[F01WB-1315 A and B, two dihydroorotate dehydrogenase inhibitors from microbial metabolites].
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 microg/mL and 0.51 microg/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.


CONCLUSIONS
F01WB-1315A and B are two strong specific DHODH inhibitors and show moderate inhibitory activity against spleen lymphocytes proliferation.
Qi
Qiaojuan
Q
College of Life Science, Hebei Normal University, Shijiazhuang 050016, China. qqj@sohu.com
Lu
Xinhua
X
Zheng
Zhihui
Z
Li
Yeying
Y
Fan
Yuling
Y
Zhu
Jingtong
J
Ren
Xiao
X
Cui
Xiaolan
X
Shi
Ying
Y
Li
Shaojing
S
Zhang
Hua
H
Zhao
Baohua
B
D000475:Alkenes / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D005658:Fungi / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors*; D010636:Phenols / Q000378:metabolism / Q000494:pharmacology; D012717:Sesquiterpenes / Q000378:metabolism / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization
D000475:Alkenes; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D010636:Phenols; D012717:Sesquiterpenes; D044925:Oxidoreductases Acting on CH-CH Group Donors; C006640:ascofuranone; C415745:ascochlorin