New antimitotic agents with activity in multi-drug-resistant cell lines and in vivo efficacy in murine tumor models

During a screen for compounds that could inhibit cell proliferation, a seri es of new tubulin-binding compounds was identified with the discovery of ox adiazoline 1 (A-105972). This compound showed good cytotoxic activity again st non-multi-drug-resistant and multi-drug-resistant cancer cell lines, but its utility in vivo was limited by a short half-life. Medicinal chemistry efforts led to the discovery of indolyloxazoline 22g (A-259745), which main tained all of the in vitro activity seen with oxadiazoline 1, but also demo nstrated a better pharmacokinetic profile, and dose-dependent in vivo activ ity. Over a 28 day study, indolyloxazoline 22g increased the life span of t umor-implanted mice by up to a factor of 3 upon oral dosing. This compound, and others of its structural class, may prove to be useful in the developm ent of new chemotherapeutic agents to treat human cancers.