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

Tautomycetin （TMT）是一种来自灰色链霉菌的抗真菌药物，与tautomycin （TM）具有独特的生物学和结构相似性，tautomycin （TM）是一种有效的蛋白磷酸酶（PP） I型和2A型抑制剂。这强烈提示TMT也是PP1和PP2A的抑制剂，并且TMT和TM的结构差异是可交换的。为了获得这一假设的相关数据，并开发一种特异性的PP1抑制剂，我们研究了TMT的全合成以及TMT和TM的正确片段的构象分析。并对其生物活性进行了研究。以不对称丁基合成法为关键反应，构建了tautomycetin的右半部分。通过内炔的区域选择性氢锡化和随后的Stille偶联，有效地构建了二烯酮片段，从而合成了两个用于合成TMT的大亚基。分子力学计算和H-NMR数据均表明，变异构体右半部分以“弯曲构象”的形式存在。最密集的构象的右半部分的他霉素显示出明显的相似性在右半部分的他霉素。研究了他霉素及其衍生物对人白血病Jurkat细胞蛋白磷酸酶PP1和PP2A的影响及其诱导凋亡活性，并讨论了其化学结构与功能的关系。

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.