Investigational New Drugs

, Volume 1, Issue 3, pp 203–211 | Cite as

Structure-activity relationship of 1-propargyl-5-halopyrimidin-2-ones

Metaphase arresting properties an competitive inhibition of colchicine binding to tubulin
  • John M. Dornish
  • Reidar Oftebro


The structure-activity relationship of 1-propargyl-5-halopyrimidin-2-ones with respect to mitotic inhibitory potential and inhibition of colchicine binding to tubulin was investigated. A correlation between accumulation in metaphase of cultured human NHIK 3025 cells and drug competition with colchicine binding to tubulin was found for each compound. Effects on division of NHIK 3025 cells were determined in stained preparations following a 6 h treatment with drugs. The four halogen-substituted compounds displayed metaphase arresting ability while the H-substituted 1-propargylpyrimidin-2-one did not. 1-Propargyl-5-fluoropyrimidin-2-one was active at 1.5 and 0.75 mM while the 5-chloro, 5-bromo and 5-iodo compounds caused metaphase arrest at 0.375 and 0.18 mM.

The ability of these drugs to compete with colchicine binding to DEAE-cellulose purified tubulin was also investigated. 1-Propargylpyrimidin-2-one at 5 mM did not inhibit (3H)colchicine binding to tubulin as determined by Sephadex G-50 gel filtration. The halogen-substituted pyrimidones, however, demonstrated competitive inhibition of colchicine binding to tubulin. Five mM 1-propargyl-5-iodopyrimidin-2-one inhibited colchicine binding by 43.2%, the highest value obtained within the metahalone group. The drugs tested had no effect on vincristine binding to tubulin. With respect to the halogen substitution, the increasing order of mitotic inhibitory potential and competition with colchicine binding to tubulin is H ≪ F < Cl ≦ Br ≦ I.

Key words

metahalone metaphase arrest colchicine drug competition tubulin 


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Copyright information

© Martinus Nijhoff Publishers 1983

Authors and Affiliations

  • John M. Dornish
    • 1
  • Reidar Oftebro
    • 1
  1. 1.Department of Tissue CultureNorsk Hydro's Institute for Cancer Research, The Norwegian Radium HospitalMontebelloNorway

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