a distortion is not possible in the sequence used for NMR under those specific solution conditions, then the
disparity between NMR and viscosity studies might be explained.
9.6.5.1 Bisintercalating Anthracyclines: Bisdaunomycin. In 1997 Brad Chaires and co-workers
reported the structure-based design of a new bisintercalating anthracycline antibioticbased on two cova-
lently linked daunomycin molecules.25,26The starting point for the design of this molecule (code named
WP631) was the high-resolution X-ray structures of daunomycin monomers bound to DNA hexanucleotides
(Figure 9.6). In this structure, two ligand molecules have their amino sugar groups in the minor groove and
pointing towards one another with a separation of7 Å. An obvious way forward was to join covalently
the two NH 2 groups (one from each drug) to form a bisanthracyclinethat would have the potential to bis-
intercalate into DNA. A linker of about 7 Å in length was designed by Waldemar Priebe so as to fit into the
DNA minor groove without any steric constraints to give the structure of WP631 (Figure 9.9).
Viscosity studies confirmed that WP631 bisintercalates. The ultra-tight binding observed for WP631
(Kobs2.7 1011 M^1 ) approaches that predicted for a bisintercalator comprised of two daunomycin
moieties and is close to the affinity observed for many specific protein–DNA interactions. The overall
thermodynamic profile shows that binding of WP631 is driven by a large favourable enthalpy change
( 126.4 kJ mol^1 ). Binding is opposed by a substantial unfavourable entropy term, which at 20°C T Sis
62.3 kJ mol^1. This unfavourable entropic term is comparatively larger for WP631 than for daunomycin,
Reversible Small Molecule–Nucleic Acid Interactions 357
Figure 9.9 Structure of the bisanthracycline WP631. Two daunomycin molecules are covalently attached to each
other through their 3 -NH 2 groups using a p-xylene linker