Benzimidazole analogs as potent hypoxia inducible factor inhibitors

Synthesis, biological evaluation, and profiling drug-like properties

Jianjun Chen, Jin Wang, Luciana P. Schwab, Kyung Tae Park, Tiffany Seagroves, Lisa K. Jennings, Duane Miller, Wei Li

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3891-3904
Number of pages14
JournalAnticancer research
Volume34
Issue number8
StatePublished - Aug 1 2014

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Drug Evaluation
Platelet Aggregation
Protein Binding
Solubility
Western Blotting
Cell Migration Inhibition
Neoplasms
Liver Microsomes
Metabolic Networks and Pathways
Luciferases
Pharmaceutical Preparations
Half-Life
Real-Time Polymerase Chain Reaction
Proteins
benzimidazole
Hypoxia
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Benzimidazole analogs as potent hypoxia inducible factor inhibitors : Synthesis, biological evaluation, and profiling drug-like properties. / Chen, Jianjun; Wang, Jin; Schwab, Luciana P.; Park, Kyung Tae; Seagroves, Tiffany; Jennings, Lisa K.; Miller, Duane; Li, Wei.

In: Anticancer research, Vol. 34, No. 8, 01.08.2014, p. 3891-3904.

Research output: Contribution to journalArticle

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AU - Park, Kyung Tae

AU - Seagroves, Tiffany

AU - Jennings, Lisa K.

AU - Miller, Duane

AU - Li, Wei

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AB - 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.

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