Potent oxazoline analogue of apratoxin C: synthesis, biological evaluation, and conformational analysis.
Potent oxazoline analogue of apratoxin C: synthesis, biological evaluation, and conformational analysis.
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apratoxin C 的有效恶唑啉类似物：合成、生物学评价和构象分析。
DOI：
10.1002/bip.22781
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
T.
中科院分区：
文献类型：
--
作者：
Yoshida;M.;Onda;Y.;Masuda;Y.;Doi;T.
在本研究中，对 apratoxin C 恶唑啉类似物 (3) 的合成、生物学评价和构象分析进行了论证。合成关键中间体 9 的制备是使用改进的策略实现的，该策略涉及市售的 3-甲基戊二酸酐 (12)、酶促对映选择性醇解和非对映选择性还原。 Pro-Dtrina（3,7-二羟基-2,5,8-三甲基壬酸）部分8的合成方式与我们之前报道的阿普拉毒素 C 的合成类似 (1)。 Pro-Dtrina8 与已知的四肽 7 偶联后形成环化前体 5，以提供线性肽 6，形成恶唑啉，并除去保护基团。最后，5与O-(7-氮杂-1H-苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐 (HATU)/N,N-二异丙基乙胺 (DIEA) 的大环内酰胺化提供了阿普毒素 C 恶唑啉类似物 (3)，它对 HeLa 细胞表现出强效细胞毒性（IC50 值为 22 nM），与细胞毒性相当。 apratoxin C (1)（IC50 值为 4.2 nM）。通过NMR实验对1和3进行构象分析表明恶唑啉类似物3形成了与CD3CN中apratoxin C(1)结构相似的三级结构，这为它们具有可比的细胞毒性提供了可能的解释。 © 2015 Wiley periodicals, Inc. 生物聚合物（Pept Sci）106：404–414，2016。
In this research, the synthesis, biological evaluation, and conformational analysis of an apratoxin C oxazoline analog (3) have been demonstrated. The preparation of synthetic key intermediate9was achieved using an improved strategy that involves commercially available 3‐methylglutaric anhydride (12), an enzymatic enantioselective alcoholysis, and a diastereoselective reduction. The Pro‐Dtrina (3,7‐dihydroxy‐2,5,8‐trimethylnonanoic acid) moiety8was successfully synthesized in a similar manner as our previously reported synthesis of apratoxin C (1). The cyclization precursor5was formed after the coupling of Pro‐Dtrina8with a known tetrapeptide7to afford a linear peptide6, the formation of an oxazoline, and the removal of the protecting groups. Finally, the macrolactamization of5withO‐(7‐aza‐1H‐benzotriazol‐1‐yl)‐N,N,N′,N′‐tetramethyluronium hexafluorophosphate (HATU)/N,N‐diisopropylethylamine (DIEA) furnished an apratoxin C oxazoline analog (3), which exhibited a potent cytotoxicity against HeLa cells (IC50value of 22 nM) that was comparable with the cytotoxicity of apratoxin C (1) (IC50value of 4.2 nM). Conformational analyses of1and3through NMR experiments showed that oxazoline analog3formed a tertiary structure that was similar to the apratoxin C (1) structure in CD3CN, which provided a probable explanation for their comparable cytotoxicities. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 404–414, 2016.