Conjugates of minor groove DNA binders with oligodeoxynucleotides: Synthesis and properties

Oligodeoxynucleotide conjugates of netropsin (Nt) and distamycin A (Dst) were synthesized, and the thermal stability of several model DNA duplexes containing conjugates was studied. Two Dst residues conjugated at both ends of the oligonucleotide were needed for substantial increase in the melting temperature of the corresponding duplex (Delta T-m > 30 degrees C). Two attached Dst residues had a greater effect on the T-m value than did two free molecules of Dst per duplex, In contrast to Dst, one Nt molecule linked to the oligonucleotide was enough to influence the thermal stability of the duplexes, Like Dst, the attached Nt appeared to stabilize duplexes much more than free Nt molecules, Attachment of Nt to either the 5'- or 3'-end of the different nonadeoxynucleotides containing 5' ... TTAAA ... or 5' ... TATA ... sites increased T-m of their duplexes by 21 degrees C-25 degrees C, whereas Delta T-m for free Nt was 8 degrees C-15 degrees C (Delta Delta T-m = 10 degrees C-14 degrees C), The same phenomenon was shown for oligonucleotide phosphorothioates (Delta T-m were 8 degrees C-22 degrees C and 9 degrees C-13 degrees C for attached and free Nt, respectively; Delta Delta T-m = 9 degrees C). This effect was even more pronounced for a hairpin oligonucleotide (Delta Delta T-m = 18 degrees C).