Synthesis of new antitumor anthracyclines: Derivatives bearing a fluorine substitution at position 8 or 10

Abstract

Concentration of drug bound to nuclear DNA of cancer cells is clearly associated with the main pharmacological effects of the anthracycline aminoglycosides, the molecular mechanism of antitumor activity being identified with an interference with the topoisomerase II-DNA complex. Both x-ray diffraction analysis and theoretical computations indicate the presence of a stabilizing hydrogen bond between the 9-OH of the anthracyclines and the amino group and N-3 of a guanine residue in the DNA-drug complex. We have therefore synthesized analogs containing a fluorine atom at position 8 or 10 with the aim at obtaining derivatives with higher affinity for the typical anthracycline intercalation sites 5′-(A,T)CG-3′ or 5′-(A,T)GC-3′ in double stranded DNA. © 1994 IUPAC