Hydroxyurea (HU) has been used as a therapeutic agent for many years. It is an effective inhibitor of ribonucleotide reductase possessing drawbacks with toxicity and resistance. Efforts have been made to modify the structure to eliminate or minimize these therapeutic drawbacks and we recently developed a novel two step protocol for the synthesis of mono and di-substituted hydroxy ureas. Modeling and apoptotic studies of a series of seven synthesized analogs were undertaken with the effort to design a better inhibitor for ribonucleotide reductase. While cell studies showed a difference in activity of these HU analogs, with the α-napthyl analog being a better inducer of apoptosis than the parent HU, an initial examination of the analogs did not show a clear reason for this result. Molecular modeling studies that were carried out using AM1 suggest that the difference in activity can be correlated with the energetics associated with rotation barriers around the N-C-N-O torsion angle. These studies also showed a difference in charge at the terminal of oxygen and nitrogen which differentiates the α-napthyl HU. In addition, the HU backbone of the α-napthyl analog is electrostatically the most consistent with the parent HU. Modeling of the analogs in the active site of ribonucleotide reductase suggests that the activity of the active analog may be due to its ability to adjust conformationally to fit the required interactions in the active site as a result of its low energy barrier to rotation.
Keywords: Computational modeling, Drug design, Hydroxy ureas, Ribonucleotide reductase, Cell isolation, Cell Growth, Apoptosis, di-substituted HU, semi-empirical quantum mechanical program, DNA fragmentation, N-CN-O torsion angle, N-O-H portion, the α;-napthyl HU (4) analog
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