Novel purine-based fluoroaryl-1,2,3-triazoles as neuroprotecting agents: Synthesis, neuronal cell culture investigations, and CDK5 docking studies
Nanditha Nair, Wataru Kudo, Mark A. Smith, Ravinder Abrol, William A. Goddard III, V. Prakash Reddy
Abstract
A series of novel purine-based fluoroaryl triazoles were synthesized using the Cu(I) catalyzed 1,3-dipolar cycloaddition reactions (click reactions), and assayed for their neuroprotective effects using fluorescence electron microscopy. Among these triazoles, o-fluorophenylmetyl-triazole, 7, has comparable neuroprotective effect as that of Flavopiridol (1) and Roscovitine (2), the state of the art CDK inhibitors, against the Aβ induced neurotoxicity. These results are substantiated using computer docking methods (DarwinDock/GenDock), which predict that Roscovitine and the triazole 7 bind to the ATP-binding site of CDK5/p25 with comparable binding energies, whereas the corresponding pentafluorophenylmethyl-triazole, 9, has dramatically reduced binding energy (in accordance with its lack of neuroprotection). These combined experimental and theoretical studies support the involvement of CDK5/p25 in the neuronal cell cycle re-entry.
Group Members
Nair, N., Kudo, W., Smith, M. A., Abrol, R., III, W. A. G., & Reddy, V. P. (2011). Novel purine-based fluoroaryl-1,2,3-triazoles as neuroprotecting agents: Synthesis, neuronal cell culture investigations, and CDK5 docking studies. *Bioorganic and Medicinal Chemistry Letters*, *21*(13), 3957-3961. https://doi.org/10.1016/j.bmcl.2011.05.019