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.
Supek
Fran
F
Division of Electronics, Laboratory for Information Systems, Ruder Bosković Institute, Bijenicka cesta 54, 10002, Zagreb, Croatia. bzinic@irb.hr
Kralj
Marijeta
M
Marjanović
Marko
M
Suman
Lidija
L
Smuc
Tomislav
T
Krizmanić
Irena
I
Zinić
Biserka
B
D000465:Algorithms; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003596:Cytosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D016208:Databases, Factual; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D014105:Tosyl Compounds / Q000138:chemical synthesis / Q000494:pharmacology*
C509984:1-(4-toluenesulfonyl)cytosine; D000970:Antineoplastic Agents; D014105:Tosyl Compounds; D003596:Cytosine