Kinetically Favored Platination of Adenine in the G-Rich Human Telomeric Repeat

The interactions of PT-ACRAMTU, a cytotoxic platinum−acridine conjugate, with the human telomeric G-quadruplex have been studied using in-line high-performance liquid chromatography−mass spectrometry and footprinting assays. The conjugate reacts significantly faster with quadruplex DNA (t1/2 = 1.2 h) than with double-stranded DNA, and A-N7, and not G-N7, is the kinetically preferred target, an unprecedented reactivity feature in platinum−DNA interactions. Unlike the clinical platinum drug cisplatin, which targets the human telomeric sequence nonspecifically, the platinum−intercalator technology has the potential to produce telomere-specific anticancer agents via a mechanism that kinetically discriminates between G and A in the two DNA secondary structures.