N-Fused Imidazoles As Novel Anticancer Agents That Inhibit Catalytic Activity of Topoisomerase IIα and Induce Apoptosis in G1/S Phase

Abstract

On the basis of structures of known topoisomerase II catalytic inhibitors and initial molecular docking studies, bicyclic N-fused aminoimidazoles were predicted as potential topoisomerase II inhibitors. They were synthesized by multicomponent reactions and evaluated against human topoisomerase IIα (hTopoIIα) in decatenation, relaxation, cleavage complex, and DNA intercalation in vitro assays. Among 31 compounds of eight different bicyclic scaffolds, it was found that imidazopyridine, imidazopyrazole, and imidazopyrazine with suitable substituents exhibited potent inhibition of catalytic activity of hTopoIIα while not showing DNA intercalation. Molecular docking studies and molecular dynamics (MD) simulation analysis, ATPase-kinetics and ATP-dependent plasmid relaxation assay revealed the catalytic mode of inhibition of the title compounds plausibly by blocking the ATP-binding site. N-Fused aminoimidazoles showed potent anticancer activities in kidney and breast cancer cell lines, low toxicity to normal cells, relatively higher potency compared to etoposide and 5-fluorouracil in kidney cancer cell lines, and potent inhibition in cell migration. These compounds were found to exert apoptotic effect in G1/S phase.

Imidazole inhibits autophagy flux by blocking autophagic degradation and triggers apoptosis via increasing FoxO3a-Bim expression

“…Misonidazole can sensitize hypoxic tumor cells to radiation therapy and directly kill hypoxic cancer cells (5,6). Furthermore, N-fused imidazoles inhibited catalytic activity of topoisomerase IIα and induced apoptosis at the G1/S phase in kidney and breast cancer cell lines (7). Temozolomide is an alkylating drug that induces apoptosis and senescence in glioma cells (8).…”

Switch in Site of Inhibition: A Strategy for Structure-Based Discovery of Human Topoisomerase IIα Catalytic Inhibitors

“…16,23 With increasing concentration of the investigated compounds, the cell viability of HEK 293 significantly decreased in comparison to Vero cells. Compounds killed 50% HEK 293 cells (LC 50 ) at 10, 10, 8, 15, and 13 μM, respectively (Figure 2).…”

“…20 The hTopoIIα-inhibitory activities of synthesized compounds were investigated by in vitro ATP-dependent decatenation and relaxation assays in agarose gel electrophoresis. 16 In agarose gel, catenated kinetoplast DNA (kDNA) cannot enter due to its large size and appears at the top; whereas the decatenated products (nicked (Nck), relaxed (Rel), and supercoiled (SC) DNA) move easily into the gel. 16,21 Interestingly, compared to etoposide, negligible decatenated products were observed in the presence of compounds 5f, 5g, and 6a−e, and relatively less decatenation occurred for compounds 5d, 5e, and 5i ( Figure 1a).…”

Synthesis and cytotoxicity studies of 1-propenyl-1,3-dihydro-benzimidazol-2-one

“…Benzimidazolone scaffold is one of the key scaffolds of a variety of heterocyclic compounds that play crucial roles in the modulation of a number of biologically important pathways [8][9][10][11]. Thus, benzimidazole and its derivatives representing a major class of nitrogencontaining heterocycles have gained an important role in the drug discovery [12][13][14][15]. The biological importance of benzimidazole derivatives is due to their structural resemblance to the naturally occurring nucleotides.…”