ABSTRACT
Methods are described for the syntheses of chloromethyl propargyl ethers and propargyl halides substituted with a hydroxyalkyl group, and their use in alkylation reactions of 2-pyrimidinones. The N-alkynyl derivatives are reversible inhibitors of mitosis in the metaphase of the cell-cycle. The in vivo screening was on Chang liver cells.
Subject(s)
Metaphase/drug effects , Pyrimidinones/chemical synthesis , Alkylation , Cells, Cultured , Humans , Liver/cytology , Liver/drug effects , Pyrimidinones/pharmacologyABSTRACT
Methods are described for the syntheses of chloromethyl hydroxyalkylphenyl and benzyl ethers, and for the synthesis of bromomethyl phenyl ketone analogs. The hydroxy groups were protected as acetates. The halogenomethyl derivatives have been used for N-alkylation of 5-chloro-2(1H)-pyrimidinone. The acetyl groups in the products were removed by aminolysis or by enzymatic (pig liver esterase) hydrolysis. The hydroxy derivatives are chemically labile because of polymerization reactions. Adduct formation (1:1) with sodium hydrogensulfite improved the stability. The products are specific inhibitors of the cell cycle in the metaphase. In vitro data are given from screening in cultivated Chang liver cells.
