News
Unlocking mixtures with LC/MS/MS In the increasingly high-speed world of pharmaceutical research, analytical methods that are specific, sensitive, and fast are highly prized. Timothy V. Olah and colleagues at Merck Research Laboratory describe the use of LC with tandem MS for determining mixtures of drug candidates as part of a high-throughput bioanalysis involving pharmacokinetics and metabolic stability studies. This approach relies on simple isolation methods, isocratic chromatography, and LC/MS/MS conditions that can be adapted and applied to numerous agents within a specific therapeutic class. Samples used in this study consisted of plasma from single animals dosed with a mixture of several test compounds or pooled plasma from several animals given a single agent. The authors have developed methods that simultaneously determine, in a single analysis, plasma concentrations of up to 12 drug candidates that fall into a 1- to 1000-ng/mL concentration range. Data are checked with quality control samples that are assayed throughout each analytical run. Using this approach, researchers screened for than 400 compounds in two different target classes in a 24-week period. (Rapid Commun Mass Spectrom 1997 1117-23)
Finding the DNA alkylation
Sequence-selective DNA alkylation plays a significant role in the actions of anticancer drugs, mutagens, and carcinogens. X-ray crystallography and NMR spectroscopy both provide detailed structural information about DNA adducts, but both methods are time consuming and use a lot of sample. Margaret M. Sheil, Geoffrey Wickham, and Paula Iannitti at the University of Wollongong (Australia) demonstrate electrospray ionization tandem MS for rapid and sensitive characterization of DNA adducts. They studied, as a model, the binding of DNA and hedamycin, an antitumor antibiotic that binds to DNA by intercalation or preferential alkylation at guanine sites in CGT or CGG sequences In contrast to the mass spectrum of the unmodified oligonucleotide, the ESI tandem mass spectrum of the hedamycin-5'CACGTG-3' adduct had only five product ions, all of which indicated only one major fragmentation pathway. The mass spectrum was consistent with a loss ESI tandem mass spectra of the [M-2Hf~ ions of the alkylated guanine via of the hedamycin-5'-CACGTG-3' (a) and ./V-glycosidic bond cleavage. In hedamycin-5'-CGTACG-3' (b) adducts.
Pesticides on the surface
Plasma concentration-iime profiles for compounds given orally in a mixture to a single dog. (Adapted with permission from John Wiley & Sons.) 224 A
the sequence 5'-CGTACG-3', the hedamycin preferentially binds to the guanine at the 3'-end, and this was clearly shown in the mass spectrum. The authors looked at several other hexamers and were able to clearly identify the hedamycin binding site in each. (J. Am. Chem. Soc. 1199,119,1490-91)
Pesticides on plant surfaces typically are analyzed by chromatographic techniques requiring an extraction step. Jani C. Ingram and colleagues at the Idaho National Engineering Laboratory investigated an alternative technique, secondary ion MS, that could offer faster analysis as well as information on the spatial distribution of pesticides on the plant surface. In this study, the researchers evaluated the applicability of SIMS by looking for 20 common pesticides on four substrates: dandelion leaves, grass, soil, and stainless steel. Using SIMS eliminates sample pretreatment and provides an analysis in about 10 min. The researchers detected 16 of the 20 pesticides on all four substrates. Of the remaining four pesticides, only one was not detected on any samples. In addition, they determined that
Analytical Chemistry News & Features, April 1, 1997
the minimum detection limit of paraquat on soil—a "best case" scenario for testing SIMS—was 3 pg/mm2. These results indicate that SIMS can detect a range of pesticides with low volatility, especially when the compounds are polar. (Environ. Sci. Technol. .197,31,402-8)
Log/log plot showing ion abundance for the m/z 171* ion versus paraquat coverage on soil.
