DNA sequence recognition by Hoechst 33258 conjugates of hairpin pyrrole/imidazole polyamides

A series of hairpin pyrrole/imidazole polyamides linked to a Hoechst 33258 (Ht) analogue (5–7) were synthesized on solid-phase by adopting an Fmoc technique using a series of PyBOP/HOBt mediated coupling reactions. The dsDNA binding properties of Ht-polyamides 5–7 were determined by thermal denaturation experiments. Hairpin Ht-polyamides 5–7 bound to dsDNA sequences 16 and 18 show ΔTm values that are 14–18 degrees higher than linear Ht-polyamides bound to the same sequences. All three Ht-polyamides were found to be selective for their 9-bp match dsDNA sequences, supporting a relative stronger interaction of an Im/Py anti-parallel dimer with an appropriately positioned G/C bp rather than sequences containing only A/T bps. In addition, Ht-polyamides 5 and 7 showed a 20-fold preference for a properly placed G/C bp over a C/G bp, while 6 showed a 10-fold preference.