Identification of Novel Bisbenzimidazole Derivatives as Anticancer Vacuolar (H+)-ATPase Inhibitors

Abstract

The vacuolar (H+)-ATPases (V-ATPases) are a family of ATP-driven proton pumps and they have been associated with cancer invasion, metastasis, and drug resistance. Despite the clear involvement of V-ATPases in cancer, the therapeutic use of V-ATPase-targeting small molecules has not reached human clinical trials to date. Thus, V-ATPases are emerging as important targets for the identification of potential novel therapeutic agents. We identified a bisbenzimidazole derivative (V) as an initial hit from a similarity search using four known V-ATPase inhibitors (I–IV). Based on the initial hit (V), we designed and synthesized a focused set of novel bisbenzimidazole analogs (2a–e). All newly prepared compounds have been screened for selected human breast cancer (MDA-MB-468, MDA-MB-231, and MCF7) and ovarian cancer (A2780, Cis-A2780, and PA-1) cell lines, along with the normal breast epithelial cell line, MCF10A. The bisbenzimidazole derivative (2e) is active against all cell lines tested. Remarkably, it demonstrated high cytotoxicity against the triple-negative breast cancer (TNBC) cell line, MDA-MB-468 (IC50 = 0.04 ± 0.02 μM). Additionally, it has been shown to inhibit the V-ATPase pump that is mainly responsible for acidification. To the best of our knowledge the bisbenzimidazole pharmacophore has been identified as the first V-ATPase inhibitor in its class. These results strongly suggest that the compound 2e could be further developed as a potential anticancer V-ATPase inhibitor for breast cancer treatment.

Bisbenzimidazoles: Anticancer Vacuolar (H+)-ATPase Inhibitors

“…We recently reported the synthesis and detailed characterization of all these new bisbenzimidazoles [42]. In brief, we developed a fast and efficient synthetic one pot procedure to prepare all these analogs (RP-3-RP-15).…”

“…For the more detailed synthesis and spectral and analytical characterization of all these compounds please see Ref. [42].…”

“…Bisbenzimidazoles are nitrogen heterocycles with wide spectrum of biological activities. We reported the focused set of bisbenzimidazoles as anticancer V-ATPase agents (Figure 3) [42]. Bisbenzimidazole derivatives (RP-3-RP-15) have been screened in selected human breast cancer (MDA-MB-231, MDA-MB-468, MCF-7) and ovarian cancer (cisplatin-sensitive A2780, cisplatin-resistant Cis-A2780 and PA-1) cell lines.…”

Vacuolar H+-ATPases (V-ATPases) as therapeutic targets: a brief review and recent developments

“…Results of such an approach to identifying V-ATPase-directed anti-cancer molecules recently appeared. Virtual screening was performed, directed by the structures of four disparate V-ATPase-inhibitors, enoxacin, diphyllin, benzimidazole analog and NIK-12192 (105). The virtual screen was performed assaying chemical compounds in the University of Cincinnati, Drug Discovery Center (UC DDC) Library, consisting of 362,000 compounds, and the National Cancer Institute (NCI) Small Molecule Repository (SMR), with 263,365 compounds.…”

“…An initial lead molecule was identified and variations were synthesized. This process identified a novel bisbenzimidazole pharmacophore that has a mid-nanomolar IC 50 toward MDA-MB-468 cells and represents the first V-ATPase inhibitor of its class (105).…”