Development of karapinchamine A-related carbazoles with antiproliferative activity against glioblastoma-derived cancer stem cells and blood-brain barrier permeability.

Karapinchamine A (1)-a geranylated carbazole isolated from the leaves of Bergera koenigii (syn. of Murraya koenigii) (curry leaf)-was synthesized together with twelve N-substituted carbazole derivatives. Their antiproliferative activities were evaluated against cancer stem cells (CSCs) derived from the human glioblastoma (GBM) U-251 MG cell line and against GBM cells (non-CSCs). In addition to compound 1, compounds 4 and 5 bearing a hydroxy group on the carbazole scaffold and a geranyl group at the N-position exhibited activity against CSCs, indicating that these functional groups are essential for biological activity. Furthermore, compound 5 showed stronger activity against CSCs (IC50 = 3.9 μM) than non-CSCs (IC50 = 19.2 μM), suggesting CSC-selective activity. Moreover, compounds 4 and 5 were found to possess blood-brain barrier (BBB) permeability comparable to that of caffeine. Thus, N-geranylated carbazole derivatives such as compound 5, which exhibit selective antiproliferative activity against CSCs and possess BBB permeability, are attractive pharmaceutical lead compounds for the treatment of GBM.