Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
Japan Biological Informatics Consortium (JBIC), 2-4-32 Aomi, Koto-ku, Tokyo 135-0064, Japan.
Bioorg Med Chem. 2018 Dec 15;26(23-24):6023-6034. doi: 10.1016/j.bmc.2018.11.001. Epub 2018 Nov 7.
The synthesis and biological evaluation of thielocin B1 analogues have been demonstrated. Fourteen analogues modified in the central core and terminal carboxylic acid moiety were concisely synthesized by simple esterification or etherification reaction. The evaluation of synthetic analogues as inhibitors of proteasome assembling chaperone (PAC) complexes (the PAC3 homodimer and PAC1/PAC2) revealed that the natural product-like bending structure and terminal carboxylic acid groups were crucial for its biological activity. Moreover, SAR and in silico docking studies indicated that all methyl groups on the diphenyl ether moiety of thielocin B1 contribute to the potent and selective inhibition of the PAC3 homodimer via hydrophobic interactions.
已经证明了噻可霉素 B1 类似物的合成和生物评价。通过简单的酯化或醚化反应，简洁地合成了十四种在中心核和末端羧酸部分修饰的类似物。作为蛋白酶体组装伴侣 (PAC) 复合物（PAC3 同源二聚体和 PAC1/PAC2）抑制剂的合成类似物的评估表明，类似天然产物的弯曲结构和末端羧酸基团对其生物活性至关重要。此外，SAR 和计算机对接研究表明，噻可霉素 B1 的二苯醚部分的所有甲基均通过疏水相互作用有助于对 PAC3 同源二聚体的强效和选择性抑制。
