PREFERRED INTERACTION OF D-PEPTIDYL-ANTHRAQUINONES WITH DOUBLE-STRANDED B-DNA

The quest for more specific drugs in antitumor chemotherapy led us to the design of anthraquinone-peptide conjugates capable of selective re cognition of the nucleic acid. We present here the DNA binding charact eristics, sequence specificity and geometry of interaction of a pair o f enantiomers containing the lysine-glycine dipeptide in the side chai ns. The D enantiomer binds right handed double stranded DNA more effic iently than the L form under all conditions tested. The source of high er binding affinity is not electrostatic in nature and rests in the mo re favorable hydrophobic contacts of the D-lysyl side chains in the dr ug-DNA complex. Both derivatives exhibit preference for alternating GC base sequences and intercalate into DNA in a threading mode as sugges ted by chiroptical and theoretical studies. The D enantiomer, being a peptidyl derivative that contains a non-natural amino acid, has the co nsiderable advantage of being less susceptible to enzymatic hydrolysis and could therefore represent a lead compound for further development . (C) 1997 Elsevier Science B.V.