Cooperative alkylation of double-strand human telomere repeat sequences by PI polyamides with 11-base-pair recognition based on a heterotrimeric design.

We designed and synthesized alkylating conjugates 5-7 and their partner N-methylpyrrole-N-methylimidazole (PI) polyamides 8, 9. The DNA alkylating activities of conjugates 5-7 were evaluated by high-resolution denaturing polyacrylamide gel electrophoresis with a 219 base pair (bp) DNA fragment containing the human telomere repeat sequence. Conjugate 5 efficiently alkylated the sequence, 5'-GGTTAGGGTTA-3', in the presence of partner PI polyamide 8 or distamycin A (Dist). In contrast, the heterodimer system of 5 with 9 showed very weak alkylating activity. Accordingly, this heterotrimeric system of 5 with two short partners is an expedient way to attain improved precision and extension of the recognition of DNA sequences.