Pyrrolo[2,3-α]carbazole derivatives as topoisomerase I inhibitors that affect viability of glioma and endothelial cells in vitro and angiogenesis in vivo.

Topoisomerase I is one of the most significant molecular targets through which indolocarbazoles inhibit tumour growth. In the present work, we studied the effect of new pyrrolo[2,3-α]carbazole derivatives on topoisomerase I activity in vitro, as well as on the viability of glioma and endothelial cells in vitro and on angiogenesis in vivo. All the tested compounds significantly decreased topoisomerase I activity in a concentration dependent manner, with the most effective being 1c, 1d(1), 1d(2) and 1f. The number of viable glioma and endothelial cells in vitro was also decreased in a concentration-dependent manner by all the tested compounds, although efficacy and potency differed in endothelial compared with glioma cells. Compounds 1c, 1d(1), 1e and 1f were the most effective in glioma cells, while compounds 1d(2) and 1e were the most effective in decreasing the number of viable endothelial cells. Finally, all the tested compounds inhibited angiogenesis in the chicken embryo chorioallantoic membrane in a significant and dose-dependent manner, with the most effective inhibitor being compound 1d(2). These data suggest that the tested pyrrolo[2,3-α]carbazole derivatives inhibit topoisomerase I activity and may be potentially useful for inhibition of glioma cell growth and angiogenesis.