Use of copper(I) catalyzed azide alkyne cycloaddition (CuAAC) for the preparation of conjugated pyrrolo[2,3-a]carbazole Pim kinase inhibitors

We have previously demonstrated that pyrrolo[2,3-a]carbazole-3-carbaldehydes are potent Pim kinase inhibitors with in vitro antiproliferative activities. In the present study, we report the synthesis of new pyrrolocarbazoles substituted at the N-10 position. When their ability to inhibit Pim kinase activities were evaluated in in vitro assays, we observed that this nitrogen atom can be substituted without loss of Pim-1 and Pim-3 inhibitory potencies. Moreover, when we added a fluorescent dansyl group (compound 13), we were able to show that 13 penetrates the plasma membrane and enters the cytoplasm.

Graphical abstractCopper (I) Catalyzed Azide Alkyne Cycloaddition (CuAAC) was used for N-10 functionalization of pyrrolo[2,3-a]carbazole kinase inhibitors. CuAAC also enabled the grafting of a fluorescent tracer.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► CuAAC reaction was used for the preparation of conjugated pyrrolo[2,3-a]carbazoles. ► We evaluated Pim kinase inhibitory potency of conjugated pyrrolo[2,3-a]carbazoles. ► Cellular localisation of a fluorescent derivative was determined. ► N-10 can be substituted without loosing inhibitory potencies against Pim-1 or Pim-3.