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Published in: Investigational New Drugs 2/2008

01-04-2008 | Preclinical Studies

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

Authors: Fran Supek, Marijeta Kralj, Marko Marjanović, Lidija Šuman, Tomislav Šmuc, Irena Krizmanić, Biserka Žinić

Published in: Investigational New Drugs | Issue 2/2008

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Summary

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.
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Metadata
Title
Atypical cytostatic mechanism of N-1-sulfonylcytosine derivatives determined by in vitro screening and computational analysis
Authors
Fran Supek
Marijeta Kralj
Marko Marjanović
Lidija Šuman
Tomislav Šmuc
Irena Krizmanić
Biserka Žinić
Publication date
01-04-2008
Publisher
Springer US
Published in
Investigational New Drugs / Issue 2/2008
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-007-9084-1

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