Kohli Rahul M, Burke Martin D, Tao Junhua, Walsh Christopher T
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Am Chem Soc. 2003 Jun 18;125(24):7160-1. doi: 10.1021/ja0352202.
Hybrid peptide-polyketides are a class of medically and biologically important natural products characterized by stereochemical and functional diversity. In their biosynthesis, hybrids are often macrocyclized to achieve rigid structures that populate bioactive conformations. We herein present a chemoenzymatic strategy to access the stereochemical and functional diversity found in macrocyclic hybrid natural products in a manner amenable to efficient library synthesis. Our method makes use of small building blocks in the form of Fmoc-protected epsilon-amino acids containing embedded polyketide functionality. The building block approach allows for combinatorial synthesis of linear molecules that can be activated as soluble thioesters or tethered to a solid-phase resin. We demonstrate that these linear molecules are substrates for macrocyclization by a tolerant catalyst, TycC TE, derived from a nonribosomal peptide synthetase. The method should allow for access to diverse structures with hybrid peptide-polyketide character that can be screened for improved or novel activities.
杂合肽 - 聚酮化合物是一类在医学和生物学上具有重要意义的天然产物，其特点是具有立体化学和功能多样性。在其生物合成过程中，杂合物通常会进行大环化以形成刚性结构，从而产生生物活性构象。我们在此提出一种化学酶策略，以一种适合高效文库合成的方式获取大环杂合天然产物中存在的立体化学和功能多样性。我们的方法利用了含有嵌入式聚酮功能的Fmoc保护的ε - 氨基酸形式的小分子构建块。构建块方法允许组合合成线性分子，这些分子可以被激活为可溶性硫酯或连接到固相树脂上。我们证明这些线性分子是由源自非核糖体肽合成酶的耐受性催化剂TycC TE进行大环化的底物。该方法应能够获得具有杂合肽 - 聚酮特征的多种结构，可对其进行筛选以寻找改进的或新的活性。
