The d(GGCGCC)2 palindrome is encountered in
several
oncogenic and retroviral sequences. In order to target it, we previously
designed several oligopeptide derivatives of the mitoxantrone and
ametantrone anticancer intercalators. These have two arms with a cationic
side-chain in the major groove, each destined to bind along each strand
O6/N7 of the two successive guanine bases (G1-G2/G1′-G2′)
upstream from the central anthraquinone intercalation site. We retained
from a previous study (El Hage et al., 2022) a tris-intercalating
molecule with two outer 9-aminoacridine (9-AA) intercalators, denoted
as III. We sought enhancements in both affinity and selectivity
by simultaneously targeting the minor groove of the extracyclic −NH2 groups of these bases and G4-G4′ of the intercalation
site. We considered derivatives of distamycin, having each pyrrole
ring replaced by an imidazole to act as an in-register electron acceptor
from the −NH2 group of a target guanine. We substituted
the C6 and C7 carbons of anthraquinone, or the
C8 and C9 ones of anthracycline, by an (imidazole-amide)3
chain. Four different derivatives of III were designed
with different connectors to the anthraquinone/anthracycline and 9-AA.
Polarizable molecular dynamics simulations of their complexes with
a double-stranded DNA 18-mer with a central d(C GGGC GCCC G)2 palindrome sequence showed in-register minor groove binding to −NH2 of G1-G2/G1′-G2′ to coexist with
major groove recognition of O6/N7. Up to 12
H-bonds could be stabilized in the minor groove coexisting with four
bidentate interactions of the alkyl diammonium moieties in the major
groove. Since there is no mutual interference, the binding enthalpies,
ΔH, contributed by each groove could add up
and enable significant enhancements of the affinity constants. As
was the case for their Lys precursor, these derivatives are amenable
to chemical syntheses and in vitro and in vivo tests, for which the
present results provide an incentive. The construction of derivatives III-A–III-D is modular. For in vitro experiments,
this should enable unraveling the most important structural elements
to further optimize both ΔH and TΔS and sequence selectivity and how this could
translate to in vivo tests.