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Evaluation of Manassantin A Tetrahydrofuran Core Region Analogues and Cooperative Therapeutic Effects with EGFR Inhibition.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-06-24 , DOI: 10.1021/acs.jmedchem.0c00151 Seung-Hwa Kwak 1 , Tesia N Stephenson 1 , Hye-Eun Lee 2 , Yun Ge 2 , Hyunji Lee 1 , Sophia M Min 1 , Jea Hyun Kim 1 , Do-Yeon Kwon 1 , You Mie Lee 2 , Jiyong Hong 1, 3
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-06-24 , DOI: 10.1021/acs.jmedchem.0c00151 Seung-Hwa Kwak 1 , Tesia N Stephenson 1 , Hye-Eun Lee 2 , Yun Ge 2 , Hyunji Lee 1 , Sophia M Min 1 , Jea Hyun Kim 1 , Do-Yeon Kwon 1 , You Mie Lee 2 , Jiyong Hong 1, 3
Affiliation
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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 α,α′-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 (∼80% inhibition for combination vs ∼30% inhibition for monotherapy). Our findings will provide important frameworks for the future therapeutic development of manassantin A-derived chemotherapeutic agents.
中文翻译：
评估Manassantin A四氢呋喃核心区域类似物和EGFR抑制的协同治疗效果。
肿瘤通过调节血管生成，转移潜能和新陈代谢来适应缺氧。由缺氧诱导因子1（HIF-1）介导的这些适应使肿瘤更具侵略性，并且对化学疗法和放射线具有抵抗力。因此，HIF-1是经过验证的癌症治疗靶标。为了开发利用天然产物manassantin A的潜力开发的新型HIF-1抑制剂，我们合成并评估了manassantin A的四氢呋喃核心区域中有修饰的manassantin A类似物。我们的结构-活性关系研究表明α，α'-反式-甘露糖苷A中心环的构型对HIF-1抑制至关重要。我们还证明了，将Manassantin A与一种表皮生长因子受体抑制剂联合使用可表现出协同的抗肿瘤活性（联合用药抑制约80％，而单一疗法约抑制30％）。我们的研究结果将为今后从甘蓝素A衍生的化学治疗剂的治疗开发提供重要的框架。
更新日期：2020-07-09
中文翻译：
评估Manassantin A四氢呋喃核心区域类似物和EGFR抑制的协同治疗效果。
肿瘤通过调节血管生成，转移潜能和新陈代谢来适应缺氧。由缺氧诱导因子1（HIF-1）介导的这些适应使肿瘤更具侵略性，并且对化学疗法和放射线具有抵抗力。因此，HIF-1是经过验证的癌症治疗靶标。为了开发利用天然产物manassantin A的潜力开发的新型HIF-1抑制剂，我们合成并评估了manassantin A的四氢呋喃核心区域中有修饰的manassantin A类似物。我们的结构-活性关系研究表明α，α'-反式-甘露糖苷A中心环的构型对HIF-1抑制至关重要。我们还证明了，将Manassantin A与一种表皮生长因子受体抑制剂联合使用可表现出协同的抗肿瘤活性（联合用药抑制约80％，而单一疗法约抑制30％）。我们的研究结果将为今后从甘蓝素A衍生的化学治疗剂的治疗开发提供重要的框架。
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