Polycyclic indole derivatives as novel structures for neuroprotection

Abstract

The lethal triplet of metabolic compromise, excitotoxicity and oxidative stress causes neuronal cell death that is both necrotic and apoptotic in nature. Aspects of each of these mechanisms are believed to play a role in the neurodegeneration that occurs in both Parkinson's and Huntington's diseases. The overstimulation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors is involved in excitotoxicity, a process in neurodegeneration that characterises some neurological disorders and acute cerebral insults. In this process excess NO formation and oxidative stresses are key factors. In searching for compounds with neuroprotective properties, a series of tryptarnine derivatives were synthesised and their effects were evaluated on both NOS and lipid peroxidation activity. Computer modelling was performed using Catalyst 4.9 and the Ligandfit module of cerius2 to determine the feasibility for synthesis and biological evaluation of the novel compounds. The hydrogen bond network formed in the enzyme was used as an indication for possible inhibitory activity. H-bonds with Tpr587, Glu592 and heme were taken as essential for NOS activity. Hydrogen bonds with Tyr588, GIn478 and Asp597 could also be important, since these amino acids play a role in the stabilisation and orientation of ligands in the cavity. The molecular modelling study indicated that the novel compounds were potential candidates for future investigation in view of their interaction at the NOS active site. Compounds were synthesised by reductive amination or activation chemistry with various linkers. Novel rearranged polycyctic structures were obtained when linkers were applied. Difficulties were experienced with yields, purification and isolation of the compounds and could be attributed to solubility and multiple reactions taking place. Selected compounds were characterised and evaluated for NOS and antioxidative properties. The oxyhemoglobin assay was employed to determine the NOS activity of the polycyclic indole derivatives. Results from the assay showed that four compounds, containing the indole moiety, 8-[3-(2-aminoethyl)indole]-pentacycto[5.4.0.0 2,6 .0 3,10 .0 5,9]undecane-11-one (1)3-,hydroxy-4-[3-(2-aminoethyl)indole]-azahexacyclo[5.4.1.0 2,6 .0 3,10 .0 5,9 .0 8,11]dodecane (3), 8-[3-(2-aminoethyl)indole]-pentacyclo[5.4.0 2,6 .0 3,10 .0 5,9]undcane (4) and 8-[3-(2-aminoethyl)indole]-pentacyclo[5.4.0 2,6 .o 3,10 .0 5,9]undecane (5) displayed potencies in the sub millimolar range. Compounds such as 19 and 21 that do not possess an indole moiety, were poor inhibitors of NOS. From the lipid peroxidation study, compounds 1, 2, 3, 4 and 5 showed antioxidative properties comparable to that of trolox. The results obtained in this study clearly indicate the potential of these novel indole cage structures as NOS inhibitors and anti-oxidants. Taking the above aspects into account, together with the described calcium channel activity of the cage structures, these novel compounds may find applications as multipotent drugs in neuroprotection.