College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China.
Shanghai Engineering Research Center of Hadal Science and Technology, College of Marine Sciences, Shanghai Ocean University, Shanghai 201306, China.
Mar Drugs. 2021 Apr 15;19(4):218. doi: 10.3390/md19040218.
2,5-Bis-[8-(4,8-dimethyl-nona-3,7-dienyl)-5,7-dihydroxy-8-methyl-3-keto-1,2,7,8-teraahydro-6-pyran[]isoindol-2-yl]-pentanoic acid (FGFC1) is a marine pyran-isoindolone derivative isolated from a rare marine microorganism FG216, which showed moderate antithrombotic(fibrinolytic) activity. To further enhance its antithrombotic effect, a series of new FGFC1 derivatives (-) were synthesized via chemical modification at C-2 and C-2' phenol groups moieties and C-1″ carboxyl group. Their fibrinolytic activities in vitro were evaluated. Among the derivatives, - and showed significant fibrinolytic activities with EC of 59.7, 87.1, 66.6, 82.8, and 42.3 μM, respectively, via enhancement of urokinase activity. Notably, derivative presented the most remarkable fibrinolytic activity (2.72-fold than that of FGFC1). Furthermore, the cytotoxicity of derivative was tested as well as expression of Fas/Apo-1 and IL-1 on HeLa cells. The results showed that, compared to FGFC1, derivative possessed moderate cytotoxicity and apoptotic effect on HeLa cells (statistical significance > 0.1), making a potential antithrombotic agent towards clinical application.
2,5-双-[8-(4,8-二甲基-3,7-壬二烯基)-5,7-二羟基-8-甲基-3-酮-1,2,7,8-四氢-6-吡喃[2,3-b]异吲哚-2-基]-戊酸（FGFC1）是一种从罕见海洋微生物 FG216 中分离得到的海洋吡喃异吲哚酮衍生物，具有中等抗血栓（纤溶）活性。为了进一步增强其抗血栓作用，通过化学修饰 C-2 和 C-2'酚基团和 C-1″羧基，合成了一系列新型 FGFC1 衍生物（-）。体外评估了它们的纤溶活性。在这些衍生物中，-和-通过增强尿激酶活性，表现出显著的纤溶活性，EC 分别为 59.7、87.1、66.6、82.8 和 42.3 μM。值得注意的是，衍生物-表现出最显著的纤溶活性（比 FGFC1 高 2.72 倍）。此外，还测试了衍生物-的细胞毒性以及 Fas/Apo-1 和 IL-1 在 HeLa 细胞中的表达。结果表明，与 FGFC1 相比，衍生物-对 HeLa 细胞具有中等的细胞毒性和凋亡作用（统计学意义 > 0.1），使其成为一种有潜力的抗血栓药物，可用于临床应用。
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