Synthesis, anti-cancer activity, Pim-3 inhibitory potency and zebrafish larvae toxicity evaluation of indolopyrazolocarbazole derivatives

The pyrazole analogue of the staurosporine aglycone K252c (12,13-dihydro-5 H -indolo[2,3- a ]pyrazolo[3,4- c ]carbazole) was substituted on the indolocarbazole nitrogens by a functionalized three-carbon bridge leading to a series of hemiaminal, hemiaminal ether and aminal derivatives. Cytotoxicity of the new compounds was evaluated toward MOLM-13 acute myeloid leukemia (AML) cell line, identifying compounds 25 , 26 and 29 as highly potent with IC 50 values between 0.015 and 0.064 μM after 24 hours of incubation. These hits were further assessed for their activity against two neuroblastoma (NBL) cell lines (MHH-NB-11 and LAN-5), showing IC 50 values in the range of 0.51 μM to 1.3 μM. We also confirmed that Pim-3 kinase is one target for these pyrazole K252c analogues, even if there is no obvious correlation with the observed cytotoxities. Finally, toxicity toward zebrafish larvae was evaluated to assess the safety profile of compounds 25 , 26 and 29 . Our results demonstrated that the potency and therapeutic window of these hits are favorable for further in vivo study using AML or NBL models.