Novel chalcone derivatives as hypoxia-inducible factor (HIF)-1 inhibitor: Synthesis, anti-invasive and anti-angiogenic properties
Abstract
A novel series of chalcone derivatives were synthesized and their biological activities against HIF-1 were evaluated. Among these compounds, 5d exhibited clearly inhibitory effects on HIF-1 by downregulating the expression of HIF-1α under hypoxic conditions. Meanwhile, it also significantly suppressed VEGF-induced migration and invasion of Hep3B and HUVEC cells in nontoxic concentrations. Additionally, tube formation assay demonstrated its anti-angiogenesis activity. Moreover, the in vivo study indicated that compound 5d could retard tumor growth of Hep3B xenograft models and reduced CD31 and MMP-2 expression in tumor tissues. Finally, in acute intravenous toxicity, 5d was well tolerated and was found to be non-toxic up to 200 mg/kg in Swiss mice. These findings support the further investigation on the anti-invasive and anti-angiogenic potential of this class of compounds as HIF-1 inhibitor.
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3-oxoglutarate (DE-3-oxo) reduces HIF-1α protein levels in normoxic cancer cells independent of PHD-driven proteasomal degradation.
“3-oxoglutarate (DE-3-oxo), an analog of 2-oxoglutarate that is PHDs cofactor, was able to reduce HIF-1α protein levels in normoxic cancer cells independent of PHD -driven proteasomal degradation [361].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [361]
DE-3-oxo was not effective under hypoxia (1% O2), and showed some effect under severe hypoxia (0.1%).
“The compound, however, was not effective under hypoxia (1% O2), and showed some effect under severe hypoxia (0.1%).”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [361]
Cites
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RetractedAngiogenesis as a therapeutic target
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Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth
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HIF inhibition: Current strategies and clinical challenges
Więch-Walów, A., Bartoszewska, S., Barton, A., Czechowicz, P., Dudzik, J., Wielockx, B., Collawn, J. F., & Bartoszewski, R. (2026) · Redox biology · doi:10.1016/j.redox.2026.104220 · Cited by 3 · see citing works
“3-oxoglutarate (DE-3-oxo), an analog of 2-oxoglutarate that is PHDs cofactor, was able to reduce HIF-1 α protein levels in normoxic cancer cells independent of PHD -driven proteasomal degradation [361].”
- Authors
- Wang, L., Chen, G., Lu, X., Wang, S., Han, S., Li, Y., Ping, G., Jiang, X., Li, H., Yang, J., & Wu, C.
- Affiliations
- Shenyang Pharmaceutical University (CN)
- Corresponding author
- Yang, Jingyu
- Wu, Chunfu
- Venue
- European Journal of Medicinal Chemistry
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 89
- Pages
- 88-97
- ISSN
- 0223-5234 (ISSN-L)
- OpenAlex
- W2039343555
- Cited by
- 64
- References
- 6
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 5 · 2023: 5 · 2022: 2 · 2021: 6 · 2020: 9 · 2019: 11 · 2018: 3 · 2017: 5 · 2016: 9 · 2015: 5
- FWCI
- 2.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National High Technology Research and Development Program of China (2012AA020305)
- Excellent Talents Plan in Liaoning Province (LJQ2014111)
- China Postdoctoral Science Foundation funded project (20100481213, 2012T50474)
- Shenyang Pharmaceutical University Science Foundation (ZCJJ2013401)
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Pharmacology › Synthesis of Organic Compounds
- Keywords
- chalcone derivatives, HIF-1, HIF-1α, HIF-1 inhibition, antiangiogenic activity, anti-invasive activity, tube formation, tumor xenografts, Hep3B cells, HUVEC cells, CD31, MMP-2, acute toxicity
- MeSH terms
- Animals, Antineoplastic Agents, Cell Movement, Chalcone, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Male, Mice, Inbred BALB C, Mice, Nude, Neoplasms, Experimental, Structure-Activity Relationship, Tumor Cells, Cultured, Molecular Structure, Angiogenesis Inhibitors, Cell Proliferation, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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