New 1,4-Dihydropyrazolo[4,3-b]indoles Induce Antiproliferation of Acute Myeloid Leukemia Cells and Inhibition of Selective Inflammatory Cytokines

Research on multitargeting drugs is emerging, focusing on the discovery of agents that simultaneously act on more than one biological target. Here, a novel synthetic route to access the fused-heterocycles 1,4-dihydropyrazolo[4,3-b]indoles (4) from pyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide (3) via [H2O-SO2] elimination and an intramolecular ring-closing reaction is reported. Two lead compounds 3b and 4b were found to show significant inhibition of cell growth by suppressing cell cycle progression at the G(0)/G(1) phases and inducing apoptosis of the acute myeloid leukemia OCI-AML3 cell line. Both compounds also significantly decreased tumor necrosis factor-alpha and transforming growth factor-beta (at all tested concentrations), whereas no effect was seen on other cytokines (interleukin-4, interferon-gamma, interleukin-9, interleukin-12). Thus, these compounds are promising leads in the discovery of novel anticancer agents.

Automated summary

The research focuses on multitargeting drugs and the discovery of agents that can act on multiple biological targets. In this study, a novel synthetic route to fused-heterocycles, 1,4-dihydropyrazolo[4,3-b]indoles, was reported. Two lead compounds, 3b and 4b, showed significant inhibition of cell growth, induced apoptosis in leukemia cells, and decreased levels of tumor necrosis factor-alpha and transforming growth factor-beta. These compounds have potential as novel anticancer agents.