摘要
环四肽在药物研发中具有重要的潜在应用价值,然而目前尚缺乏高效率合成环四肽的方法.我们发展了以N端为半胱氨酸的四肽酰肼为原料的分子内环化方法,合成了全L型氨基酸组成的环四肽.该方法通过形成13元环的内硫酯中间体,再经过S-to-N酰基迁移形成酰胺键,最后通过脱硫反应,得到目标环四肽分子.
Naturally occurring or man-made cyclic tetrapeptides have unique rigid skeletons and therefore, represent an interesting class of candidate bioactive molecules in drug discovery. However, efficient chemical synthesis of cyclic tetrapep- tides often presents a difficult problem due to the large strain involved in this category of target compounds. To overcome this problem we describe in the present study the use of peptide hydrazides for the preparation of highly strained 12-membered all-L cyclic tetrapeptides. The new synthetic route starts with the easy Fmoc solid phase synthesis of a linear N-Cys-tetrapeptide hydrazide precursor. Upon quick activation by NaNO2 at pH 3 and --10 ℃ for 20 min followed by treatment with a pH 7 buffer containing an external thiol (4-mercaptophenylacetic acid, 40 equiv.) at room temperature, the N-Cys-tetrapeptide hydrazide precursor is converted in situ to an N-Cys-tetrapeptide thioester. This thioester undergoes a fast intramolecular thioester exchange reaction to generate a 13-membered thiolactone intermediate. Then an S-to-N acyl shift is expected to take place to create an amide bond, which affords the desired cyclic tetrapeptide in a modest overall yield (ca. 40%). Finally, desulfurization of the cyclic peptide product can be carried out to produce the target cyclic tetrapeptide that does not contain any Cys residue. Through detailed IH, 13C, and TOSCY NMR and HPLC analyses, it is found that the new method for tetrapeptide synthesis can be carried out at relatively high substrate concentrations (0.8--1.0 mmol/L) without causing the formation of much cyclic octapeptide byproduct. Our test also showed that the reaction can generate the desired cyclic tetrapeptide in an epimerization free manner. By using the new method we have successfully prepared several cyclic tetrapeptides including cyelo(Ala-Leu-Ala-Leu), cyelo(Ala-His-Gly-Trp), and cyclo(Ala-Val-Gly-Ile) in 18%--25% overall yields. We expect that our method of cyclic tetrapeptide synthesis may find applications in the development of cyclic peptide libraries for bioactivity screening.
出处
《化学学报》
SCIE
CAS
CSCD
北大核心
2012年第13期1471-1476,共6页
Acta Chimica Sinica
基金
国家自然科学基金(Nos.20932006
91013007)资助~~
关键词
环四肽
多肽酰肼
连接反应
酰基迁移
cyclotetrapeptides
peptide hydrazides
ligation
acyl shift