Total synthesis and biological evaluation of 7-hydroxyneolamellarin A as hypoxia-inducible factor-1α inhibitor for cancer therapy

  • Bioorg Med Chem Lett. 2021 Oct 15;50:128338. doi: 10.1016/j.bmcl.2021.128338.
Guangzhe Li  1 ,  Yujie Shao  2 ,  Yue Pan  2 ,  Yueqing Li  2 ,  Yang Wang  3 ,  Liu Wang  2 ,  Xu Wang  2 ,  Kun Shao  3 ,  Shisheng Wang  2 ,  Naixuan Liu  2 ,  Jingdong Zhang  4 ,  Weijie Zhao  2 ,  Hiroyuki Nakamura  5
Affiliations
  • 1. State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Sciences, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China. Electronic address: [email protected].
  • 2. State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Sciences, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China.
  • 3. State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China.
  • 4. Medical Oncology Department of Gastrointestinal Cancer, Liaoning Cancer Hospital & Institute, Cancer Hospital of China Medical University, Shenyang 110042, China.
  • 5. Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Nagatsuta-cho, Midori-ku, Yokohama 226-8503, Japan.
PMID: 34469710 DOI: 10.1016/j.bmcl.2021.128338
Abstract

7-Hydroxyneolamellarin A (7-OH-Neo A, 1), a natural marine product derived from Sponge Dendrilla nigra, was first synthesized with 10% overall yield under the instruction of convergent synthetic strategy. We found that 7-OH-Neo A could attenuate the accumulation of hypoxia-inducible factor-1α (HIF-1α) protein and inhibit vascular epidermal growth factor (VEGF) transcriptional activity, showing well inhibitory effect on HIF-1 signaling pathway. Meantime, 7-OH-Neo A had the well anti-tumor activities, such as inhibiting tumor angiogenesis, proliferation, migration and invasion. More importantly, 7-OH-Neo A exhibited profound anti-tumor effect in mice breast Cancer model by suppressing the accumulation of HIF-1α in tumor tissue. Mechanism study demonstrated that 7-OH-Neo A might target the protein with the ability of stabilizing HIF-1α in hypoxia. Due to the excellent water solubility, superior anti-tumor activity and good biocompatibility, 7-OH-Neo A shows the promising potential for being exploited as an anti-tumor agent in near future.

Keywords
7-Hydroxyneolamellarin A; Anti-tumor; HIF-1α inhibition; Total synthesis.
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