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

• Published in: Bioorganic & medicinal chemistry letters 2021-10, Vol.50, p.128338-128338, Article 128338
• Main Authors: Li, Guangzhe, Shao, Yujie, Pan, Yue, Li, Yueqing, Wang, Yang, Wang, Liu, Wang, Xu, Shao, Kun, Wang, Shisheng, Liu, Naixuan, Zhang, Jingdong, Zhao, Weijie, Nakamura, Hiroyuki
• Format: Article
• Language: English
• Subjects: 7-Hydroxyneolamellarin A; Animals; Anti-tumor; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological Products - chemical synthesis; Biological Products - chemistry; Biological Products - pharmacology; Cell Line, Tumor; Gene Expression Regulation, Neoplastic - drug effects; HIF-1α inhibition; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors; Porifera; Total synthesis; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2021.128338

[Display omitted] •7-Hydroxyneolamellarin A (7-OH-Neo A) was first total synthesized.•The HIF-1 inhibitory effects of 7-OH-Neo A were evaluated in vitro and in vivo.•The anti-tumor activities of 7-OH-Neo A were first evaluated in vitro and in vivo.•7-OH-Neo A might inhibit the protein activity which could stabilize HIF-1α. 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.