Synthesis of vincamine derivatives via Pictet-Spengler reaction leads to additional unexpected oxidized spirocyclic byproducts-Initial investigations in cytotoxic, anti-diabetic, enzyme inhibition as well as anti-herbivore activities.

Vincamine, a monoterpene indole alkaloid from Vinca minor, possesses a wide range of pharmacologically important biological activities including anticancer properties as well as antidiabetic and anti-Alzheimer's effects. Starting from tryptamine and various functionalized 5-chlorovaleraldehydes, seven vincamine derivatives containing a tetrahydro-β-carboline- (THBC)-scaffold were synthesized via Pictet-Spengler reaction. Selected products were further converted to their corresponding N-Boc functionalized counterparts. In addition to the THBC-compounds two sets of oxidized byproducts, open-chain formamides and spirocyclic molecules, were isolated from the Pictet-Spengler reaction. The latter showed a very distinct three-dimensional curved structure, which could lead to potential applications not only as lead compounds in drug development but also as ligands for metal ion coordination and thus as potential catalysts in synthesis. In this work, selected synthesized compounds were tested for biological activities in various assays representing the abovementioned properties of vincamine to gain insight in structure-activity-relationships. We could determine cytotoxic effects of vincamine derivatives in the low double digit micromolar range with the lowest IC50 value being 16 μM for 1-cyclohexyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine. Furthermore, promising results were obtained for BChE inhibition, again with IC50 values in the low micromolar range for most of the compounds. The most interesting result for α-glucosidase inhibition was achieved by N-Boc-1-methyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine with an IC50 value of 17 μM.