Atypical cytostatic mechanism of N-1-sulfonylcytosine derivatives determined by in vitro screening and computational analysis.

We have previously shown that N-1-sulfonylpyrimidine derivatives have strong antiproliferative activity on human tumor cell lines, whereby 1-(p-toluenesulfonyl)cytosine showed good selectivity with regard to normal cells and was easily synthesized on a large scale. In the present work we have used an interdisciplinary approach to elucidate the compounds' mechanistic class. An augmented number of cell lines (11) has allowed a computational search for compounds with similar activity profiles and/or mechanistic class by integrating our data with the comprehensive DTP-NCI database. We applied supervised machine learning methodology (Random Forest classifier), which offers information complementary to unsupervised algorithms commonly used for analysis of cytostatic activity profiles, such as self-organizing maps. The computational results taken together with cell cycle perturbation and apoptosis analysis of the cell lines point to an unusual mechanism of cytostatic action, possibly a combination of nucleic acid antimetabolite activity and a novel molecular mechanism.

[Etiology of atypical pneumonias in 2002. Results of the Croatian Institute of Public Health]. / Etiologija atipicnih pneumonija u 2002 godini: rezultati Hrvatskog zavoda za javno zdravstvo.

AIM: This investigation was performed at Department of Virology, Croatian National Institute of Public Health, the same diagnostic laboratory using the same serologic method as in earlier studies (in 1982 and 1992) to determine the incidence of the most common agents of atypical pneumonia in Croatia between January 1 and December 31, 2002. PATIENTS AND METHODS: The study included 630 patients from nearly all regions of Croatia with a clinical diagnosis of atypical pneumonia based on epidemiologic data, clinical symptoms, laboratory findings and chest X-rays. Most of them were from Zagreb (n = 370), followed by those from Slavonia, Istria, northwest Croatia, and Dalmatia. In all of them paired sera were collected at an interval of two weeks or more and tested for complement-fixing (CF) antibodies against the most common causative agents of the atypical pneumonia syndrome using CF test (micromethod). RESULTS: An etiologic diagnosis was established in 25% (158/630) patients (81 male and 77 female). Respiratory viruses were the most frequently demonstrated pathogens in 2002, accounting for 72% of cases (adenoviruses 47%, parainfluenza viruses 14%, influenza viruses 9% and respiratory syncytial virus (RSV) 2%). These were followed by Chlamydophila (C.) psittaci; (19%), Mycoplasma (M.) pneumoniae; (6%) and Coxiella (C.) burnetii (3%). There were 3 cases of double infection: a combination of adenovirus and M. pneumoniae, of RSV and parainfluenza virus, and of RSV and M. pneumoniae in one patient each. Adenoviral, mycoplasmal and psittacosal pneumonia occurred throughout the year; influenza and most of RSV pneumonias occurred in winter months. Parainfluenza viruses caused pneumonias throughout the year but were more common in winter months. CF test does not distinguish type-specific antibodies to parainfluenza viruses. In March, a small epidemic of psittacosis (11 patients) was registered in the Split area while was responsible for the high incidence of psittacosal pneumonia in 2002. While M. pneumoniae-caused pneumonia occurred mainly in children and adolescents, viral pneumonias were distributed across all age groups. Psittacosal pneumonia occurred in only one child but was more common in adolescents and especially adults. Q-fever pneumonia occurred only in adults.

Mass spectrometric investigation of N-sulfonylated purine nucleic bases and nucleosides.

The gas/phase behaviour of N-sulfonylated purine nucleic bases and nucleosides towards electron impact (EI) and matrix-assisted laser desorption/ionization (MALDI) occurring in a ion trap of a Fourier transform ion cyclotron resonance mass spectrometer is investigated. The influence of the storage time on the protonated molecule ([M+H](+)) abundance under EI conditions confirms that the formation of these ions proceeds through ion/molecule reactions. Using stored-waveform inverse Fourier transform (SWIFT) selective isolation of M(+.) or H(3)O(+), self-chemical ionization, M(+.)/M, and chemical ionization, H(3)O(+)/M, are detected. Investigation of specific EI expulsion of SO(2), SO(2)H and/or SO(2)H(2) from M(+.) and/or [M+H](+) shows that oxygen protonation in bond;SO(2)bond; proceeds faster than nitrogen protonation. Expulsion of SO(2) from molecular ions is not observed in MALDI mass spectra of nucleosides.