Hegde V R, Miller J R, Patel M G, King A H, Puar M S, Horan A, Hart R, Yarborough R, Gullo V
Schering-Plough Research Institute, Kenilwooth, NJ 07033.
J Antibiot (Tokyo). 1993 Feb;46(2):207-13. doi: 10.7164/antibiotics.46.207.
A highly potent inhibitor of calmodulin-sensitive phosphodiesterase (PDE) activity was isolated from the culture broth of an unidentified fungal isolate, SCF-125. A chemically defined medium was developed for production of this compound. The PDE inhibitor was isolated from the fermentation filtrate by adsorption on a macro-reticular resin and further purified by gel filtration chromatography and reverse-phase HPLC. The major PDE inhibitor was identified as cephalochromin, a bis-naphthopyrone, by spectral data analysis. The compound, SCH 45752, inhibited calmodulin-sensitive PDE activities with IC50 values of 40-47 nM. It inhibited the activities of calmodulin-independent PDE and various protein kinases with higher IC50 values (2-40 microM). SCH 45752 does not appear to be a calmodulin antagonist. Furthermore, SCH 45752 affects smooth muscle contraction at a concentration of 30 microM; it potentiated the relaxing effect of sodium nitroprusside on carotid artery media contracted by histamine. Thus SCH 45752 is one of the most potent inhibitors of calmodulin-sensitive PDE activity known, and it is capable of exerting a pharmacological effect in at least one intact tissue model.
从一株未鉴定的真菌分离株SCF-125的培养液中分离出一种对钙调蛋白敏感的磷酸二酯酶（PDE）活性有高效抑制作用的物质。开发了一种化学成分明确的培养基用于生产该化合物。通过大孔网状树脂吸附从发酵滤液中分离出PDE抑制剂，并通过凝胶过滤色谱和反相高效液相色谱进一步纯化。通过光谱数据分析，主要的PDE抑制剂被鉴定为头孢色菌素，一种双萘并吡喃酮。化合物SCH 45752抑制钙调蛋白敏感的PDE活性，IC50值为40 - 47 nM。它以较高的IC50值（2 - 40 μM）抑制不依赖钙调蛋白的PDE和各种蛋白激酶的活性。SCH 45752似乎不是一种钙调蛋白拮抗剂。此外，SCH 45752在30 μM的浓度下影响平滑肌收缩；它增强了硝普钠对由组胺收缩的颈动脉中层的舒张作用。因此，SCH 45752是已知的对钙调蛋白敏感的PDE活性最有效的抑制剂之一，并且它能够在至少一种完整组织模型中发挥药理作用。
