Phenylthio-derivatives of α-methylene-γ-lactones as pro-drugs of cytotoxic agents

Abstract A series of substituted phenylthio-derivatives of grosheimin ( 1 ), a natural cytotoxic guaianolide, were investigated with the aim of providing insight into their mechanism of action as cytotoxic agents against KB cell lines. Hydrolysis data, kinetics, in the presence and in the absence of H 2 O 2 , and the valuation of lipophilicity were correlated with cytotoxicity values and with Hammett-σ-values of substituents (R) at the thiophenol ring. These compounds behave as `pro-drugs' which release the cytotoxic agent grosheimin by sulphur-oxidation promoted by H 2 O 2 and subsequent retro-elimination which depends on the nature and position of the R substituent.