Antitumour activity of N-[[1-[[2-(diethylamino)ethyl]amino]-9-oxo-9H-thioxanthen-4-yl]methyl]methanesulfonamide (WIN33377) and analogues

Abstract

WIN33377 (Sterling/Kodak) entered Phase I clinical trials in 1994. The dose limiting toxicity has not been reached with completion of the 225 mg/m² level, Q28 day schedule. To date, the agent has been very well tolerated with no evidence of liver toxicity. Eventually, a weekly schedule will be undertaken, which is consistent with the rapid host recovery time for this agent (six days). WIN33377 is an analogue of Hycanthone, an antischistosomal agent, that also has antitumour activity in preclinical models. However, Hycanthone is very poorly tolerated at the efficacious dose levels. Clinical trials of Hycanthone were carried out between 1978 and 1983, producing severe liver toxicity with drug induced deaths. No antitumour activity was recorded. WIN33377 and a variety of analogues were discovered to have markedly improved antitumour activity, and were well tolerated in mice. Most analogues had no evidence of liver toxicity with WIN33377 being totally devoid of liver toxicity. The key to better efficacy and toxicity was the replacement of a -CH₂OH functional group in the 4-position of the molecule with a -CH₂NR₁R₂ group (an oxygen to a nitrogen). Structure-Activity-Relationships (SAR) in vitro and in vivo are discussed for the series of WIN33377 analogues.