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

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Oncology

Background:

• Vacuolar (H⁺)-ATPases (V-ATPases) are proton pumps implicated in cancer progression, including invasion, metastasis, and drug resistance.
• Despite their known role in cancer, V-ATPase-targeting therapeutics have not yet advanced to human clinical trials, highlighting the need for novel agents.
• V-ATPases are emerging as critical targets for developing new anticancer therapies.

Purpose of the Study:

• To identify and synthesize novel bisbenzimidazole analogs as potential V-ATPase inhibitors.
• To evaluate the anticancer activity of these compounds against various human cancer cell lines, including breast and ovarian cancers.
• To assess the potential of these compounds as therapeutic agents for cancer treatment.

Main Methods:

• A similarity search identified a bisbenzimidazole derivative (V) as an initial hit against known V-ATPase inhibitors.
• A focused library of novel bisbenzimidazole analogs (2a-e) was designed and synthesized based on the initial hit.
• The synthesized compounds were screened for cytotoxicity against human breast cancer (MDA-MB-468, MDA-MB-231, MCF7), ovarian cancer (A2780, Cis-A2780, PA-1), and normal breast epithelial (MCF10A) cell lines.

Main Results:

• Compound 2e demonstrated activity against all tested cancer cell lines.
• Remarkably, compound 2e exhibited high cytotoxicity against the triple-negative breast cancer (TNBC) cell line MDA-MB-468, with an IC50 of 0.04 ± 0.02 μM.
• Compound 2e was shown to inhibit V-ATPase activity, which is crucial for cellular acidification.

Conclusions:

• The bisbenzimidazole scaffold represents a novel class of V-ATPase inhibitors.
• Compound 2e is a potent V-ATPase inhibitor with significant cytotoxicity against multiple cancer cell lines, particularly TNBC.
• Compound 2e warrants further investigation as a potential therapeutic candidate for breast cancer treatment.