Designing anticancer drugs via the achilles heel: Ceramide, allylic ketones, and mitochondria

Published reports are reviewed as the basis of a proposal that an effective antineoplastic drug should contain several features: (a) resemblance to the natural lipid, ceramide; (b) an allylic alcohol and/or allylic ketone moiety; (c) a hydroxyl and/or a nitrogen atom near the allylic group; (d) conjugated double bonds as part of the allylic region. The drug should produce reactive oxygen species in tumor mitochondria, stimulate the generation of ceramide in the tumor, and condense with mitochondrial glutathione. It is pointed out that some antibiotics with these features are also active against cancer cells; perhaps anticancer drugs with these features will prove useful as antibiotics. Common problems in working with lipoidal substances are discussed. (C) 2003 Elsevier Science Ltd. All rights reserved.