An improved synthesis of the indolequinone anticancer agent EO9

Mitomycin C (MMC) 1, a clinically useful antitumour agent, is the archetypical quinone bioreductive agent.(1-3) The fact that MMC and related mitosenes, such as aziridinomitosenes 2 and the indolequinone 3, designated EO9,4,5, require reductive activation to form electrophilic species toxic to cells is well known, and the drugs presumably act as substrates for one or more of the reductases present in most cells. Bioreductive drugs are assuming increasing importance since they are highly effective against hypoxic tumour cells.(6-13) In this respect, the indolequinone EO9 3 is proving particularly interesting; it is an excellent substrate for the 2-electron reductase DT-diaphorase,(14-20) and is showing promising results in biological and clinical evaluation.(21-27) The quinone EO9 3 was first synthesised by Speckamp and co-workers by a multi-step route involving at least 20 steps.(4,5) In view of the potential of EO9 as an anticancer drug, and because of our own interest in indolequinones, in particular the cyclopropamitosenes 4,(28-31) we have developed an improved synthesis of this important compound, the details of which are reported herein. An alternative synthesis of EO9 has also been devised by the Kyowa Hakko Kogyo Company, although no details have been published.(32)