Planta Med 2008; 74 - P-42
DOI: 10.1055/s-2008-1075238

Regio-controlled Nitration of Manzamine A as Intermediates for Producing Manzamine Analogues with Better Docking Scores with GSK-3β

AE Wahba 1, J Peng 1, P Sivaprakasam 2, S Odde 2, RJ Doerksen 2, 3, MT Hamann 1, 3
  • 1Department of Pharmacognosy, The University ofMississippi, University, MS 38677, USA
  • 2Department of Medicinal Chemistry, The University ofMississippi, University, MS 38677, USA
  • 3The National Center for Natural Products Research,The University of Mississippi, University, MS 38677, USA

The manzamines are a unique group of sponge derived alkaloids containing a complex polycyclic system with a β-carboline moiety. Manzamine A shows significant antimalarial activity with IC50 4.5 ng/mL and was identified as a new class of human Glycogen Synthase Kinase-3 (GSK-3β) inhibitors. The structure of this protein is known from X-ray and the protein plays many roles in signaling pathways and phosphorylation of glycogen synthase. Docking studies of manzamine A and 8-hydroxmanzamine A in the non-ATP binding site of GSK-3β show that the manzamines fit very nicely. The GOLD docking pose showed polar residues close to the benzene ring of the β-carboline moiety, which suggested that modification at the 5–8 positions would provide analogues, which would bind better to this pocket. Nitro products of manzamine A at the 6- & 8- positions were obtained by direct nitration of manzamine A while nitration at the 5- & 7- positions were achieved by using 8-hydroxymanzamine A as starting material.