title: Benzimidazole analogs as potent hypoxia inducible factor inhibitors: synthesis, biological evaluation, and profiling drug-like properties.
abstract: OBJECTIVE
  To develop potent HIF-1α inhibitors for potential treatment of cancer.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors: 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.
authors: Jianjun
authors: J
authors: Chen
authors: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, U.S.A.
authors: Jin
authors: J
authors: Wang
authors: Center for Cancer Research, Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, U.S.A.
authors: Luciana P
authors: LP
authors: Schwab
authors: Center for Cancer Research, Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, U.S.A.
authors: Kyung-Tae
authors: KT
authors: Park
authors: Center for Cancer Research, Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, U.S.A.
authors: Tiffany N
authors: TN
authors: Seagroves
authors: Vascular Biology Center, Department of Internal Medicine, University of Tennessee Health Science Center, Memphis, TN, U.S.A.
authors: Lisa K
authors: LK
authors: Jennings
authors: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, U.S.A.
authors: Duane D
authors: DD
authors: Miller
authors: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, U.S.A. wli@uthsc.edu.
authors: Wei
authors: W
authors: Li
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004355:Drug Stability; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D012995:Solubility; D013045:Species Specificity
chemical_list: D001562:Benzimidazoles; D051795:Hypoxia-Inducible Factor 1, alpha Subunit
keywords: Benzimidazole; HIF-1α inhibition; drug metabolism; luciferase assay; platelet aggregation running