepines (1a-e) were synthesized to investigate their potential CNS activity. The key step in the synthesis was the formation of the 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (13) by reduction and concomitant cyclization of the nitroketone (11). Biological evaluation of 1a-e revealed interesting properties for 1b (CGS 7525A) [2].     

Synthesis, structures and comparative electrochemical study of 2,5-bis(trimethylsilylethynyl)thiophene coordinated cobalt carbonyl units

The reaction between 2,5-bis(trimethylsilylethynyl)thiophene and Co₂(CO)₈ or Co₂(CO)₆(X), (X = dppa, dppm), gave rise to the formation of substituted ethynylcobalt complexes containing one or two Co₂(CO)₆ or Co₂(CO)₄(X) units, 2-[Co₂(CO)₄(X){μ₂-η²-(SiMe₃)C₂}]-5-(Me₃SiCC)C₄H₂S (X = 2CO (1), dppa (3) or dppm (4)) and 2,5-[Co₂(CO)₄(X){μ₂-η²-SiMe₃C₂}]₂C₄H₂S (X = 2CO (2), dppa (5) or dppm (6)). Desilylation of the non-metallated and metallated alkynes in 3, 4 and 6 occurred on treatment with KOH and tetrabutylammonium fluoride to give 2-[Co₂(CO)₄(μ-X){μ₂-η²-SiMe₃C₂}]-5-(CCH)C₄H₂S (X = dppa (7), dppm (8)) and 2,5-[Co₂(CO)₄(μ-dppm){μ₂-η²-HC₂}]₂C₄H₂S (9), respectively. Crystals of 6 suitable for single-crystal X-ray diffraction were grown and the molecular structure of this compound is discussed. A comparative electrochemical study of all these complexes is presented by means of the cyclic and square-wave voltammetry techniques.     

Partial-wave analysis of the low-mass (π+π−p) system produced in K−p interactions at 4.2 GeV/c

A partial-wave analysis of the low-mass (π⁺π^?p) system produced in the reaction K^?p → K^?(π⁺π^?p) at 4.2 GeV/c incident momentum is performed in order to study the two (π⁺π^?p) enhancements around 1500 and 1700 MeV. It is found that the low-mass (π⁺π^?p) system can be described using the spin-parity states $\text{J}{}^{\mathrm{P}}\text{=}\text{1}\text{2}{}^{\mathrm{+}}\text{,}\text{3}\text{2}{}^{\mathrm{?}}$ and $\text{5}\text{2}{}^{\mathrm{+}}$ only. In the 1500 MeV region contributions are observed from the $\text{1}\text{2}{}^{\mathrm{+}}$ wave decaying into p? and the $\text{3}\text{2}{}^{\mathrm{?}}$ wave decaying into Δ⁺⁺π^?; in the 1700 MeV region contributions are found from the $\text{1}\text{2}{}^{\mathrm{+}}$ wave decaying into Δ⁺⁺π^?, the $\text{3}\text{2}{}^{\mathrm{?}}$ wave decaying into p?, and the $\text{5}\text{2}{}^{\mathrm{+}}$ wave decaying into p?.     

Backward production of the B meson in K−p interactions at 4.2 GeVc

The backward production of the B(1235) meson is studied in the reaction K^?p→Σ^?π⁺ω. This reaction is observed in the final state Σ^?π⁺π⁺π^?π⁰. A π⁺ω mass enhancement is visible in the region of the B meson for events with small |u|K^? →Σ^?) squared four-momentum transfer. The properties of the enhancement agree with those of the B meson. The cross section for K^?p→Σ^?B⁺ at $\text{4.15}\text{GeV}\text{c}$ incident K^? momentum is (3.2 ± 0.5) μb. The backward production of the B meson is compared with similar baryon exchange productions of the A₁ and C(Q₁) axial vector mesons observed in the same experiment.     

π − ω interference in the reactions K− p → π+ π− (Λ, ϵ0) at 4.2 GeV/c

π ? ω interference is studied in the reactions K^? p → π⁺ π^? (Λ⁰, ?) at 4.2 GeV/c using data from a high statistics experiments in the CERN 2m HBC. The phenomenon is analysed in terms of the conventional formalism as well as in terms of a new model for π ? ω interference proposed by Earles and Srivastava. Satisfactory agreement with the data is found for both models. The rate of ω → 2π obtained in the latter model is in agreement with the VMD (Vector Meson Dominance) prediction for ω → γ → ? → 2π.     

Ω− produced in K−p reactions at 4.2 GeV/c

Forty $\text{Ω}{}^{\mathrm{?}}$ events have been observed in a large (133 events/βb) experiment at 4.2 GeV/c incident K^? momentum. Thirty nine of the events come from the three-body reaction $\text{K}{}^{\mathrm{?}}\text{p}\text{→Ω}{}^{\mathrm{?}}\text{K}{}^{\mathrm{+}}\text{K}{}^0$. The $\text{Ω}{}^{\mathrm{?}}$ is mainly produced in the forward hemisphere (direction of the incident K^?). The lifetime is measured to be τ = (0.75 _+0.14?0.11 × 10^?10 sec substantially less than the Particle Data Group value of (1.3 _?0.3^+0.2) × 10^?10 sec. The mass is determined to be 1671.7 ± 0.6 MeV, in good agreement with other determinations. The decay asymmetry parameter α (for the decay mode $\text{Ω}{}^{\mathrm{?}}\text{→ Λ}\text{K}{}^{\mathrm{?}}$) is found to be ?0.2 ± 0.4.     

Observation of the B meson in K−p interactions at 4.2 GeVc

A πω enhancement at 1245 MeV is observed in the reaction K^?p → Σ⁺π^?ω. Its properties agree with those of a B meson produced by natural-parity exchange thus establishing a coupling of the B to a $\text{K}\text{K}{}^1$ system.