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Anticancer Res. 2014 Aug;34(8):3891-904.

Benzimidazole analogs as potent hypoxia inducible factor inhibitors: synthesis, biological evaluation, and profiling drug-like properties.

Author information

1
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, U.S.A. Department of Pharmaceutical Sciences, School of Pharmacy, South College, Knoxville, TN, U.S.A.
2
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, U.S.A.
3
Center for Cancer Research, Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, U.S.A.
4
Vascular Biology Center, Department of Internal Medicine, University of Tennessee Health Science Center, Memphis, TN, U.S.A.
5
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, U.S.A. wli@uthsc.edu.

Abstract

AIM:

To develop potent HIF-1α inhibitors for potential treatment of cancer.

MATERIALS AND METHODS:

Chemical synthesis, HIF-luciferase assay, cytotoxic assay, platelet aggregation assay, western blot analysis, quantitative real-time PCR, aqueous solubility, protein binding, metabolic stability, and metabolic pathways.

RESULTS:

Thirteen novel benzimidazole analogs were synthesized. Compounds 3a and 3k showed the highest anti-HIF-1α activity. They are significantly more effective than YC-1 in the suppression of HIF-1α protein expression based on western blot assay. They show comparable potency in inhibition of cancer cell migration. They are less potent in the inhibition of platelet aggregation. 3k had the most favorable drug-like properties, including long half-life in human liver microsomes, medium protein binding level and reasonable aqueous solubility.

CONCLUSION:

The potent anti-HIF-1α activity and favorable drug-like properties of compound 3k suggest that it may hold great potential as an adjuvant therapy for cancer treatment through repression of HIF-1α protein expression.

KEYWORDS:

Benzimidazole; HIF-1α inhibition; drug metabolism; luciferase assay; platelet aggregation running

PMID:
25075010
PMCID:
PMC5346463
[Indexed for MEDLINE]
Free PMC Article
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