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Molecules 2014, 19(11), 17173-17186; doi:10.3390/molecules191117173

2-(1H-Benzimidazol-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol, a Benzimidazole Derivative, Inhibits T Cell Proliferation Involving H+/K+-ATPase Inhibition

1
Department of Immunology, Chengdu Medical College, Chengdu 610500, China
2
Department of Oncology, Chengdu Military General Hospital, Chengdu 610083, China
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 1 September 2014 / Revised: 13 October 2014 / Accepted: 21 October 2014 / Published: 24 October 2014
(This article belongs to the Section Medicinal Chemistry)
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Abstract

In this study, a benzimidazole derivative named BMT-1 is revealed as a potential immunomodulatory agent. BMT-1 inhibits the activity of H+/K+-ATPases from anti-CD3/CD28 activated T cells. Furthermore, inhibition the H+/K+-ATPases by use of BMT-1 should lead to intracellular acidification, inhibiting T cell proliferation. To explore this possibility, the effect of BMT-1 on intracellular pH changes was examined by using BCECF as a pH-dependent fluorescent dye. Interestingly, increases in the pHi were observed in activated T cells, and T cells treated with BMT-1 showed a more acidic intracellular pH. Finally, BMT-1 targeted the H+/K+-ATPases and inhibited the proliferative response of anti-CD3/CD28-stimulated T cells. A cell cycle analysis indicated that BMT-1 arrested the cell cycle progression of activated T cells from the G1 to the S phase without affecting CD25 expression or interleukin-2 (IL-2) production; treating IL-2-dependent PBMCs with BMT-1 also led to the inhibition of cell proliferation. Taken together, these findings demonstrate that BMT-1 inhibits the proliferation of T cells by interfering with H+/K+-ATPases and down-regulating intracellular pHi. This molecule may be an interesting lead compound for the development of new immunomodulatory agents. View Full-Text
Keywords: benzimidazole derivative; T cell proliferation; H+/K+-ATPases; immunomodulatory benzimidazole derivative; T cell proliferation; H+/K+-ATPases; immunomodulatory
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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).

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MDPI and ACS Style

Liu, J.; Huang, N.; Li, N.; Liu, S.-N.; Li, M.-H.; Li, H.; Luo, X.-Y.; Wang, Y.-T.; Li, L.-M.; Zou, Q.; Liu, Y.; Yang, T. 2-(1H-Benzimidazol-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol, a Benzimidazole Derivative, Inhibits T Cell Proliferation Involving H+/K+-ATPase Inhibition. Molecules 2014, 19, 17173-17186.

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