通过化疗选择性先转移酶和它们的α-葡萄糖酶抑制作用的二甲基化 stilbenoids
Min Yang1, Jun Jin2, Jiale Yi3
1School of Pharmaceutical Sciences, Key Laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region, Ministry of Education, Guizhou University, Guiyang 550025, China.
Bioorganic chemistry
|February 12, 2025
概括
工程酶创造了新的C-二甲基化 stilbenoids,扩大了结构的多样性. 几种化合物显示出显著的α-葡萄糖酶抑制,为糖尿病和抗肥胖药物开发提供了潜力.
科学领域:
- 自然产品化学 自然产品化学
- 酶合成酶的合成
- 药用化学 医学化学
背景情况:
- 甲基前化斯蒂尔贝诺酸具有有益的健康特性,并表现出显著的α-葡萄糖酶抑制活性.
- 双甲基化 stilbenoids 是一类具有潜在治疗应用的天然产品.
研究的目的:
- 通过使用工程化真菌prenyltransferase AnaPT.研究八种stilbenoids的酶式二甲基化.
- 通过化学选择性C-dimethylallylation扩大自然存在的二甲基化 stilbenoids 的结构多样性.
- 评估合成化合物对潜在的抗糖尿病和抗肥胖应用的α-葡萄糖酶抑制作用.
主要方法:
- 采用工程性真菌前转移酶AnaPT变体 (AnaPT_F265D,AnaPT_F265G) 进行化学选择性C-二甲基化八种斯蒂尔贝诺因.
- 合成十七种C-二甲基化 stilbenoids,包括十二个单基和五个二基替代产品.
- 进行分子对接研究,以确定参与酶基质相互作用的关键残留物.
- 评估合成化合物的α-葡萄糖酶抑制活性,并将其与acarbose进行比较.
主要成果:
- 成功合成了十七种C-二甲基化 stilbenoids,其中十种化合物首次报告.
- 通过分子对接,确定N115是AnaPT中可能的关键残留物.
- 在AnaPT突变AnaPT_F265D_N115K和AnaPT_F265D_N115A.A.中证明了增强的催化效率.
- 合成的8种化合物表现出显著的α-葡萄糖酶抑制作用,其中8D1化合物显示出大约40倍于阿卡尔的强度.
结论:
- 这项研究通过酶合成显著丰富了二甲基化 stilbenoids 的结构多样性.
- 合成化合物,特别是8D1的强有力的α-葡萄糖酶抑制活性突出了它们作为治疗剂的潜力.
- 这些发现为开发由stilbenoids衍生的新型抗糖尿病和抗肥胖药物提供了基础.
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