Syntheses of Novel Biologically Active Compounds Utilizing Countesactive Action in diving Body and their Clinical Trials

基于前药的概念，从泼尼松龙和地塞米松衍生的相应的乙醇酸甲酯制备了新型甾体化合物半琥珀酰乙醇酸甲酯。通过巴豆诱导的耳肿胀和纸片肉芽肿生物测定来评价它们的局部抗炎活性。两种（20 S）-琥珀酰地塞米松衍生物显示出比母体化合物更有效的抗炎活性，并且由于琥珀酰衍生物容易转化为活性化合物，随后从大鼠的循环系统中快速消除，因此未显示出胸腺、肾上腺退化或体重减轻的皮质类固醇副作用。从这些结果来看，这两种衍生物可能是没有皮质类固醇的全身副作用的新型类固醇的候选者。另一方面，我们试图分离抗verotoxin（VT）的中和性人抗体，这是一种由大肠杆菌O 157-H7产生的肠毒素。我们从O 157感染后供体的PBL中构建了人源抗体组合文库。我们从针对VT的抗体组合抗体淘选中选择了三个VT 1反应性rFab克隆和两个VT 2反应性rFab克隆。发现这些克隆与另一种类型的VT交叉反应，并且对VT没有显示出中和活性。这些结果表明，分离的克隆将识别VT 1和VT 2中通常存在的中和无关表位。

Novel steroids, hemisuccinyl methyl glycolates were prepared from the corresponding methyl glycolates derived from predonisolone and dexamethasone based on a concept of the antedrug. Their topical anti-inflammatory activity was evaluated through croton-induced ear edema and paper disk granuloma bioassay. Two (20S)-succinyl dexamethasone derivatives indicated more potent anti-inflammatory activity than the parent compounds and did not show corticosteroidal side effects of thymic, adrenal involution or body weight loss due to easy conversion of the succinyl derivatives into active compounds followed by rapid elimination from the circulation system in the rat. From these results, these two derivatives might be candidates as the novel steroids without the systemic side effects of corticosteroids.On the other hand, we tried to isolate the neutralizing human antibody against verotoxin (VT), which is an enterotoxin produced from Escherichia coli, O157-H7. We constructed human antibody combinatorial library from PBL of the O157-postinfected donor. We selected three VT1-reactive rFab clones and two VT2-reactive rFab clones from the antibody combinatorial antibody panning against VTs. These clones were found to be cross-reactive with another type of VT, and showed no neutralizing activity against VTs. These results suggest that isolated clones would recognize the neutralization-unrelated epitope commonly presented in both VT1 and VT2.