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.

Copper (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 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.