A new series of 2-substituted 3-phosphonic derivatives of chromone. Part II. Synthesis, in vitro alkylating and in vivo antitumour activity

Abstract

Products of the reaction of (±)-O-acetylmandeloyl chloride with, respectively, sodium 2-hydroxy- or 2-hydroxy-5-methyl-acetophenone were brominated and coupled with trimethyl phosphite to give the Perkov products 4a and 4b, the Wittig-type products 6a and 6b and the title 3-phosphonic derivatives of chromone, 7a {2-[1-(±)-acetoxybenzyl]-3-(dimethoxyphosphoryl)-4-oxo-4H-chromene} and 7b {2-[1-(±)-acetoxybenzyl]-3-(dimethoxyphosphoryl)-4-oxo-6-methyl-4H-chromene}. Esters 7a and 7b were subjected to acidic hydrolysis to give the corresponding phosphonic acids 8a and 8b, and the unexpected phosphonolactones 9a and 9b. They were also treated with benzylamine forming the corresponding salts of the cyclic phosphonolactones (10a and 10b). Derivatives 4a,b, 6a,b–10a,b were tested for in vitro alkylating activity while compounds 7a, 7b and 9a were tested for in vivo antitumor activity. As determined by in vitro Preussmann tests, compounds 4, 6 and 7 possess strong alkylating activity. Compounds 10 have moderate potential for alkylation, whereas the remaining compounds 8 and 9 are only weakly active. The derivatives 7a, 7b and 9a demonstrated low in vivo antitumour activity against lymphocytic leukaemia L1210, whereas compound 7b exhibited significant antitumour activity against leukaemia P388 in mice.