Potential Antidiabetic Fumiquinazoline Alkaloids from the Marine Derived Fungus Scedosporium apiospermum F41-1
Potential Antidiabetic Fumiquinazoline Alkaloids from the Marine Derived Fungus Scedosporium apiospermum F41-1
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来自海洋源性真菌 Scedosporium apiospermum F41â1 的潜在抗糖尿病文喹唑啉生物碱
DOI：
10.1021/acs.jnatprod.9b01096
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发表时间：
2020-04-24
影响因子：
5.1
通讯作者：
Lan, Wen-Jian
中科院分区：
文献类型：
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作者：
Li, Chan-Juan;Chen, Pei-Nan;Lan, Wen-Jian
富米喹唑啉类生物碱因其独特的结构和潜在的生物学价值而受到医药和天然产物化学家的广泛关注。本研究从海洋真菌apiospermum F41-1中分离得到3个新的和12个已知的fumiquinazoline生物碱，并对其进行了鉴定。新化合物的结构及其绝对构型通过核磁共振波谱、ECD和OR计算确定。通过使用3T3-L1脂肪细胞测定其甘油三酯促进活性来评估这些化合物的抗糖尿病潜力。其中一种新化合物，scequinadoline J(14)，以及scequinadoline D(9)和E(10)，被发现可以促进甘油三酯在3T3-L1细胞中的积累。Scequinadoline D(9)的活性最强，EC50值为0.27 +/- 0.03 μ m。定量聚合酶链反应实验表明，Scequinadoline D(9)通过激活PPAR γ通路起作用。刺激PPAR γ、AMPK α、C/EBP α、LXR α、SCD-1和FABP4的mRNA表达。此外，双剂量PPAR γ拮抗剂GW9662可阻断其促进甘油三酯的作用。这些结果表明，scequinadoline D(9)是一种有效的针对脂肪细胞的胰岛素增敏剂，在进一步研究后可能对2型糖尿病的治疗有用。
Fumiquinazoline alkaloids have attracted much attention from medicinal and natural product chemists due to their interesting structures and biological potential. In this study, three new and 12 known fumiquinazoline alkaloids were isolated and characterized from the marine fungus Scedosporium apiospermum F41-1. The structures of the new compounds and their absolute configurations were determined using NMR spectroscopy, ECD, and OR calculations. The compounds were evaluated for their antidiabetic potential by determining their triglyceride-promoting activity using 3T3-L1 adipocytes. One of the new compounds, scequinadoline J (14), as well as scequinadolines D (9) and E (10), was found to promote triglyceride accumulation in 3T3-L1 cells. Scequinadoline D (9) demonstrated the most potent activity, with an EC50 value of 0.27 +/- 0.03 mu M. Quantitative polymerase chain reaction experiments suggested that scequinadoline D (9) acts through activation of the PPAR gamma pathway. It stimulated the mRNA expression of PPAR gamma, AMPK alpha, C/EBP alpha, LXR alpha, SCD-1, and FABP4. In addition, its triglyceride-promoting efficacy could be blocked by a double dose of the PPAR gamma antagonist GW9662. These results indicated that scequinadoline D (9) is a potent insulin sensitizer that targets adipocytes and may be useful for the treatment of type 2 diabetes mellitus after further investigation.