Synthesis and evaluation of the HIF-1α inhibitory activities of novel ursolic acid tetrazole derivatives

Bioorg Med Chem Lett. 2019 Jun 15;29(12):1440-1445. doi: 10.1016/j.bmcl.2019.04.028.

Lin-Hao Zhang ¹, Zhi-Hong Zhang ¹, Ming-Yue Li ¹, Zhi-Yu Wei ², Xue-Jun Jin ³, Hu-Ri Piao ⁴

Affiliations

1 Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Yanbian University College of Pharmacy, Yanji 133002, China.
2 Medical College of Dalian University, Dalian, Liaoning Province, 116622, China.
3 Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Yanbian University College of Pharmacy, Yanji 133002, China. Electronic address: xjjin@ybu.edu.cn.
4 Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Yanbian University College of Pharmacy, Yanji 133002, China. Electronic address: piaohr@ybu.edu.cn.

PMID: 31006525 DOI: 10.1016/j.bmcl.2019.04.028

Abstract

The hypoxia-inducible factor-1α (HIF-1α) pathway has been implicated in tumor angiogenesis, growth, and metastasis. Therefore, the inhibition of this pathway is an important therapeutic target for the treatment of various types of cancers. Here, we designed and synthesized 31 ursolic acid (UA) derivatives containing a tetrazole moiety and evaluated them for their potential anti-tumor activities as HIF-1α transcriptional inhibitors. Of these, compound 14d (IC₅₀ 0.8 ± 0.2 µM) displayed the most potent activity and compounds 14a (IC₅₀ 4.7 ± 0.2 µM) exhibited the most promising biological profile. Analysis of the structure-activity relationships of these compounds with HIF-1α suggested that the presence of a tetrazole group located at C-28 of the UA derivatives was critical for their inhibitory activities.

Keywords

Cytotoxicity; HIF-1α inhibitor; Tetrazole; Ursolic acid.

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