C. Escude et al., SELECTIVE STABILIZATION OF DNA TRIPLE HELICES BY BENZOPYRIDOINDOLE DERIVATIVES, Journal of the American Chemical Society, 117(41), 1995, pp. 10212-10219
A major challenge in the use of oligonucleotides in an anti-gene strat
egy is to stabilize triple helix formation under physiological conditi
ons. A benzo[e]pyridoindole derivative was shown earlier to stabilize
triple-helical better than double-helical complexes (Mergny, J. L. et
al. Science 1992, 256, 1681-1684). New derivatives of the benzopyridoi
ndole family were synthesized, and their ability to stabilize triple h
elices was investigated by thermal denaturation experiments using UV a
bsorption spectroscopy. The stabilizing effects of all the available d
erivatives were compared and allowed us to infer some general rules re
garding the role of the geometry of the molecule and of its various su
bstituents. The melting temperature (T-m) of the tripler-to-duplex tra
nsition is increased from 18 to 49 degrees C (Delta T-max = +31 degree
s C) upon binding of ropyl)propyl]amino-11H-benzo[g]pyrido[4,3-b]indol
e (BgPI), in a 10 mM sodium cacodylate buffer (pH 6.2) containing 0.1
M NaCl. Sequence-specific effects were also investigated. Benzo[e]- an
d benzo[g]pyrido[4,3-b]indole derivatives exhibited different properti
es regarding the role of the alkylamine side chain attached to the pyr
idine ring. Effects of these compounds on the melting of duplex DNA we
re also sensitive to changes in the chemical nature of the alkylamine
side chain. Results are discussed in terms of respective affinities fo
r tripler and duplex structures. A model is proposed to explain the di
fferent roles played by the alkylamine side chain for both types of mo
lecules. For the benzo[e]pyridoindole derivatives, the chain is sugges
ted to lie in the major groove of the triple helix, whereas for the be
nzo[g]pyridoindole derivatives, it lies in the minor groove. These res
ults provide an experimental and theoretical basis for understanding i
ntercalation of dyes in triple helices and should help to conceive mor
e specific triple helix ligands and to design oligonucleotide-intercal
ator conjugates for stable triple helix formation.