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.
Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina 27109, USA.
Lu
L
Rao
Ulrich
U
Bierbach
D000225:Adenine / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007700:Kinetics; D013058:Mass Spectrometry; D010984:Platinum / Q000737:chemistry*; D016615:Telomere
D000970:Antineoplastic Agents; D010984:Platinum; D000225:Adenine