Next Article in Journal
A New Erythrinan Alkaloid Glycoside from the Seeds of Erythrina crista-galli
Next Article in Special Issue
Anticarcinogenic Effect of Spices Due to Phenolic and Flavonoid Compounds—In Vitro Evaluation on Prostate Cells
Previous Article in Journal
Comparison of Two Components of Propolis: Caffeic Acid (CA) and Caffeic Acid Phenethyl Ester (CAPE) Induce Apoptosis and Cell Cycle Arrest of Breast Cancer Cells MDA-MB-231
Previous Article in Special Issue
Design and Antiproliferative Evaluation of Novel Sulfanilamide Derivatives as Potential Tubulin Polymerization Inhibitors
Article Menu
Issue 9 (September) cover image

Export Article

Open AccessArticle
Molecules 2017, 22(9), 1559; doi:10.3390/molecules22091559

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

1
Pharmaceutical Sciences Department, College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
2
Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
3
Division of Oncology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
Part of the research was presented in 253rd American chemical Society (ACS) National Meeting & Exposition, San Francisco, CA, United States, April 2-6, 2017, MEDI-155.
*
Authors to whom correspondence should be addressed.
Received: 14 July 2017 / Revised: 31 August 2017 / Accepted: 13 September 2017 / Published: 16 September 2017
View Full-Text   |   Download PDF [5312 KB, uploaded 16 September 2017]   |  

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 (IIV). Based on the initial hit (V), we designed and synthesized a focused set of novel bisbenzimidazole analogs (2ae). 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
Keywords: vacuolar (H+)-ATPase (V-ATPase); inhibitor; bisbenzimidazole; breast cancer; ovarian cancer; antiproliferative activity; proton (H+) pump activity vacuolar (H+)-ATPase (V-ATPase); inhibitor; bisbenzimidazole; breast cancer; ovarian cancer; antiproliferative activity; proton (H+) pump activity
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Supplementary material

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

MDPI and ACS Style

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.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]

Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top