BIOCHEMICAL AND PHARMACOLOGICAL ACTIVITY OF NOVEL 8-FLUOROANTHRACYCLINES - INFLUENCE OF STEREOCHEMISTRY AND CONFORMATION

In an attempt to better understand the role of the cyclohexene ring (r ing A) in the biochemical and pharmacological properties of anthracycl ines related to doxorubicin and daunorubicin, we investigated the effe cts of introduction of a fluorine atom at position 8 of idarubicin (4- demethoxydaunorubicin) on drug molecular conformation and biochemical and pharmacological activities. The study showed that the stereochemis try of the substituent at position 8 influenced the ''half-chair'' con formation, so that in the (8R)-fluoroepimer the A ring retained the al pha half-chair conformation, which is the most stable for natural comp ounds (i.e., daunorubicin and doxorubicin), and the (8S)-fluoroepimers preferred the beta half-chair conformation. The (8R)-fluoroepimer was more effective than the (8S)-fluoroepimer and idarubicin in stimulati ng topoisomerase II-mediated DNA cleavage. Similarly, the epimer with the alpha conformation was markedly more potent than the (8S)-epimer a s a cytotoxic agent in a variety of human tumor cell lines and was mor e effective as an antitumor agent in the treatment of an ovarian carci noma xenograft. In addition, 8-fluoro derivatives were able to overcom e the resistance to doxorubicin in a number of human tumor cell lines expressing different mechanisms of resistance. In conclusion, these fi ndings provide evidence that drug interactions involving the external (nonintercalating) moiety of the anthracycline chromophore play an imp ortant role in determining pharmacological properties, including drug ability to induce DNA cleavage, and therefore their antitumor efficacy .