Specific alkylation of human telomere repeats by hairpin pyrrole-imidazole polyamide.

Abstract A novel hairpin polyamide-cyclopropapyrroloindole (CPI) conjugate PyImImIm-γ-PyPyPyLDu86 (conjugate 11 ), which targets human telomere repeats d(TTAGGG) n /d(CCCTAA) n , was synthesized. High resolution denaturing polyacrylamide gel electrophoresis using 44 bp DNA fragments and HPLC product analysis of a synthetic nonanucleotide demonstrated that conjugate 11 alkylates the target adenine in the telomere repeats, 5′-CCCT A A-3′. Examination of the antitumor activity of conjugate 11 using a panel of 39 cancer cell lines demonstrated that the average concentration of conjugate 11 required for 50% growth inhibition was 5.75 μM, which is superior to pepleomycin and bleomycin and comparable to cisplatin.