Department of System Chemotherapy and Molecular Sciences and §Department of Bioorganic Medicinal Chemistry & Chemogenomics, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University , Kyoto 606-8501, Japan.
Org Lett. 2015 Jan 16;17(2):258-61. doi: 10.1021/ol503340k. Epub 2015 Jan 5.
Two new microbial metabolites, tryptopeptins A (1) and B (2), were isolated from the cultured broth of Streptomyces sp. KUSC-G11, as modulators of the transforming growth factor-β (TGF-β) signaling pathway. Their chemical structures consisting of isovalerate, N-Me-L-Val, L-allo-Thr, and a tryptophan-related residue were elucidated on the basis of spectroscopic analyses, while they were unambiguously determined by total syntheses. A structure-activity relationship (SAR) study using natural and synthesized tryptopeptins revealed the importance of the α,β-epoxyketone function located at the C terminus. These new TGF-β signaling modulators would be highly useful for development of new drug leads targeting TGF-β-related diseases such as fibrosis and cancer.
从链霉菌属 KUSC-G11 的发酵液中分离到两种新的微生物代谢产物，tryptopeptins A（1）和 B（2），它们是转化生长因子-β（TGF-β）信号通路的调节剂。基于光谱分析，确定了它们的化学结构，由异戊酸、N-Me-L-Val、L-allo-Thr 和色氨酸相关残基组成，而通过全合成则明确确定了它们的结构。使用天然和合成的 tryptopeptins 进行的构效关系（SAR）研究表明，位于 C 末端的α，β-环氧酮功能的重要性。这些新的 TGF-β 信号调节剂对于开发针对 TGF-β 相关疾病（如纤维化和癌症）的新型药物先导物将非常有用。
