Conversion of a bisquinone methide–acridine conjugate to its monofunctional analogue releases the constraints that limit migration of its reversible adducts within DNA.
Polyamine and polyammonium ion conjugates
are often used to direct
reagents to nucleic acids based on their strong electrostatic attraction
to the phosphoribose backbone. Such nonspecific interactions do not
typically alter the specificity of the attached reagent, but polyammonium
ions dramatically redirected the specificity of a series of quinone
methide precursors. Replacement of a relatively nonspecific intercalator
based on acridine with a series of polyammonium ions resulted in a
surprising change of DNA products. Piperidine stable adducts were
generated in duplex DNA that lacked the ability to support a dynamic
cross-linking observed previously with acridine conjugates. Minor
reaction at guanine N7, the site of reversible reaction, was retained
by a monofunctional quinone methide-polyammonium ion conjugate, but
a bisfunctional analogue designed for tandem quinone methide formation
modified guanine N7 in only single-stranded DNA. The resulting intrastrand
cross-links were sufficiently dynamic to rearrange to interstrand
cross-links. However, no further transfer of adducts was observed
in duplex DNA. An alternative design that spatially and temporally
decoupled the two quinone methide equivalents neither restored the
dynamic reaction nor cross-linked DNA efficiently. While di- and triammonium
ion conjugates successfully enhanced the yields of cross-linking by
a bisquinone methide relative to a monoammonium equivalent, alternative
ligands will be necessary to facilitate the migration of cross-linking
and its potential application to disrupt DNA repair.
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