微生物来源的二氢乳清酸脱氢酶抑制剂F01WB-1315A，B

F01WB-1315 A and B, two dihydroorotate dehydrogenase inhibitors from microbial metabolites

摘要:

摘要：目的 从微生物次生代谢产物中筛选免疫相关疾病治疗药物重要靶点—－二氢乳清酸脱氢酶的抑制剂。方法 利用自建的快速、高效的二氢乳清酸脱氢酶抑制剂的高通量筛选方法，从4560株真菌菌株中筛选阳性菌株。阳性菌株的发酵产物进行分离纯化获得活性化合物，再通过对活性化合物的紫外、质谱、核磁等理化数据的分析进行结构鉴定。结果 筛选分离得到2个活性化合物F01WB-1315A和F01WB-1315B。F01WB-1315A对二氢乳清酸脱氢酶有强的抑制活性，IC50=0.07 μg/mL，于20 μg/mL浓度下对体外

Abstract:

Abstract：Objective Dihydroorotate Dehydrogenase (DHODH) catalyzes the rate-limiting step in pyrimidine biosynthesis, and its inhibitors have been developed as drugs for treatment of immune diseases. We studied new DHODH inhibitors from microbial metabolites. Methods We established a rapid and effective high throughput screening method for screening DHODH inhibitors from microbial metabolites. The active compounds were isolated from the candidate strain by column chromatography and preparative HPLC. Results We picked out F01WB-1315 strain as candidate from 4560 fungal strains. We isolated two active compounds F01WB-1315A and B, with IC50 of 0.07 μg/mL and 0.51 μg/mL, respectively. F01WB-1315B could completely inhibit the spleen lymphocytes proliferation stimulated by ConA in vitro, but F01WB-1315A only had 31.62% inhibitory activity. F01WB-1315A, B were identified to be Ascofuranone and Ascochlorin by their physicochemical properties, MS, 13C-NMR and 1H-NMR analysis. Conclusion F01WB-1315A and B are two strong specific DHODH inhibitors and show moderate inhibitory activity against spleen lymphocytes proliferation.