Identification of Novel Bisbenzimidazole Derivatives as Anticancer Vacuolar (H+)-ATPase Inhibitors†
AbstractThe 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. View Full-Text
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Patil, R.; Kulshrestha, A.; Tikoo, A.; Fleetwood, S.; Katara, G.; Kolli, B.; Seibel, W.; Gilman-Sachs, A.; Patil, S.A.; Beaman, K.D. Identification of Novel Bisbenzimidazole Derivatives as Anticancer Vacuolar (H+)-ATPase Inhibitors. Molecules 2017, 22, 1559.
Patil R, Kulshrestha A, Tikoo A, Fleetwood S, Katara G, Kolli B, Seibel W, Gilman-Sachs A, Patil SA, Beaman KD. Identification of Novel Bisbenzimidazole Derivatives as Anticancer Vacuolar (H+)-ATPase Inhibitors. Molecules. 2017; 22(9):1559.Chicago/Turabian Style
Patil, Renukadevi; Kulshrestha, Arpita; Tikoo, Anjali; Fleetwood, Sara; Katara, Gajendra; Kolli, Bala; Seibel, William; Gilman-Sachs, Alice; Patil, Shivaputra A.; Beaman, Kenneth D. 2017. "Identification of Novel Bisbenzimidazole Derivatives as Anticancer Vacuolar (H+)-ATPase Inhibitors." Molecules 22, no. 9: 1559.
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