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

Invest New Drugs. 2008 Apr;26(2):97-110. doi: 10.1007/s10637-007-9084-1. Epub 2007 Sep 27.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cytosine / analogs & derivatives*
  • Cytosine / chemical synthesis
  • Cytosine / pharmacology
  • Databases, Factual
  • Drug Evaluation, Preclinical
  • Drug Screening Assays, Antitumor
  • Humans
  • Tosyl Compounds / chemical synthesis
  • Tosyl Compounds / pharmacology*


  • 1-(4-toluenesulfonyl)cytosine
  • Antineoplastic Agents
  • Tosyl Compounds
  • Cytosine