2-(5,6-Dimethyl-9-oxo-9H-xanthen-4-yl)acetic acid (DMXAA,ASA404; 1) is a Tumour Vascular Disrupting Agent (Tumour-VDA),in Phase Ⅲ clinical trials for the treatment of non-small cell lung cancer.We report the development ofDMXAA prodrugs that can be metabolised in vivo to release the active compound and alter its pharmacokinetic profile.There are only two functional sites in DMXAA that can be used for the formation of prodrugs; the acid and the carbonyl groups.We have synthesized a series of esters of the carboxylic acid group,and evaluated them for stability in both water and tissue culture medium containing fetal calf serum.Prodrug-induced haemorrhagic necrosis was assessed in subcutaneously implanted murine colon 38 adenocarcinomas in C57/BL mice.Esters of the carboxylic acid bearing weak bases,created either by proximity effects (a C2 chain) or by electronic control,show the largest differential stability in water and tissue culture medium,and show the largest in vivo effects.Increasing the steric crowding on the-carbon to the ester has a pronounced stabilising effect.