Incorporation of cis- and trans-4,5-Difluoromethanoprolines into Polypeptides
Incorporation of cis- and trans-4,5-Difluoromethanoprolines into Polypeptides
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DOI：
10.1021/ol302412a
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发表时间：
2012-10-19
期刊：
影响因子：
5.2
通讯作者：
Komarov, Igor V.
中科院分区：
文献类型：
--
作者：
Kubyshkin, Vladimir S.;Mykhailiuk, Pavel K.;Komarov, Igor V.
取代脯氨酸对蛋白质骨架构象有不同的影响。通过与N-叔丁氧羰基-4，5-去氢脯氨酸甲酯加成，得到了新的二氟类似物，反式加成物为唯一产物，产率为71%。在N-保护基裂解后，游离氨基酸迅速分解。因此，使用二肽策略完成其掺入富含脯氨酸的细胞穿透“甜箭肽”。通过4，5-脱氢脯氨酸的氨酰基衍生物的二氟环丙烷化，得到两个结构单元，含有顺式或反式-4，5-二氟甲脯氨酸。所得的二肽在Fmoc固相肽合成的标准条件下是稳定的，因此适合于研究构象效应。
Substituted prolines exert diverse effects on the backbone conformation of proteins. Novel difluoro-analogues were obtained by adding difluorocarbene to N-Boc-4,5-dehydroproline methyl ester, which gave the trans-adduct as the sole product with 71% yield. Upon cleavage of the N-protection group the free amino acid decomposed rapidly. Its incorporation into the proline-rich cell-penetrating "sweet arrow peptide" was thus accomplished using a dipeptide strategy. Two building blocks, containing either cis- or trans-4,5-difluoromethanoproline, were obtained by difluorocyclopropanation of the aminoacyl derivatives of 4,5-dehydroproline. The resulting dipeptides were stable under standard conditions of Fmoc solid phase peptide synthesis and, thus, suitable to study conformational effects.