Wd. Wilson et al., DNA TRIPLE-HELIX SPECIFIC INTERCALATORS AS ANTIGENE ENHANCERS - UNFUSED AROMATIC CATIONS, Biochemistry, 32(40), 1993, pp. 10614-10621
Triple-helical structures involving the interaction of an oligonucleot
ide third strand with a duplex nucleic acid sequence have recently gai
ned attention as a therapeutic strategy in the ''antigene'' approach [
cf. Helene, C. (1991) Eur. J. Cancer 27, 1466-1471]. This method utili
zes the triple helix formed from the cellular duplex and an added thir
d strand to directly regulate the activity of a selected gene. The lim
ited stability of nucleic acid triple-helical interactions, particular
ly if the third strand has backbone modifications such as methylphosph
onate or phosphorothioate substitutions, is a limiting condition for t
he use of this approach. We have designed and synthesized compounds, o
n the basis of the following three criteria, that we feel should provi
de selective interactions and significant stabilization of triplexes:
appropriate aromatic surface area for stacking with triplex bases in a
n intercalation complex, positive charge, and limited torsional freedo
m in the aromatic system to match the propeller twist of the triple-ba
se interactions in the triplex. A series of quinoline derivatives with
an alkylamine side chain at the 4-position and with different aryl su
bstituents at the 2-position has been synthesized as our first compoun
ds. A 2-naphthyl derivative provides significant and selective stabili
zation of the triplex. In a 0.2 M NaCl buffer, the naphthyl derivative
increased the T(m) for the triplex (triplex to duplex and third stran
d transition) by approximately 30-degrees-C more than the T(m) increas
e for the duplex (duplex to single strands transition). Spectral chang
es and energy-transfer results indicate that the naphthyl compound and
related derivatives bind to the triplex by intercalation. Molecular m
odeling results indicate very good stacking of the naphthylquinoline r
ing system with the bases at a triplex intercalation site, but the res
ults also indicate that the ring system is too large to stack optimall
y with base pairs at a duplex intercalation site.