Novel reduced benzo[j]fluranthen-3-ones from Cladosporium cf. cladosporioides with cytokine production and tyrosine kinase inhibitory properties.
A series of reduced benzo[j]fluoranthen-3-ones (1-4) was isolated from fermentations of a fungal strain CBUK20700 (CBS 100220), classified as Cladosporium cf. cladosporioides, during a microbial extract screening programme to identify inhibitors of anti-CD28-induced interleukin-2 (IL-2) production by Jurkat E6-1 cells as potential immunosuppressive agents. These compounds were also found to be tyrosine kinase inhibitors. The structures of compounds 1-4 were elucidated by spectroscopic methods including the HMQC, HMBC and NOESY NMR experiments. The most potent compound in the series, (6bS,7R,8S)-7-methoxy-4,8,9-trihydroxy-1,6b,7,8-tetrahydro-2H-benzo[j]fluoranthen-3-one (1) inhibited anti-CD28-induced IL-2 production and Abl tyrosine kinase with IC50 values of 400 and 60 nM respectively. The 6b-stereoisomeric 2 was a moderate inhibitor of both IL-2 production and Abl tyrosine kinase while the 8-oxo derivative 3 was inactive in both assays. The 8-O-methyl ether 4 was a moderate inhibitor of IL-2 production but exhibited potent inhibition of Abl tyrosine kinase with an IC50 of 45 nM.
Wrigley
S K
SK
Cubist Pharmaceuticals Limited, Slough, UK. swrigley@cubist.com
Ainsworth
A M
AM
Kau
D A
DA
Martin
S M
SM
Bahl
S
S
Tang
J S
JS
Hardick
D J
DJ
Rawlins
P
P
Sadheghi
R
R
Moore
M
M
D000906:Antibodies / Q000494:pharmacology; D018106:CD28 Antigens / Q000276:immunology; D002478:Cells, Cultured; D002963:Cladosporium / Q000737:chemistry* / Q000145:classification / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D005285:Fermentation; D005449:Fluorenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D019169:Jurkat Cells / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013785:Thailand
D000906:Antibodies; D018106:CD28 Antigens; D004791:Enzyme Inhibitors; D005449:Fluorenes; D007166:Immunosuppressive Agents; D007376:Interleukin-2; C429612:XR774; C007738:fluoranthene; D011505:Protein-Tyrosine Kinases; C022921:benzo(k)fluoranthene