期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 63, 期 13, 页码 6821-6833出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c00151
关键词
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资金
- American Cancer Society [122057-RSG-12-045-01-CDD]
- Korean National Research Foundation [NRF-2017R1A2B3002227]
- NSF Graduate Research Fellowship Program
Tumors adapt to hypoxia by regulating angiogenesis, metastatic potential, and metabolism. These adaptations mediated by hypoxia-inducible factor 1 (HIF-1) make tumors more aggressive and resistant to chemotherapy and radiation. Therefore, HIF-1 is a validated therapeutic target for cancer. In order to develop new HIF-1 inhibitors for cancer chemotherapy by harnessing the potential of the natural product manassantin A, we synthesized and evaluated manassantin A analogues with modifications in the tetrahydrofuran core region of manassantin A. Our structure-activity relationship study indicated that the alpha,alpha'-trans-configuration of the central ring of manassantin A is critical to HIF-1 inhibition. We also demonstrated that a combination of manassantin A with an epidermal growth factor receptor inhibitor shows cooperative antitumor activity (similar to 80% inhibition for combination vs similar to 30% inhibition for monotherapy). Our findings will provide important frameworks for the future therapeutic development of manassantin A-derived chemotherapeutic agents.
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