Study on Inhibition Mechanism and Rational Design of Protein Phosphatase Inhibitor Tautomycin

从灰色链霉菌中分离出的一种抗真菌药物曲古霉素(Tomycetin，TMT)在生物学和结构上与被认为是一种有效的蛋白磷酸酶(PP)I型和2A型抑制剂的他托霉素(TM)有明显的相似之处。这表明TMT也是PP1和PP2A的抑制剂，TMT和TM的结构差异是可以交换的。为了获得与这一假说相关的数据，并开发PP1的特异性抑制剂，我们研究了TMT的全合成以及TMT和TM的右片段的构象分析，并考察了TMT类似物的生物活性，以不对称巴豆基硼化反应为关键反应构建了TMT的右半部分。通过区域选择性氢化反应和Stille偶联反应，合成了两个用于合成TMT的大亚基。分子力学计算和~1H-核磁共振数据都表明，直链霉菌素右半部分以“弯曲构象”的形式存在。大部分直链霉菌素右半部分的构象与直链霉素右半部分的构象非常相似。研究了转霉素及其衍生物对蛋白磷酸酶PP1和PP2A的影响及其对人白血病Jurkat细胞的诱导凋亡活性，并讨论了化学结构与功能之间的关系。

Tautomycetin (TMT), an antifungal agent from Streptomyces griseo-chromogenes shows a distinctive biological and structural similarity to tautomycin (TM), which is known as a potent inhibitor of protein phosphatases (PP) type I and 2A.It strongly suggests that TMT is also an inhibitor of PP1 and PP2A and that the structural difference of TMT and TM is exchangeable. In order to obtain pertinent data for this hypothesis and to develop a specific inhibitor for PP1, we studied a total synthesis of TMT and conformational analysis of right fragments of TMT and TM.Biological activities of tautomycin analogs were also examined The right half of tautomycetin were constructed by asymmetric crotylboration as key reactions. Efficient construction of dienone moiety has been achieved by a regioselective hydrostannylation of internal alkyne and the subsequent Stille coupling, Thus, two large subunits for synthesis of TMT were synthesized.Both molecular mechanics calculations and 'H-NMR data exhibited that tautomycetin right half is present as "bent conformers". Most populated conformer of the tautomycetin right half showed a distinct similarity to the one found in the right half of tautomycin.Effects of tautomycin and its derivatives on protein phosphatases PP1 and PP2A and their apoptosis-inducing activity on human leukemia Jurkat cells were examined and the relationship between chemical structure and function was discussed.