Novel chalcone derivatives as hypoxia-inducible factor (HIF)-1 inhibitor: synthesis, anti-invasive and anti-angiogenic properties

Lihui Wang; Guoliang Chen; Xiuhong Lu; Shuang Wang; Shanghe Han; Yi Li; Guanfang Ping; Xiaorui Jiang; Huahuan Li; Jingyu Yang; Chunfu Wu

doi:10.1016/j.ejmech.2014.10.036

Novel chalcone derivatives as hypoxia-inducible factor (HIF)-1 inhibitor: synthesis, anti-invasive and anti-angiogenic properties

Eur J Med Chem. 2015 Jan 7:89:88-97. doi: 10.1016/j.ejmech.2014.10.036. Epub 2014 Oct 14.

Authors

Lihui Wang¹, Guoliang Chen², Xiuhong Lu², Shuang Wang¹, Shanghe Han², Yi Li¹, Guanfang Ping³, Xiaorui Jiang¹, Huahuan Li¹, Jingyu Yang⁴, Chunfu Wu⁵

Affiliations

¹ Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
² Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
³ Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
⁴ Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China. Electronic address: [email protected].
⁵ Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China. Electronic address: [email protected].

PMID: 25462229
DOI: 10.1016/j.ejmech.2014.10.036

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.

Keywords: Angiogenesis; Cancer; Chalcone; Hypoxia-inducible factor-1; Invasion.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiogenesis Inhibitors / chemical synthesis
Angiogenesis Inhibitors / chemistry
Angiogenesis Inhibitors / pharmacology*
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Movement / drug effects
Cell Proliferation / drug effects
Chalcone / chemical synthesis
Chalcone / chemistry
Chalcone / pharmacology*
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Molecular Structure
Neoplasms, Experimental / drug therapy*
Neoplasms, Experimental / pathology
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Angiogenesis Inhibitors
Antineoplastic Agents
HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
Chalcone