Bromine Atom Interactions in Biologically Active Acrylamide Derivatives

Halogen bond interactions, C–Br···NC–, have been found in a crystal structure of an important drug compound WP1066. In order to characterize the nature of these interactions, experimental charge density distribution has been accomplished for a single crystal of WP1066. The energetic study of the halogen bond proved that this is one of the weakest interactions in the crystal structure and in energetic terms is close to the energy of the Br···H hydrogen bond type close contacts. Experimental charge density studies revealed a charge redistribution between molecules connected by halogen and hydrogen bonds enhancing electrostatic interaction energy. Using structural, charge density, and computational studies for WP1066 and two analogs, WP1130 and WP1220, we showed determining factors for the formation of the crystal structure, i.e. the presence of a bulky side chain next to the donor and acceptor of the hydrogen bond resulting in a change in conformation and electrostatic potential of molecules

Parsing the Free Energy of Anthracycline Antibiotic Binding to DNA^†

The DNA binding free energy of eight anthracycline antibiotics was determined as a function of NaCl concentration. Compounds were chosen for study that differed from the parent compounds, doxorubicin or daunorubicin, at a single chemical substituent. Determination of the salt concentration dependence of the binding constant allowed us to dissect the DNA binding free energy of each compound into its component nonelectrostatic and polyelectrolyte contributions. Comparison of the nonelectrostatic free energy contribution allowed us to evaluate the net energetic contribution of specific functional groups to DNA binding. These quantitative data revealed a surprisingly large and favorable energetic contribution (2 kcal mol-1) of the groove-binding daunosamine moiety and a substantial energetic penalty for alteration of its stereochemistry. The energetic cost of removal of hydroxyl groups at the C-9 and C-14 positions (which structural studies indicate may participate in hydrogen-bonding interactions with the DNA) was approximately 1 kcal mol-1. Replacement of the 3‘-amino group with a hydroxyl group led to a loss of 0.7 kcal mol-1 in binding free energy, above and beyond the energetic penalty resulting from the removal of its positive charge from the antibiotic. The results and analysis presented here provide a rigorous and detailed description of structure−DNA affinity relationships among anthracycline antibiotics. The results are of general interest in understanding how total ligand binding free energies are partitioned among substituents and will be useful in the formulation of rules for the rational design of novel DNA binding agents

A New Bisintercalating Anthracycline with Picomolar DNA Binding Affinity

A new bisintercalating anthracycline (WP762) has been designed, in which monomeric units of daunorubicin have been linked through their amino groups on the daunosamine moieties using an m-xylenyl linker. Differential scanning calorimetry and UV melting experiments were used to measure the ultratight binding of WP762 to DNA. The binding constant for the interaction of WP762 with herring sperm DNA was determined to be 7.3 (±0.2) × 1012 M-1 at 20 °C. The large favorable binding free energy of −17.3 kcal mol-1 was found to result from a large negative enthalpic contribution of −33.8 kcal mol-1 and an opposing entropic term (−TΔS = +16.5 kcal mol-1). A comparative molecular modeling study rationalized the increased binding by the m-xylenyl linker of WP762 positioning in the DNA minor groove compared to the p-xylenyl linker found in WP631, the first bis-anthracycline of this type. The cytotoxicity of WP762 was compared to that of other anthracyclines in Jurkat T lymphocytes. These studies, together with an analysis of the cell-cycle traverse in the presence of WP762, suggest that in these cells the new drug is more cytotoxic than the structurally related WP631