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

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.