Novel anti-breast cancer agents of phenylazopyrazole derivatives: Design, synthesis, Topo IIα inhibitors with potential cytotoxic activity, docking, toxicity and ADME studies

Abstract

Breast cancer remains a major cause of mortality among women globally. Human DNA topoisomerase II (TopoII) is a nuclear protein that plays a crucial role in modulating DNA configurations during the mitotic phase of the cell cycle. TopoIIα is an important therapeutic target for the development of anticancer drugs due to its significant involvement in tumor proliferation.

In this research article, we synthesized a novel series of pyrazole derivatives featuring the carbimidic N'-(4-nitrophenyl)-2-oxopropanehydrazonic thioanhydride at nitrogen-1, aimed at targeting anti-breast cancer activity (MCF-7) and inhibiting topoisomerase IIα. Our in vitro results demonstrated that six pyrazole derivatives 5f, 5e, 7a, 5d, 3, and 7b effectively inhibited MCF7 cell proliferation, with IC₅₀ values ranging from 3.58 to 8.37 μM. This is notably lower than Doxorubicin's IC₅₀ of 4.260 μM. Additionally, the two most reactive pyrazole derivatives, 5e and 5f, were further tested for their ability to inhibit the topoisomerase IIα enzyme. The results showed that derivative 5e inhibited the enzyme at concentrations of 100 mM, 10 mM, and 1 mM, while derivative 5f inhibited the enzyme at 100 mM and 10 mM only. Both derivatives 5e and 5f also caused significant increases in early, late, and total apoptotic cell percentages, recording values of 64.94 %, 31.35 %, and 96.29 % for 5e, and 46.29 %, 49.91 %, and 96.20 % for 5f, respectively. Furthermore, the results of cell cycle analysis using flow cytometry indicated an accumulation of MCF7 cells in the G2 phase for both derivatives 5e and 5f. The docking studies revealed that these two pyrazole derivatives fit well and were properly oriented within the Topo II-DNA complex. Finally, the pharmacokinetics and toxicity profiles for derivatives 5e and 5f indicated that they are less toxic, suitable for oral bioavailability, and exhibit characteristics that are acceptable for drug-like properties.