Bisek Nicola, Wetzel Stefan, Arndt Hans-Dieter, Waldmann Herbert
Abteilung Chemische Biologie, Max-Planck-Institut für Molekulare Physiologie, Otto-Hahn-Straße 11, 44227 Dortmund (Germany), Fax: (+49) 231-133-2499.
Fakultät Chemie, Technische Universität Dortmund, Otto-Hahn-Straße 6, 44227 Dortmund (Germany).
Chemistry. 2008;14(29):8847-8860. doi: 10.1002/chem.200800692.
The biological activity of macrocyclic natural products depends on their conformational properties. For both the elucidation of enzyme binding affinities as well as the development of selective drugs, rigid macrocyclic scaffolds carry high potential. In this study, 13-membered cyclodepsipeptides based on the structure of naturally occurring stevastelins were studied in detail. Six diastereomeric stevastelin C3 analogues and four phosphorylated derivatives were synthesized. The synthesis of linear precursors was achieved on solid support by starting from stereoisomerically pure 2-methyl-3-hydroxy acids. Subsequent macro-lactamization gave the cyclic depsipeptides in very good yields (36-62%). The conformational space of these stevastelin C3 analogues was computationally investigated. On the basis of NMR spectroscopic data, homogeneous conformations were determined for each benzylated depsipeptide and the influence of phosphorylation on the overall conformation was investigated. Importantly, phosphorylation was found to significantly weaken the conformational preferences of the 13-membered depsipeptides. Finally, the cyclic depsipeptides were tested for activity against phosphatases. Inhibitory activity on vaccina H1-related phosphatase was observed depending on the derivatization of the cycles. The activity profiles are discussed in the light of the structural data.
大环天然产物的生物活性取决于其构象性质。对于阐明酶结合亲和力以及开发选择性药物而言，刚性大环支架具有很大潜力。在本研究中，对基于天然存在的斯替伐他汀结构的13元环缩肽进行了详细研究。合成了六个非对映体的斯替伐他汀C3类似物和四个磷酸化衍生物。通过从立体异构纯的2-甲基-3-羟基酸开始，在固相载体上实现了线性前体的合成。随后的大环内酰胺化以非常高的产率（36-62%）得到了环缩肽。对这些斯替伐他汀C3类似物的构象空间进行了计算研究。基于核磁共振光谱数据，确定了每个苄基化环缩肽的均一构象，并研究了磷酸化对整体构象的影响。重要的是，发现磷酸化显著削弱了13元环缩肽的构象偏好。最后，测试了环缩肽对磷酸酶的活性。根据环的衍生化情况，观察到了对痘苗H1相关磷酸酶的抑制活性。结合结构数据对活性谱进行了讨论。
