Alutacenoic acids A and B, rare naturally occurring cyclopropenone derivatives isolated from fungi: Potent non-peptide factor XIIIa inhibitors
Alutacenoic acids A and B, rare naturally occurring cyclopropenone derivatives isolated from fungi: Potent non-peptide factor XIIIa inhibitors
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DOI：
10.1021/ja992355s
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发表时间：
2000-03-01
影响因子：
15
通讯作者：
Ogita, T
中科院分区：
文献类型：
--
作者：
Kogen, H;Kiho, T;Ogita, T
XIII 因子是一种血浆转谷氨酰胺酶，作用于凝血级联的最后一步。 1 因子 XIII 作为酶原存在于血浆中，并在 Ca2+ 存在的情况下被凝血酶激活为因子 XIIIa，这一过程揭示了半胱氨酸活性中心。 2 该酶可共价交联纤维蛋白单体，并将软纤维蛋白凝块转化为硬凝块。 3 这些凝块被纤溶酶或组织纤溶酶原激活剂等药物溶解的速度较慢。此外，还已知因子 XIIIa 可使纤维蛋白与细胞外基质交联，例如玻连蛋白、纤连蛋白和胶原蛋白，从而在血管壁上形成额外的凝块。因此，XIIIa 因子的特异性抑制剂被认为可以为血栓形成、1a 动脉粥样硬化和冠心病的治疗提供可能性，4 并且已经报道了一些此类抑制剂。除了几种肽 5 和合成化合物 L-722,151, 6 之外，Tymiak 还报道了一种已知的抗菌剂浅蓝素 7，它对 XIIIa 因子具有抑制活性 (10 μM) 8 。据我们所知，浅蓝素是唯一天然存在的非肽因子 XIIIa 抑制剂。在这里，我们报告了从真菌中分离出新型特异性非肽因子 XIIIa 抑制剂、五烯酸 A (1a) 和 B (1b)。这两种化合物都具有从天然来源中分离出的极为罕见的环丙烯酮环。我们最近的筛选工作集中在寻找 XIIIa 因子的特异性抑制剂。经过我们的努力，我们分离出了五烯酸 A (1a) 和 B (1b) 9 (1a，IC50) 1.9 μM； 1b，IC50) 0.61 μM)，10 一对来自 Eupenicillium alutaceum Scott 的真菌代谢物，11 并发现它们是
Factor XIII is a plasma transglutaminase which acts on the final step in the blood coagulation cascade. 1 Factor XIII exists in plasma as a zymogen and is activated to factor XIIIa by thrombin in the presence of Ca2+ in a process that reveals a cysteine active center. 2 The enzyme covalently cross-links fibrin monomers and converts soft fibrin clots to hard clots. 3 These clots are less rapidly lysed by agents such as plasmin or tissue plasminogen activator. In addition, factor XIIIa is also known to cross-link fibrin to extracellular matrixes, such as vitronectin, fibronectin, and collagen, thereby forming additional clots to the vessel wall. Specific inhibitors of factor XIIIa are therefore thought to offer possibilities in the therapy for thrombosis, 1a atherosclerosis, and coronary heart disease, 4 and a few such inhibitors have already been reported. In addition to several peptides5 and the synthetic compound L-722,151, 6 a known antimicrobial agent, cerulenin, 7 has also been reported by Tymiak to show inhibitory activity (10 μM) 8 against factor XIIIa. To our knowledge, cerulenin is the only naturally occurring non-peptide factor XIIIa inhibitor. Here we report the isolation of novel specific non-peptide inhibitors of factor XIIIa, alutacenoic acids A (1a) and B (1b), from fungi. Both compounds have an extremely rare cyclopropenone ring isolated from natural sources.Our recent screening efforts have concentrated on the search for specific inhibitors of factor XIIIa. As a result of our efforts, we have isolated alutacenoic acids A (1a) and B (1b) 9 (1a, IC50) 1.9 μM; 1b, IC50) 0.61 μM), 10 a pair of fungal metabolites from Eupenicillium alutaceum Scott, 11 and found them to be