Synthesis and Structure-Activity Studies of Potential Antitumor Agents Derived From Esters of Phorbol

A synthetic study was carried out aimed at elucidating structure-activity relationships amongst naturally occurring esters of phorbol (la) and related daphnane ortho esters which have antitumour activity. The following phorbol esters and epoxy derivatives were prepared with ester groups which were present in the structurally related antitumour natural products: the 12,13,20-tribenzoate (lb), 12,13-dibenzoate ( lc ), 12,13-dibenzoate 20-palmitate (Id), 13-acetate 12,20-dibenzoate (le) and the 12,13,20-tricinnamate (1f of phorbol , and the 6,7-epoxides of the 12,13-dibenzoate (2a) and the 12,13,20-tricinnamate (2b) of phorbol . These compounds were tested against in vivo P388 murine lymphocytic leukaemia (3PS) and were found to have low activity. Various combinations of ester and epoxy groups alone were found to be insufficient to confer 3PS activity on the compounds studied. It was concluded that the presence of other groups, such as a 5-hydroxy group, an ortho ester function, and opening of the cyclopropane ring may be important in enhancing this activity.