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

灰产色链霉菌（Streptomycesgriseo-chromogenes）的抗真菌活性物质变构霉素（TMT）与蛋白磷酸酶（PP）I型和2A型抑制剂变构霉素（TM）具有明显的生物学和结构相似性，这表明TMT也是PP 1和PP 2A的抑制剂，TMT和TM的结构差异是可交换的。为了验证这一假说，并开发PP 1的特异性抑制剂，我们研究了TMT的全合成，并对TMT和TM的右片段进行了构象分析，同时对互变霉素类似物的生物活性进行了研究。通过内炔的区域选择性锡氢化和随后的Stille偶联，有效地构建了二烯酮结构部分，从而合成了两个用于合成TMT的大亚基，分子力学计算和~ 1H-NMR数据表明，互变霉素素右半部分以“弯曲构象”存在。研究了互变霉素及其衍生物对蛋白磷酸酶PP 1和PP 2A的影响及其诱导人白血病Jurkat细胞凋亡的活性，并讨论了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.