NEUROKININ RECEPTOR INHIBITORS - FERMENTATION, ISOLATION, PHYSICOCHEMICAL PROPERTIES, STRUCTURE AND BIOLOGICAL-ACTIVITY

Seven neurokinin (NK) receptor inhibitors SCH 60059 (1), SCH 60065 (2) , SCH 64879 (3), SCH 60061 (4), SCH 60063 (5), SCH 60057 (7), and SCH 64878 (9) and two uncharacterized components 6 and 8, were isolated fr om the fermentation broth of a fungus taxonomically classified as an A cremonium sp. These compounds were isolated from the fermentation brot h by ethyl acetate extraction. Purification and separation of the indi vidual compounds were achieved by NK1 and NK2 assay-guided fractionati on using gel filtration, reverse phase chromatography and HPLC. The NK active compounds were identified to be a family of polyhydroxy isopre noid derivatives, including glycosylated members, by spectroscopic and degradation studies. Compounds 1 similar to 5 and 7 contain nine isop rene units connected in head to tail fashion and compound 9 contains f ifteen isoprene units connected in a similar manner. All these compoun ds showed dual inhibition in NK1 and NK2 assays with IC50 values rangi ng from 2.5 similar to 11 mu M in the NK1 assay and 6.8 similar to 16 mu M in the NK2 assay.