SYNTHESIS AND BIOLOGICAL-ACTIVITIES OF FLUORINATED DAUNORUBICIN AND DOXORUBICIN ANALOGS

Preparation and antitumor activities of a variety of the anthracycline antibiotics having a fluorine at C-2' are discussed. Suitably protected 2-deoxy-2-fluoroglycosyl halides have been coupled with daunomycinone, and derived into doxorubicin analogues. The anthracycline glycosides introduced a fluorine at the alpha-side of C-2' of doxorubicin and replaced the 3'-amino group with a hydroxyl group showed high antitumor activity with decreased toxicity. A 2'R-configuration was necessary to display activity; (2'S)-2'-fluoro and 2',2'-difluoro analogues were devoid of activity. While modifications at C-3' of the 2'-fluoroanthracycline antibiotics diminished their activity, most of the modifications at C-4' involving inversion of the configuration of the substituent did not significantly change activity.